COLON-SPECIFIC DRUG

DELIVERY SYSTEM

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 CONTENTS :-
Introduction
Factors to be considered in the design of colon
specific drug delivery system.
Drug absorption in the colon.
Approaches to colon-specific drug delivery .
Evaluation of colon specific drug delivery systems

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Introduction:-
 Definition:-Colon drug delivery system refers to
targeted delivery of drug in to the lower parts of GI
tract , mainly large intestine.

Inflammatory bowel diseases including irritable

bowel syndrome, ulcerative colitis and Crohn’s disease
are considered as serious colonic disorders.

Ulcerative colitis if not treated leads to colon cancer.

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Why to target colon?
As most of the conventional drug delivery systems for treating colon
disorders such as inflammatory bowel diseases, infectious diseases and
colon cancer are failing as the drugs don't reach the site of action in
appropriate concentration.

Thus an effective and safe therapy of these colonic disorders using

site specific drug delivery system.

 The therapeutic advantages of targeting drug to the diseased organ

include,
a)Delivery of drug in its intact form as close as possible to the target
site.
b)The ability to cut down the conventional dose.
c) Reduced incidence of adverse side effects.
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In recent times the colon-specific delivery systems(CSDDS) are also
gaining importance for the systemic delivery of protein and peptide
drugs . This is because,

i)as the peptide and protein drugs are destroyed and inactivated in acidic
environment of stomach or by pancreatic enzymes (or) by parenteral
route which is inconvenient and expensive.

ii) Due to the negligible activity of brush border membrane peptidase

activity and less activity of pancreatic enzymes the colon is considered as
the most suitable site.

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The colon delivery of
analgesic peptides,
contraceptive peptides,
oral vaccines,
insulin,
Human growth hormone,
erythropoietin,
interferons and interleukins
Were attempted for systemic absorption further drug
targeting to colon would prove useful where intentional
delayed drug absorption is desired from therapeutic point
of view (ex:- in the treatment of nocturnal asthma)

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Factors to be considered in the design of
CSDDS:-

Anatomy and physiology of colon.

PH in the colon.

Gastrointestinal transit.

Colonic microflora

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1. ANATOMY AND PHYSIOLOGY OF COLON

 The large intestine extending from the ileocaecal junction

to the anus is divided into three parts. They are
a)colon
b)rectum
c)anal canal

 Further colon is divided into four parts. They are

a) Ascending colon
b) Transverse colon
c) Decending colon
d)Sigmoid colon
 Colon is about 1.5meters long, transverse colon being the
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longest and most mobile part and has an average diameter
of 6.5cm
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The wall of colon is composed of four layers

(A layer of
connective
Tissue)

( areolar tissue which is

covered by squamous
mesothelial cells)

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Blood supply
For proximal colon it is from superior mesenteric artery and
inferior mesenteric artery supplies blood to distal colon.
The venous drainage is via superior veins for proximal colon
and inferior veins for distal colon.

FUNCTIONS:
1)Creation of suitable environment for growth of micro-
organisms.
2)It acts as storage reservoir of faecal contents.
3)Expulsion of the contents of the colon at an appropriate
time.
4)Absorption of potassium and water from the lumen.
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pH of the colon
Radio telemetry has been used to measure the gastro-
intestinal pH in an healthy subjects.

On entry into the colon, the pH drops to 6.4±0.6. The pH

in the mid colon is 6.6±0.8 and in the left colon 7.0±0.716.

 There is a fall in pH on 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 the colonic bacteria
to produce large amounts of lactic acid resulting in pH
drop to about 5.0.
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Gastrointestinal transit
The arrival of an oral dosage form at the colon is
determined by the rate of gastric emptying and the small
intestine transit time.
 The transit time for a dosage form in GI track are as
following

ORGAN TRANSIT TIME(HRS)

Stomach <1 (fasting)
> 3 (fed)
small intestine 3-4
large intestine 20-30

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Colonic microflora :
The upper GIT has very small number of bacteria and predominantly
consist of gram+ve facultative bacteria .
The concentration of bacteria in different parts of GIT are as follows
Part Concentration in
CFU/ml
stomach 10³
small intestine 107-108
colon 1011-1012
The bacteria flora of the colon is predominantly anaerobic and
composed of more than 400 strains.
The most important bacteria are: Bacteroides, Bifido bacterium,
Eubacterium, peptostrepto cocus, and clostridium.
 A large number of compounds ingested orally are metabolised by gut
bacteria.
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DRUG ABSORPTION IN THE COLON :-

The colon mucosa lacks well defined villi as found in small intestine
this reduces absorption surface area . But the long transit time of
compensate it.
How ever the factors like viscosity, specific and non specific drug
binding to dietary components and products released from colon bacteria
and lipid bilayer of the individual colonocyte and complex junction
between
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the cells are the physical barrier to the drug absorption.
To over come these problems absorption enhancers are used.

Absorption enhancers : These are compounds which promotes

absorption at colon.
They act by:
1)disruption of intercellular junctional complex to open the paracellular
route.
2)Modifying epithelial permeability via denaturing membrane proteins or
modifying lipid-protein interactions.
3)Disrupting the integrity of lipid bilayer of colonic enterocytes.

Examples:
a)Nonsteroidal Anti-inflamatory agents: Indomethacin, salicylates.
b)Surfactants : polyoxyethyelene lauryl ether.
c)Fatty Acids : sodium caprate, sodium caprylate, sodium laurate.
d)Mixed micelles : Monoolein-taurocholate, oleic acid –taurocholate.
e)Other
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agents : Acycarnitine, phenothiazines, dicarboxylic acids.
Criteria for selection of drugs for CSDDS

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Approaches to colon-specific drug
delivery system
Conventional Pharmaceutical approaches
1.pH-dependent drug delivery system.
2.Time-dependent drug delivery system.
3.Bacteria-dependent drug delivery system.

Novel pharmaceutical approaches

1.Pulsincap system.
2.PORT system.
3.CODESTM technology.
4.Osmotic controlled drug delivery.
5.Pressure-dependent
- delivery.
PH DEPENDENT DELIVERY :
In these systems drugs are formulated into solid dosage forms such as
tablets, capsules, and pellets and coated with pH sensitive polymers.
 widely used polymers are methacrylic resins (Eudragits) which is
available in two forms.
Eudragit L Eudragit S

Water soluble Water insoluble

pH is 6 or above pH is 7 or above

e.g.. Eudragit L100,L-30D e.g.. Eudragit s 100

Some other polymers are Cellulose acetate butyrate,

Methacrylic acid copolymer (type A & type B),
Hydroxypropylmethylcellulose acetate Succinate (HPMCAS)
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At present 5-ASA is commercially available as an oral dosage form
coated with Eudragit L.

The disadvantages of this technique is the lack of consistency in the

dissolution of the polymer at desired site.

Depending on the intensity of GI motility, the dissolution of the

polymer can be in the distal portion of the colon or at the end of
ileum.

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TIME DEPENDENT DELIVERY:
Time dependent/controlled release system (TCRS) such as
sustained or delayed release dosage forms are also very
promising drug release systems.

Enteric coated time-release press coated (ETP) tablets, are composed

of three components, a drug containing core tablet (rapidrelease
function).
 The press coated swellable hydrophobic polymer layer (Hydroxy
propyl cellulose layer (HPC), time release function) and an enteric
coating layer (acid resistance function).

The tablet does not release the drug in the stomach due to the acid
resistance of the outer enteric coating layer.

 After gastric emptying, the enteric coating layer rapidly dissolves and
the intestinal
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fluid begins to slowly erode the press coated polymer
(HPC) layer
. When the erosion front reaches the core tablet, rapid drug release
occurs since the erosion process takes a long time as there is no drug
release period (lag phase)after gastric emptying.
The duration of lag phase is controlled either by the weight or
composition of the polymer layer (HPC),

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Bacterial dependent delivery system:
The microflora produces a vast number of enzymes like
glucoronidase, xylosidase, arabinosidase, galactosidase,
nitroreductase, azoreducatase, deaminase, and urea
dehydroxylase.

This system includes :

a) coating with biodegradable azo-polymer.

b) prodrugs.

c) hydrogels.

d) polysaccharides as carriers.

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a. coating with biodegradable azo polymers:
 The azo polymers are having high degree of hydrophilicity were
degraded by colonic bacteria.

Examples: Divinyl azobenzene and substituted diamino benzene.

Drugs used are insulin and vasopressin.

b. Prodrug :
 A well known colon specific prodrug ,sulfasalazine used in ulcerative
colitis & crohn’s disease.
 Sulfasalazine is chemically 5-aminosalicylic acid coupled with
sulfapyridine by azobonding.
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 (
A
)

(
( C
B )
)
Hydrolysis of sulphasalazine (A)
into 5-aminosalicylic acid (B) and
sulfapyridine (C).
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c. Hydrogels:
The hydrogels contain acidic co-monomers and enzymatically
degradable azo-aromatic cross-links.

In acidic pH gel has low degree of swelling which protects

degradation of drug from stomach enzyme.

On entering colon, gels reach the degree of swelling which makes
crosslinks accessible to enzyme.

Crosslinks are degraded and drug is released from disintegrating

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d. Polysaccharides as carriers:
The bacteria present in the colon are capable of fermenting verity of
polysaccharides.

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List of few studies on
Polysaccharides

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Novel pharmaceutical
approaches
1.Pulsincap
Hard gelatin capsule
Main body (water insoluble)
containing hydrogel with water soluble
cap(coated with enteric polymer)
Small intestine-enteric coating
dissolve
Hydrogel plug – swells.
Drug content release after stipulated
period
- of time
PORT SYSTEM

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CODESTM technology

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Osmotic Controlled Drug
Delivery

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Pressure Controlled Drug-Delivery
Systems
As a result of peristalsis, higher pressures are encountered in the
colon than in the small intestine.

Takaya et al. developed pressure controlled colon delivery capsules

prepared using ethyl cellulose, which is insoluble in water.

In such systems, drug release occurs following the disintegration of

a water-insoluble polymer capsule because of pressure in the lumen of
the colon.

The thickness of the ethyl cellulose membrane is the most important

factor for the disintegration of the formulation.

The system also appeared to depend on capsule size and density.

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EVALUATION OF COLON SPECIFIC DRUG
DELIVERY SYSYTEM :

1. In vitro methods

2.In vivo methods

1. In vitro methods:
 The ability of the coats/ carriers to remain in the physiological
environment of the stomach and small intestine is generally
assessed by conducting drug release studies in,
i) 0.1N HCL for 2hrs (mean gastric emptying time)

ii) pH 7.4 sorensen’s phosphate buffer for 3hrs (mean small intstine
- transit time
These dissolution studies can be carried out by using paddle or basket
or flow through dissolution apparatus.

Fermentation studies
For those formulations in which polymers which are specially
degraded by the enzymes and bacteria present in colon.

This method is carried out by,

i) By incubating drug delivery system in a buffer medium in the

presence of enzymes(e.g. pectinase).

ii) By incubating drug delivery system in a fermentor with commonly

found human colonic bacteria like streptococcus faecium or Bacteroide
ovatus in a suitable medium under anaerobic conditions.

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2 In vivo methods:

Animal models
Rats, mice, pigs and dogs animal models were reported for colon
targeted drug delivery systems.

For simulating the human physiological environment of the colon,

appropriate animal model selection is depends on its approach and
design of system.

For example, guinea pigs have glycosidase and glucuronidase activities

in the colon and digestive anatomy and physiology is similar to that of
human, so they are appropriate in evaluating prodrugs containing
glucoside and glucuronate conjugated for colonic delivery.
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Techniques which are used for monitoring the in vivo behavior of
colon targeted drug delivery are
String technique,
Endoscopy,
Radiotelemetry,
Roentegenography,
Gamma scintigraphy.

String technique : In these studies, a tablet is attached to a

piece of string and the subject swallowed the tablet, leaving the free
end of the string hanging from his mouth.

At various time points, the tablet is withdrawn from the stomach by
pulling out the string and physically examining the tablet for the signs
of disintegration.

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Endoscope technique:
It is an optical technique in which a fiber scope (gastro scope) is
used to directly monitor the behavior of the dosage form after
ingestion.
This method requires administration of a mild sedative to facilitate
the swallowing of the endoscopic tube. The sedative alter the gastric
emptying and GI motility.

Radiotelemetry :
This technique involves the administration of a capsule that consist
of a small pH probe interfaced with a miniature radio transmitter
which is capable of sending a signal indicating the pH of the
environment to an external antenna attached to body of the subject.

So it is necessary to physically attach the dosage form to the capsule

which may effect the behaviour of the dosage form being studied.
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Reoentgenography :
The inclusion of a radio-opaque material into a solid dosage form
enables it to be visualized by the use of X-rays.

By incorporating Barium sulphate into a pharmaceutical dosage form,

it is possible to follow the movement, location, and the integrity of the
dosage form after oral administration by placing the subject under a
fluoroscope and taking a series of X-rays at a various time points.

Gamma scintigraphy
The most useful technique, to evaluate the in vivo behavior of dosage
forms in animals and humans is external scintigraphy or gamma
scintigraphy

It requires the presence of a gamma emitting radio active isotope in the
dosage form that can be detected in vivo by an external gamma camera.
The dosage form can be radio labeled using conventional labeling or
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neutron activation methods.
Reference :
Advances in Controlled and Novel Drug Delivery.
Edited by N.K. JAIN (page no.89-119).

 Colon specific drug delivery systems: a review on primary and

novel approaches by Threveen challa, vinay vynala,

Colon specific drug delivery system : A Review on the

pharmaceutical approaches with current trends by Cherukuri
sowmya.

 Colon targeted drug delivery system – A Novel perspective by

Bhushan Prabhakar Kolte
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