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Colon specific drug

delivery system

Why?

Anatomy of colon

The GI tract is divided into stomach, small intestine and large


intestine.
The large intestine extending from the ileocecal junction to the
anus is divided in to three main parts - the colon, the rectum and
anal canal.
The entire colon is about 5 feet (150 cm) long, and is divided in
to five major segments.
Peritoneal folds called as mesentery which is supported by
ascending and descending colon.
The right colon consists of the cecum, ascending colon, hepatic
flexure and the right half of the transverse colon
The left colon contain the left half of the transverse colon,
descending colon, splenic flexure and sigmoid.
The rectum is the last anatomic segment before the anus.

Functions of colon
The absorptive capacity is very high. The absorptive capacity is very high, each
about 2000 ml of fluid enters the colon through the ileocecal valve from which
more than 90% of the fluid is absorbed
Provides suitable environment for the growth of colonic microorganisms,

Absorption of water and Na+ from the lumen, concentrating the fecal content,
Secretion of K+ ions,

Storage reservoir of fecal contents,

Expulsion of the contents of the colon at an appropriate time.

Absorption of water
Water absorption occurs
secondary to the
absorption of electrolytes
and short chain fatty
acids by solvent drag
Colon absorbs Na+ and Cland secrets HCO3- and K+
against potential gradient
HCO3- in lumen
neutralises the acidity
caused by fatty acid
production

Absorption of other substances


Carbohydrates entering the colon get fermented

To fatty acids mostly acetic, propionic and butyric

These SCFA are rapidly absorbed from the colon


Used by colonic
epithelial
Are transported to the liver
cells or

The absorption of SCFA enhances absorption of electrolytes and water

Sugars such as glucose and sucrose are


poorly absorbed
Lipid soluble molecules are most readily
absorbed by passive diffusion

Factors affecting colonic drug


delivery
Small intestinal transit
Colonic transit
Gastric emptying
Stomach and intestinal pH
Gastrointestinal disease state
Colonic micro flora and enzymes

Lag Phase
of 5 hrs.
observed

Emptying rates
Gastric emptying Fasted state
Gastric emptying - Fed
state
Small intestinal transit

10 min. to 2 hrs

Colonic transit

20-35 hours

Higher than 2 hrs


3-4 hours

Gastrointestinal disease state


DISEASE

EFFECT ON COLONIC
ABSORPTION OF DRUGS

IBD (Crohns
disease &
Ulcerative
colitis)

Malabsorption lipophilic drugs


Mucosa & submucosa gets thick
& so reduces surface area,
reduces diffusion

Diarrhoea

Retention time reduces.


Reduces drug absorption &
release from dosage form

Constipation

Gastroenteritis

Reduction in bowel
movement & decreases the
avaibility of drug at
absorption site
Diarrhoea affects the
performance of formulations

Colonic microflora

Microflora
Aerobic
Enterobacteri
a

Staphylococc
i

Lactobacillus

Anaerobic
Fungi

Bacteroids

Bifidobacteri
a

Clostridia

Eubacteria

Metabolic reactions carried out by


gut bacteria
Hydrolysis of
glycosides,
sulphate esters,
amides, esters,
sulphamates and
nitrates

Reduction of C=C,
azo, nitro,
aldehydes,
ketones, alcohols,
N-oxides

Dehydroxylation

Decarboxylation

Dealkylation of Oalkyl and N-alkyl


groups

Dehalogenation

Desamination

Heterocyclic ring
fission

Acetylation

Esterification

Enzymes in colon
Reducing
enzymes

Hydrolyti
c
enzymes

Nitroreductas
e

Esterases

Azoreductase

Amidases

N-oxide
reductase

Glycosidases

Sulphoxide
reductase

Glucuronidas
e

Hydrogenase

Sulfatase

Applications

In local colonic pathologies

Systemic delivery of protein and peptide

Potential site for the treatment of


diseases like asthma, arthritis & angina

For the drugs that are absorbed through


colon such as steroids
For the treatment of disorders like IBS,
colitis, Crohns disease where it is
necessary to attain high concentration
of drugs in colon

Advantages

Drug
directly
available at
the target
site

Decreased
dose to be
administere
d

Decreased
side effect

Improved
drug
utilization

Limitations and challenges


Dissolution in luminal fluid.
Stability of drugs.
Binding of drugs to dietary residues, intestinal secretions, mucus or fecal matter.
Metabolic degradation by colonic microflora.
Wide range of pH values
Lower surface area and relative tightness of the tight junctions in the colon restrict
drug transport.
Longer residence time
Requires protection against variety of the gastric enzymes.
Cytochrome P450 3A class of drug metabolizing enzymes have lower activity in
colon

Drug absorption in colon


Drugs dont get well absorbed from the colon because of
following reasons:
1. Colonic mucosa lacks villi thus reduced absorptive
surface area
2. Viscosity of colonic contents is very high, therefore
difficult for drug to diffuse out
3. Drug binding to dietary components and products
released from colonic bacteria
4. Enzymatic degradation
5. Mucus layer also acts as a barrier
6. Unstirred water layer is also a barrier

Pharmaceutical
approaches for
colonic targeting
1. pH sensitive polymers
2. Microbially triggered systems

3.
4.
5.
6.

1.

Prodrug

2.

Polysaccharides

3.

Hydrogel

Time release systems


Osmotic systems
Azo polymers
Pressure dependent system

pH sensitive systems
Solid formulations for colonic delivery that
are based on pH-dependent drug release
mechanism are similar to conventional
enteric-coated formulations.
Utilize enteric polymers that have relatively
higher threshold pH for dissolution.

Polymers

Mechanism
pH sensitive polymer

Eg. Eudracol

Disadvantages
Lack of consistency in dissolution of the
polymer at desired site
Factors such as SCFA, fermentation products
reduce the colonic pH

Microbially triggered systems


Bacterial count in the colon is much higher
around 1011-1012 CFU/ml.
400 species
Fundamentally anaerobic in nature.
Predominant species: Bacteroides,
Bifidobacterium and Eubacterium.
Major metabolic processes occurring in the
colon are hydrolysis and reduction

1. Prodrugs
2. Hydrogel approach
3. Linking with polysaccharides

Prodrugs
I.
Azo conjugate
eg. Sulphasalazine for 5-ASA

Drug is conjugated with an


azo bond.

II. Glycoside conjugate


eg. Dexamithasone

Drug is conjugated with


glycoside

III. Glucuronide conjugate

Drug is conjugated with


Glucuronide

IV. Cyclodextrin conjugate(CD)

Drug is conjugated with


cyclodextrin

V. Dextran conjugate
eg. Naproxen-dextran conjugation

Drug is conjugated with


dextran

VI. Polymeric conjugate

Drug is conjugated with


polymer

VII. Amino acid conjugate


eg. Proteins.

Drug is conjugated with


aminoacid

Azo-bond conjugate
Azoreductase enzyme produced in colon by
colonic bacteria which degrades azo bond.
This principle is utilized in preparation of
prodrug derivative of active drug for
targeting in colon

Hydrolysis of sulphasalazine (i) into 5-aminosalicylic acid (ii)


and
sulfapyridine (iii).

Azo polymers
Azo-polymers used include:
Copolymers of styrene and 2-hydroxyethyl
methacrylate cross-linked by N,N`bis(bstyrene sulphonyl)-4,4`-diaminoazo-benzene
Poly (ether-ester) azopolymers

Glycoside conjugation
Certain drugs can be conjugated to different
sugar moieties to form glycosides
Glycosides are bulky and hydrophilic
They do not penetrate the biological
membranes upon ingestion
They are poorly absorbed from the small
intestine
When it reaches the colon, it will be cleaved
by colonic bacterial glycosidase

Dexamethasone-21--D-glucoside
(Arrow shows site of action of
glycosidase)

Glucuronide conjugation
Same as that of glycoside conjugation.
Here, glucuronide moiety is joined
Example: Dexamethasone is tried for
conjugation and the results were evaluated
in ulcerative colitis induced in the rates

Dexamethasone-b -D-glucuronide.

Cyclodextrin conjugate
Cyclodextrin metabolizing enzymes
produced by colonic bacteria degrades
Cyclodextrin particularly -CD. This principle
can be used for preparation of prodrug with
CD.
The -CD is practically resistant to gastric
acid and salivary and pancreatic amylases.
But they are complete degraded by the
colonic microflora.

Dextran conjugates
NASIDS ware directly coupled to dextran by
using carboxylic groups of drugs
Acted upon by dextranase
Eg. Dextran ester of naproxen

Amino acid conjugation


In the amino acid, acid group increase
hydrophilicity and chain length of carrier
amino acid, decrease the permeability of
amino acids and proteins.
So the amino acid conjugate showed more
enzymatic specificity for hydrolysis by
colonic enzyme

Glycine and glutamic acid


conjugates of salicylic acid

Polysaccharides as carriers
Natural polysaccharides such as pectin and
xylan are not digested by human stomach or
small intestine but are degraded by colonic
resident bacteria
The bacteria ferment the polysaccharides to
gases such as methane, CO2, hydrogen and
SCFA

Polysaccharides evaluated include:


Polysaccharides

Drug targeted to colon

Guar gum
Pectin
Inulin
Amylase
Cyclodextrin ()
Dextran
Chitosan
Eudragits

Rofecoxib , Tinidazole
Naproxen
Azathioprine
5-Amino salicylic acid
Albendazole
Ibuprofen
Satranidozole
5-fluorouracil

Hydrogels
Hydrogels contain acidic comonomers and enzymatically degradable azoaromatic
cross-links

In acidic pH, gels have low degree of swelling. Thus, drugs are protected against
degradation by digestive enzymes

As gels pass down the GIT its swelling increases

On entering colon, the gels reach a degree of swelling such that crosslinks are
accessible to enzymes (azoreductase)

Crosslinks gets degraded and drug is released

Time-dependent delivery
Difficult to predict in advance.
The strategy is to resist the drug release in
acidic & intestinal environment
In this approch, specific lag time is
previously determined.

Eg. Pulsincap
It consists of enteric coated capsule
containing water soluble cap and water
insoluble body.
The body is loaded with Hydrogel plug and
drug layer.
Enteric coat dissolves in small intestine and
the water soluble cap also dissolves.
The Hydrogel plug absorbs water and swell
and release drug at a predetermined lag
time of 4 hours.

Osmotic controlled drug delivery OROS-CT (Alza corporation)


Immediately after the OROS-CT is swallowed, the
gelatin capsule containing the push-pull units dissolve
Because of its enteric coating, each push-pull unit is
prevented from absorbing water in the acidic
environment.
As the unit enter the small intestine, the coating
dissolve in this higher pH (pH >7), water enters the
unit, causing the osmotic push compartment to swell
and concomitantly creates a flowable gel in the drug
compartment.
Swelling of the osmotic push layer forces drug gel
out of the orifice.

Pressure controlled systems


Muscular contraction of the gut wall
generate pressure
Colon has higher luminal pressure
System can be developed which withstand
the
Pressure in intestine and ruptures in response
To raised pressure in colon.

Ethyl cellulose capsules have been used for


this purpose.

Evaluation

In vitro dissolution study

Invitro test for


intactness of
coating and
carriers in
simulated
conditions of
stomach and
intestine

Drug release
study in 0.1N HCL
for 2 hours (mean
gastric emptying)

Drug release
study in
phosphate buffer
for 3 hours (mean
small intestine
transit time)

In vitro enzymatic degradation


Method I

Method
II

Drug release in buffer


medium containing
enzymes(e.g.pectinase,
dextranase) or rat or
guinea pig or rabbit
fecal contents

Incubating carrier drug


system in fermenter

Amount of drug release


in particular time
directly proportional to
the rate of degradation
of polymer carrier.

Suitable medium
containing colonic
bacteria (streptococcus
faecium or B.ovatus)

Amount of drug
released at different
time intervels
determined.

In vivo studies
Animal models
String technique
Endoscope technique
Radiotelemetry
Roentgenography
Gamma scintigraphy

Human models

Animal models

Guine
a pigs

Glucoside
prodrug of
dexamethasone

Other
animal Rats and pigs
s

String technique

Tablet is
attached to
piece of string

Subject
swallows the
tablet

The free part of


string hangs
from his mouth

Physically
examined for
signs of
disintegration

At various timepoints the


tablet was
withdrawn

Endoscope technique
Optical technique
A fiber scope (gastroscope) monitors the
behavior of dosage form
This method requires administration of mild
sedative to facilitate the swallowing of
endoscopic tube

Radiotelemetry
Administration of capsule containing
a small pH probe interfaced with a
miniature radio transmitter which
sends signal indicating the pH of the
environment to an external antenna
attached to the subjects body
Dosage form is physically attached
to the capsule
The dosage form must contain
significant amount of buffers the
release of which produces a
detectable pH change. Most
formulations do not have such high
amounts of buffers. Hence this
technique has less spplications

Roentgenography (X-rays)
Involves inclusion of radio-opaque material
into the dosage form to be viewed by X rays
Eg. Barium sulphate
Use of X rays involves the exposure of
subject to high amount of radiations
Radio-opaque material has high density and
not suitable for most pharmaceuticals

Gamma scintigraphy
Most useful technique
-emitting radio isotope is present in the dosage form
Gamma rays detected by gamma camera
Advantages:
1. Very little radiation exposure to subjects
2. Gives both qualitative and quantitative results
3. Totally non-invasive
4. Allows for in vivo evaluation under normal
physiological conditions

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