COLON TARGETED

DRUG DELIVERY
SYSTEM (CTDDS)

TARGETED DRUG DELIVERY

SYSTEM
Targeting of drugs is a special form
of DDS in which the pharmacological
active ingredients or drugs that
selectively targeted or delivered
only at the site of action or
absorption site and not to nontarget organs or tissues / cells are
normal

DELIVERY OF THE
DRUG
In the capillaries of the active site
for a specific type of cell or
intracellular region.
Ex: - the tumor cells but not in
normal cells.
For organ / tissue that forms a
specific complex with the carrier
that know the target.

OBJECTIVES
The main objective of targeting the drug to
achieve the desired pharmacological
response in only one location, outside of
undesirable interactions elsewhere so that
the drug has a specific action with minimal
side effects and a better therapeutic index.
The main purpose of targeted
drug delivery system is to
extend, localize, target and has
the protection of drug
interactions with the diseased
tissue.

IDEAL CHARACTERISTICS

1) The delivery system should be biochemical inert

(non toxic), non immunogenic.

2) Both physically and chemically stable in vivo &

invitro.

3) Restrict drug distribution to target cells or tissues

or organs & should have uniform capillary
distribution.

4) Controllable & predicate rate of drug release.

5) Drug release does not effect drug action

IDEAL CHARACTERISTICS:

Therapeutic amount of drug release.

Minimal drug leakage during

transit.

Carriers used must be biodegradable or readily

eliminated from the body without any problem and
no carrier induced modulation of disease state.

The preparation of the delivery system should be

easy or reasonable simple, reproducible & cost
effective.

Drug Delivery System (DDS)

ORAL
DDS

Nano
Technol
ogy
DDS

Buccal
DDS

Parentral
DDS

DRUG
DELIVERY
SYSTEMS

Pulmona
ry
DDS

Rectal
DDS

MUCOSA
L

Topical
DDS

Vaginal
DDS

Nasal
DDS
7

Route of drug delivery

ORAL
Gastric, enteric, colonic

INJECTION AND IMPLANT

IV, SC, IM, intra-epidural, intra-kranial

TRANSDERMAL
Skin
MUCOSAL
Ophtalmic, nasal, vaginal, buccal, sub-lingual
INHALATION
pulmonary

Objectives of Targeted Drug

Delivery

ensure direct therapy

at the site of the
disease
using a lower
dose, and
reduce side
effects

Major Challenges to An Oral

Controlled Release Medication
Gastric

emptying time which can not

be predicted

High

variations in gastric emptying

time which is influenced by age,
race, gender, and disease status

The

contact time at the site of

absorption is limited

Challenges to An Oral Drug

Delivery
ORAL
1/3 of the population having trouble

swallowing
Tablets disintegrate in the mouth: the
solution
Buccal Tablet Bio-Adhesive: avoid first
pass effect
In-situ gelling formulations for dental
treatment

Challenges to An Oral Drug Delivery

Intestine:

The formulations to increase

the absorption of poorly soluble
drugs and drugs with high BM
Solubility is less: the main
problem in oral DD
Delivering protein peptides: not
stable in GI

Challenges to An Oral Drug

Delivery
D.COLON
Delivery of enzymes and drugs that are
not acid resistant
Systemic delivery of peptide drugs and
proteins
Local delivery to the colon: in certain
diseases in the colon
TECHNOLOGY:

Enteric coated modified

Biodegradable swellable polymers
pH-controlled systems
Time delayed systems

Colon DDS
Site specific drug delivery to colon : approaches and drug
development

Route of Colon DDS

1.
2.

Oral : The most convenient and preferred

Rectal : the shortest route to the
destination delivery to the colon

Challenge:
- Achieving the proximal part of the colon
through a rectal route is quite difficult
- Not comfortable for the patient
- Compliance will be less than optimal
Dosage forms: abruption, foam, suppository

Gastrointestinal (GI) Tract

Anatomy

Anatomy of Colon

Ascending Colon
Mucosa

Transverse colon
Submucos
a

Descending Colon

Sigmoid Colon
Muscularis
externa

Serosa

Advantages Colon Conditions for Colonic Drug Delivery System

Relatively free of peptidase enzymes: for oral drug

delivery of peptides to be absorbed systemically
Rich in Lymphoid Tissue: for Effective Vaccine Delivery
antigen uptake to mast cells in the colonic mucosa will
accelerate local production of antibodies
Transit time
Gastric (<3 hours); Small intestine (3-5 hours); Colon (20
hours)
Factors affecting drug transit time in a different part of
the gastrointestinal tract: food, GIT motility, the patient's
physical activity, fasting conditions / dining patient
Enzyme Activity of Microbial Colon
For example: azoreductive (-N = N-) polymers are broken
down by azoreductase; saccharides are broken down by
saccharidase
Respond well to absorption enhancers

 Human colonic: > 400 species of bacteria as the

resident flora, the population could reach 10 10
bacteria per gram of colonic contents
to protect GIT of pathogenic bacteria by reducing
azo and nitrogen from the environment
Colonic microflora produces many enzymes
HYDROLYSIS AND REDUCTION:
- azoreductase enzyme (for a polymer-based
prodrug and salute azoaromatic and matrix
containing azoaromatic cross-links)
- Glycosidase: polysaccharide degradation
The process of metabolism in the colon:
responsible for the metabolism of most drugs
For colon-targeted delivery of macromolecules
such as insulin peptides for oral administration

Colonic Microflora

Human intestinal microflora distribution in number

(Log 10 scale) per gram faeces.

Rational for the Development of

Colon Targeted Drug Delivery
Treatment

of local pathologies

Chronotherapy

(asthma, hypertension, cardiac

arrhythmias, arthritis or inflammation )

Greater
Less
Site

responsiveness to the absorption enhancers.

enzymatic activity

for delivery of delicate drugs (Proteins and

Peptides)

Objectives of Colon DDS

Diseases

Therapy in Colon
ulcerative colitis, Crohn's disease, and
infection in the colon carcinoma

Systemic

absorption (= improve the

absorption of drugs "complicated")
- The drugs are not stable in the upper GI
tract (peptide / protein: insulin, vaccines)
- The drugs that are less absorbed in the GI
tract
- Drugs targeted

Characteristic of Colon
DDS
Time

Dependent System : transit

time; time delay

pH

dependent system: CDDS

preparation is well protected in
the stomach, no systemic
absorption occurs unnecessary

Utilizing

colonic microflora

Colon Diseases
Inflammatory

Kanker Kolon

Bowel Disease

Diagram of Pathology at Colon

PATHOLOGY INColonic
COLON
and
mucosal morphology
Changes inPATHOLOGY
colonic mucus
changes: Loosening tight
LOCATION
production

junctions, epithelial damage

and inflammatory

ABSORPTION affect the drug in the colon

The permeability of the intestinal

mucosa

Increase Exposure luminal contents, drug,

or substance pathology

Nocturnal Diseases

Asthma

Arthritis Hypertension

Advantages of Colon DDS

Drug directly available at the target site

Decreased dose to be administered
Decreased side effect
Improved drug utilization
Giving glucocorticoids
(dexamethasone,
methylprednisolone) oral and iv
systemic side effect
(adenosupresi, immunosuppresi,
cushinoid symptoms, and bone
resorption)
Chronic colitis / ulcerative
colitis, and Crohn's disease
treated with glucocorticoids
and other anti-inflammatory

Target sites, Pathology in Colon and

The Drugs

Target sites, Pathology in Colon

and The Drugs

Target sites, Pathology in Colon

and The Drugs used in Colon DDS

Criteria of Drug for Colon

DDS
Candidate of CDDS:
Poorly absorption in gastric :
peptides
Drugs

used for the treatment of

pathology in colon (IBD, ulcerative
colitis, diarrhea, and cancers of the
colon): Local CDDS

Criteria for Selection of Drugs for CDDS

Selection of Drug Carrier for

CDDS
The

physicochemical properties of the drug:

- chemical properties
- stability
- the partition coefficient

Type

of absorption enhancer

Functional

group of the drug molecule

Aniline or nitro group: benzene groups to link to
another group with a BUNCH AZO. carriers,
containing additives such as polymers (as matrix and
hdrogel or liners) INFLUENCE ON DISPOSAL SYSTEM
effksi system

The

type of disease

The simplest method for targeting of

drugs to the colon is to obtain
slower release rates or longer
release periods by the application
of thicker layers of conventional
enteric coatings or extremely
slow releasing matrices.

Formulation Approaches for

Colon DDS
Primary Approach CDDS
a. pH Sensitive Polymer Coated
b. Delayed (Time Controlled Release
System) Release
c. Microbially Triggered Drug Delivery to
Colon
i) Prodrug Approach for Drug Delivery to
Colon
(ii) Azo-Polymeric
Newly
DevelopedProdrugs
Approaches for
(iii) Polysaccharide Based Delivery
CDDS
a.Systems
Pressure Controlled Drug-Delivery
Systems
b. Novel Colon Targeted Delivery System
(CODESTM)

Pharmaceutical Approaches for

Colon DDS

Approach

Based Fitur

1. Covalent bonding of drug-carrier

1. Azo conjugate
Conjugated drug with azo
bond
2.
3.
4.
5.
6.

Siclodextrin conjugate
Gycoside conjugate
Glucuronate conjugate
Dextran conjugate
Polypeptide conjugate
polyaspartate

7. Prodrug polimerik

Conjugated drug with siclodextrin

Conjugated drug with glycoside
Conjugated drug with glucoronate
Conjugated drug with dextran
Conjugated drug with
acid
Conjugated drug with polymer

2. Approach for delivery of molecules attached to the colon

(the intact molecule to colon)

Approach

Basic features

2. Approach for delivery of molecules attached to the colon

(the intact molecule to colon)
3. Coating with Polymer
1. Coating with a pH sensitive polymer Coated enteric
polymers that
release the
drug when an alkaline pH
2. The coating with a biodegradable
Drug is released
after polymer
polymer
degradation by colonic
bacteria
the drug is released after
1.Embedding in matrix/

biodegradable hidrogel
2. Embedding in matrix
2. Embedding in the pH

sensitive matrix

the polysaccharide
swelled and degraded

pH-sensitive polymer
degradation which releases
the drug

Approach
3.Time-release

Basic features

after the formulation of multi-coated

pass through the stomach, the drug is
System released after a lag time of 3-5 hours
which is equivalent to the transit time
in the
small intestine
Drugs
formulated
with azo and

4. Redox-sensitive Polymer

5. Bioadhesive

disulfide polymer that selectively

responds to the redox potential of the
colon
bioadhesive drug coated with
System polymers
that selectively provides
power to the adhesion of the colonic
mucosa which can release a drug in
the colon

6. Penyalutan dengan mikropartikel

the drug bound
with microparticles

7.Osmotic-controlled drug

the drug is released

through a
semipermeable
deliverymembrane due to
osmotic pressure

Pharmaceutical approaches to Colon DDS

BONDING COVALENT DRUG-CARRIER

Prodrug Concept
Dru
g

Carrier
Molecule

Stimulus enzymatically
breaking bonds in the GI
tract drug-carrier
Troubleshooting STABILITY drug in the upper GI
tract, as a new parent drug is released when the
colon
Utilizing colon characteristics: pH is increased or

Enzymes in Colon
Reducing enzymes
Nitroreductase
Azoreductase
N-oxide reductase
Sulphoxide reductase
Hydrogenase

Hydrolytic enzymes
Esterases
Amidases
Glycosidases
Glucuronidase
Sulfatase

Azoreductases, which reduces azo-bonds selectively

and
Polysaccharidases which degrades the polysaccharides.

Conjugate Bond AZO

Sulfasalazine Hydrolysis (i) 5amino

salicylate acid(ii) and
sulfapiridine

 Sulfasalazine:

rheumatoid arthritis therapy and

antiinflammatory.
Salicylazosulfapiridine sulfasalazine (SASP):
- Sulfapyridine radical binds to salicylate
through azo bond
Oral: small doses that are absorbed in the small
intestine
bulk sulfasalazine reaches the
colon
Sulfapyridine: groups which are responsible for
side effects of sulfasalazine
IBD therapy
seeking carrier molecules which are safer

The chemical structure of SASP, balsalazide, ipsalazide and OSZ

showing where termination azo bond by bacteria that releases the

Conjugate Bond AZO:

Polymeric Prodrug

POLI ASA: based on the SASP

carrier concept: SP unit
berikatan dengan inert
polymer backbone
Carrier nya adalah
polisulfonamidoetilen yang
berikatan azo dengan 5-ASA

GLYCOSIDE CONJUGATE

Dexametasone-21--D-glucoside
(Arrows: the work site glucosidase)

 The

main glycosidase found in

human feces: -D-galactosidase, D-glucosidase, -Larabinofuranosidase, -Dxylopiranosidase
The location of these enzymes:
brush border
easily reach the substrate

Glucuronate Conjugate

Dexamethasone--D-glucoronide

Amino Acid Conjugate

Glycine and glutamic

acid conjugate of
salicylic acid:
- Conjugate Acid
Salicilurat
- Conjugate salicylic
acid glutamate

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Coating with
Polymers
1. Coating with pH-sensitive polymers
Sr.
No.
1
2

Polymer
Eudragit L 100
Eudragit S 100

Threshold
pH
6.0

Polymer of

7.0

methacryli
c acid are

mostly
used

Eudragit L 30D

5.6

Eudragit FS 30D

6.8

Eudragit FS 30D

5.5

Polyvinyl acetate phthalate

5.0

Hydroxy propyl methyl cellulose

phthalate

Cellulose acetate trimelliate

4.8

Cellulose acetate phthalate

5.0

4.5-4.8
Threshold
pH of
commonly

Drug

Trade Name

Coating Polymer / Formulation

Budesonide

Entrocort
Budenofalk
Targit

Eudragit L 100-55, ethylcellulose

Eudragit S (Dissolution pH-7)
Coated Starch Capsule

Mesalazine

Claversal
Asacolitin
Salofalk
Pentasa
Mesazal
Calitofalk
Asacol

Eudragit L100 (Dissolution pH-6)

Eudragit S (Dissolution pH-7)
Eudragit S (Dissolution pH-6)
Ethyl cellulose coated pellets
Eudragit L100 (Dissolution pH-6)
Eudragit L100 (Dissolution pH-6)
Eudragit S (Dissolution pH-7)

Sulfasalazin
e

Azulfidine
Colo-Pleon

Cellulose acetate phthalate

(Dissolution pH6.2-6.5)
Eudragit L100-55 (Dissolution pH5.5)

GI Tract: pH sensitive
systems

(pH= 6,6)

(pH= 5,7)
(pH= 6,4)

(pH= 7,0)

GI tract
segment

PH

STOMACH

1-3

SMALL
INTESTINE
(proximal
to distal)

5 - 7.5

LARGE
INTESTINE

6.8-7.8

RECTUM

7.8-8

pH sensitive systems
GI TRACT SEGMENT

PH

STOMACH

1-3

SMALL INTESTINE
(proximal to distal)

5 - 7.5

LARGE INTESTINE

6.8-7.8

RECTUM

7.8-8

MECHANISM OF ACTION OF PH
DEPENDENT SYSTEM FOR DRUG
DELIVERY IN THE COLON
pH sensitive polymer +
drug core
DRUG
CORE

Release of drug in
Colon
Colonic pH

Polymer rely pH: not soluble at pH levels are low but becomes
more soluble as the pH rises Although polymer depends pH can
protect the formulation in the stomach and small intestine
proximal, may begin to dissolve in the small intestine lower, and
the site-specificity of the formulations can be low
A decrease in the pH of the end of the small intestine to the
colon can also cause problems, the long lag time in the junction
ileo-cecal or rapid transit through the ascending colon that can
lead to poor site-specificity of a single unit, enteric coated
formulation

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Coating with
Polymers
1. COATING WITH pH-SENSITIVE
POLYMERS

The chemical structure of various formulations

Eudragit

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Coating with
Polymers

2.

COATING WITH BIODEGRADABLE POLYMERS

Tabel Azopolymer untuk Colon DDS

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Coating with
Polymers

Behavior of Enteric-coated
Polysaccharide Matrix
Coloni
c
bacter
ia

Enteric
coated matrix
tablet

Enteric
coated
matrix
tablet in
upper GI

Solublization
of enteric
coat and
swelling of
inner matrix
followed by
degradation

Degradation
of swelled
matrix tablet
and drug
release

The Effect of Rat Caecal Content on Drug

Release : of Boswellia gum based enteric
coated

Compression Coated Tablets

Coloni
c
bacteri
a

Intact
compression
coated
tablet

Swelling of
coat in
upper GI
Environment

Swelled coat
Degraded by
colonic
bacterial
enzymes

Degradation
of coat and
drug release

Mixed Film Coated Tablets

Colonic
bacteri
a

Mixed film
coated
tablet

Intact tablet
in upper GI
tract

Swelled coat
Degraded by
colonic
bacterial
enzymes

Degradation
of coat and
drug release

Natural Polysaccharide for

CDDS
Chitosan
Pectin
Guar

gum
Chondroitin sulphate
Dextran
Almond gum
Locust bean gum
Siclodextrin
Inulin
Boswellia gum
Khaya gum

Chitosan-Coating Technology for ColonSpecific DDS (Aicello Chemical Company Ltd and Freund Corporation)

To improve the effectiveness of drugs that target applications

for bowel diseases, supplements for improving intestinal flora
and intestinal drugs lainnya.
Characteristic:
- Solutions and film coating method using chitosan as the main
ingredient.
- Chitosan membrane can be formed on the surface of the
object with s standard coater.
- Chitosan membrane dissolves in acids, is biodegradable but
watertight.
- DDS Special Colon can be achieved by coating with an enteric
coating on chitosan membranes.

Behavior of colon specific delivery

system using Chitosan in
Alimentary Canal

Table Characteristics of Polysaccharides

biodegradable for Colon DDS

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Embedding in
Matrices
1. Embedding in Biodegradable Matrices and
Tabel
Karakteristik Polisakarida yang biodegradable
Hydrogels
untuk Colon DDS

Table Type Hydrogels for Colon DDS

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Embedding
in Matrices
2.

Embedding in pH-sensitive Matrices

- The drug molecules are embedded in
the polymer
matrix.
- The polymers used for this technique
should exhibit degradability in the
colon for
liberation of entrapped drug.

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Timed
Release System
Releases the drug after a predetermined lag
time
The lag time usually starts after gastric
emptying because most of the timecontrolled formulations are enteric coated.
the press coated
Drug release from
these systems is not pH
swellable hydrophobic

dependent

polymer layer

Enteric-coated Timed-release Press coated Tablet (ETP Tablet)

PULSINCAP

The first
introduced
formulation
The main parts:
water
insoluble (exposing the body
thdp formaldehyde vapors,
which can be generated by the
addition of tablet
trioxymethylene or potassium
permanganate to formalin or
other means). Contents:
contained within the body by a
hydrogel plug, which is covered
by a cap soluble in water
The entire unit is coated with
an enteric polymer to avoid the
problem of variable gastric
emptying.
When the capsule enters the
small intestine enteric coating
dissolves and the hydrogel plug
began to swell, the number of
the hydrogel is adjusted in such
a way that it appears only after

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Timed
Release System
Lag
Phase of
5 hrs.
obeserve
d

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Timed
Release System
Time

Controlled Release System : sustained and

delayed release dosage form

Fact:

Variations in gastric emptying time >>>

preparation time arrives in the colon can not be
predicted availability of drugs at the lower colon
Extend

lag time (no drug release period / transit

time from mouth to colon) up to 5-6 hours

The

duration of the lag time depends on the

weight and composition of the coating HPC

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Timed
Release System
Disadvantages of Timed Release System:
1. Gastric emptying time varies among individuals or
depending on the amount and type of food
consumed
2. Movement of the gastrointestinal tract, particularly
peristaltic and contraction of the stomach, can
change transit time of drugs in the gastrointestinal
tract
3.
TimeReleased
drug transit
along the
tract will be
Timed
System
be GI
applied
in IBD patients, carcinoid syndrome,
forincreased
the preparation
of local therapy in colon
diarrhea and ulcerative colitis

Integration system pH-dependent with time contr

system

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Timed
Release System
The others timed release technologies :
Multicoated preparations consisting of a core coated
by three types of polymers
- The system is designed to anticipate the small
bowel transit
time is relatively short:
- The outer layer dissolves at pH> 5, the middle
layer of coating
that expands made from enteric material.
Pellet preparations with powder coating 5ASA on
nonpareil: drug layered pellets were coated with the
coating in the form of a combination of two polymers
that do not depend pH (Eudragit RL and RS) and the

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Redoxsensitive polymers

Average redox potential in the proximal small

intestine: -67 90 mV, distal: -196 97 mV, in
the colon: -145 72 mV

Redox potential changes induced by microflora

as highly selective mechanism for targeting
to the colon

Noncrosslinked redox-sensitive polymers

containing azo bond and / or disulfide

Analog termination azo bond by enzymes in the

gut, a new polymer which is hydrolysed
nonenzimatik by flavin produced enzymatically
being developed for the CDDS

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Bioadhesive
System

Oral administration: requires a high concentration

of the drug in the colon for optimal therapeutic
effect.
Bioadhesive: a process wherein a preparation
remain in contact on a particular organ for a
period of time longer
improve performance
and extend the residence time of the drug in the
CDDS
Material for bioadhesive system: polycarbophils,
polyurethanes and polyethylene oxidepolypropyline oxide copolymers (already
examined)

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Bioadhesive
System
In

the
environment of
the colon, azo
network
degraded can
provide a
structure that
can build
mucoadhesive
interaction with

Mucoadhesive azo crosslinked

acrylic acid and predicted colonic

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Coating with
Mirelman
et al. developed and evaluated the
microparticles

formulations: composed of fine particles of silica (510M diameter) covalently bound by a powerful drug
antiamoebic, 2 - (4-aminophenoxymethyl) -5-nitro-1methylimidazole.
Drug-silica particle was injected into mice, hamsters
and guinea pigs: found that trophozoites
phagocytosed particles in vivo and in vitro, followed by
rapid cell death due to drug released.
Analysis rat serum stated that there are drugs that are
absorbed from the intestine after placement of drugcontaining particles in a particle recovering
antiamoebic intestine.
Activity of the intestine almost completely preserved
useful for luminal therapy for asymptomatic amebiasis
and to minimize side effects and frequency of

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Osmotic
Controled Drug Delivery

Depending
on
the
osmotic pressure given
by osmogen the drug
compartment with drugs
could be released slowly
through a hole

OROS-CT
(Alza Corporation)

Irisan melintang sistem OROS CT

to target the drug locally or to achieve systemic

absorption
can be single or osmotic units can combine as
many as 5-6 units of push-pull, each 4 mm,
packed in hard gelatin capsules

Each unit containing a bilayer push pull boost osmotic layer and
layer of drugs, both surrounded by a semipermeable membrane
holes are drilled through the membrane layer Immediately take
medication after the OROS-CT swallowed gelatin capsules
containing soluble push-pull unit. Because drug-resistant enteric
coated, each push-pull units prevented from absorbing water in
dilute acid environment of the stomach, and hence no drug is
delivered. When the unit enters the small intestine, the coating
dissolves in the higher pH environment (pH> 7), water gets into
the unit, causing osmotic push compartment swell, and
simultaneously make the gel to flow in the drug compartment.
Swelling of the osmotic push compartment gel force drug out of
the pit at a rate that is precisely controlled by the rate of transport
of water through a semipermeable membrane.

OROS-CT
(Alza Corporation)
- To treat ulcerative colitis, each unit is designed with
a push pull delay of 3-4 hours in the stomach to
prevent the delivery of the drug in the small intestine.
Drug release begins when the unit reaches the large
intestine.
- Oros-CT unit can maintain a constant release rate
for more than 24 hours in the colon or can deliver
drugs over periods as short as four hours.
- Various evaluation techniques in vitro / in vivo has
been developed and proposed to test the
performance and stability of the CDDS.

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Pressure
Dependent Release System
Rely on relatively strong peristaltic waves in the
colon also increases luminal pressure. When the
pressure in the colon increases, the dosage form
rupture and release the drug at the desired location
Takaya et al. develop pressure control colon-delivery
capsules made using ethylcellulose, which is
insoluble in water.
Drug release occurred after the disintegration of the
water-insoluble polymer capsules because of the
pressure in the lumen of the colon. Ethylcellulose
membrane thickness is the most important factor
for the disintegration of the formulation.

APPROACHES TO DELIVER THE INTACT

MOLECULE TO THE COLON: Pressure
Dependent Release System
The system also seems to depend on the capsule size
and density. Because the reabsorption of water from
the large intestine, the viscosity of the luminal content
is higher in the colon than in the small intestine
- It was therefore concluded that the solubility of the
drug in the colon can cause problems in relation to
oral drug delivery system of the intestine - specific.
- In the pressure-controlled, single-unit drug capsules
ethylcellulose is in fluid BTK.
- when administered to humans acquired lag time 3-5
hours

Platform Technologies for

CTDDS

PULSINCAP
OROS-CT
CODESTM
PORT SYSTEM
TIME CLOCK SYSTEM
CHRONOTROPIC SYSTEM
COLAL-PRED
TARGIT TECHNOLOGY
ENTERIONTM CAPSULE
TICKING CAPSULE

CODES

TM

designed to avoid the inherent problems associated

with pH or time dependent systems

CODESTM

designed to avoid the inherent problems associated

with pH or time dependent systems
CODESTM is combined dr approach is pH dependent
and microbially triggered CDDS utilize a unique
mechanism involving lactulose, which acts as a trigger
for the site release of certain drugs in colon, system is
comprised of a core of traditional tablet containing
lactulose, which is over coated with a material that
dissolves acid, Eudragit E, and then subsequently
overcoated with an enteric material, Eudragit L. The
idea of this technology is that an enteric coating to
protect the tablet while the drug is in the stomach and
then dissolve the gastric emptying quickly.

CODESTM
Acid-soluble coating material then protects
the manufacture of alkaline pH as it passes
from the small intestine. After the tablet
arrives in the colon, bacteria degrade
polysaccharide enzymetically (lactulose)
into organic acids. This lowers the pH
around the system enough to affect the
solubility of the acid-soluble coating and
subsequent drug release.

PORTSYSTEM

TIME CLOCKSYSTEM

Solid preparations coated with a

lipid barrier that contains
carnauba wax and bees wax with
surfactant
Next to the outer layer, the
preparations coated with
polymer-coated to prevent
premature drug release
The release of the drug depends
on the pH of the gastrointestinal
tract or digestive conditions

Enteric coated

Drug core
Wax
coated
with
surfactan

CHRONOTROPIC
SYSTEM
Enteric coated

HPMC coated

Drug core

COLAL-PREDTM
Preparations

pellets containing the

drug prednisolone metasulfobenzoat
coated with ethylcellulose and
special amylose

Being

entered phase III clinical trials

for maintaining remission of
ulcerative colitis.

TARGITTM TECHNOLOGY
TargitTM

Technology (West
Pharmaceutical Services): salut pHsensitive on the injection-molded
starch capsules

From

research -scintigraphy:
Capsule Targit 90% (n = 84) releases
the active substance in the terminal
ileum and the colon

ENTERIONTM CAPSULE
1

mL drug reservoir
Common dosage forms:
solution
suspension
API
Formulated powder /granulate
Pellet/minitablet

EnterionTM capsule tracking

and evaluation

Ticking Capsule

Chronotherapeutic device : use an electronic

device to control the release of pulsatile drug
combined with an electronic timer

Evaluation of CDDS
For in vitro evaluation, there is no
standard evaluation techniques are
available for evaluation because ideally
CDDS vitro model should possess in-vivo
conditions of the GIT such as pH,
volume, stirring, bacteria, enzymes,
enzyme activity, and other components
of food. Generally, these conditions
affected by diet, physical stress, and
these factors make it difficult to design
a model-vitro. In vitro models used for
the CDDS is:
a) In vitro Dissolution test
b) In vitro enzimatic test
c) In vivo evaluation

Evaluation of CDDS: In vitro

dissolution test
The solubility of controlled-release formulations that
are used for specific intestinal drug delivery are
usually complex, and the method described in USP
dissolution can not fully replicate in vivo conditions
as related to pH, bacteria and strength mixing
environment.
CDDS dissolution testing can be done using
conventional basket. Dissolution studies parallel in
different buffers can be done to characterize the
behavior of formulations at different pH levels.

Evaluation of CDDS: In vitro

dissolution test
Dissolution colon specific formulations in various
media replicate the conditions of pH and time
that might be found in various locations in the
gastrointestinal tract has been investigated.
Selected media is, for example, pH 1.2 to
simulate gastric fluid, pH 6.8 to simulate the
jejunal region of the small intestine, and pH 7.2
to simulate ileal segment.
Enteric-coated capsules for the CDDS has been
investigated in the study of changes in the three
buffer dissolution. The capsules were tested for
two hours at pH 1.2, then one hour at pH 6.8,
and finally at pH 7.4

Evaluation of CDDS: In vitro

enzymatic tests
Incubation of drug carrier systems fermentors
containing a suitable medium for bacteria
(Streptococcus faccium and B. ovatus). The
amount of drug released at different time
intervals specified
Studies conducted drug release in buffer medium
containing the enzyme (enzypectinase,
dextranase), or a rat or guinea pig or rabbit cecal
contents.
The amount of drug released in a given time is
determined, which is directly proportional to the
rate of degradation of the polymer carrier.

Evaluation of CDDS: In vivo

evaluation
Dogs, guinea pigs, mice and pigs: resembles the
anatomical and physiological conditions as well as
human GIT microflora
While choosing a model to test the CDDS, the
model relative to colonic disease also considered.
Guinea normally used for experimental pig model
of IBD.
Distribution and glucouronidase azoreductase
activity in rats and rabbits GIT quite comparable
to that in humans.

Evaluation of CDDS: Drug Delivery

Index (DDI) and Clinical Evaluation of
Colon-Specific Drug Delivery Systems
DDI is a matter of the pharmacokinetic
parameters, followed by single or multiple doses
of oral prodrugs colon.
DDI is a relative ratio RCE (colon tissue exposure
to the drug) thd RSC (relative amount of drug in
the blood is exposed systemic medicine;). DDI
high medicinal value indicates better CDD
Drug absorption from the colon is monitored by
colonoscopy and intubation.
Currently, gamma scintigraphy is the most
preferred techniques used to evaluate CDD

Technology of Colon DDS

DELIVERY
METHOD

PHCONTROLLED
DRUG RELEASE
1.

PRINCIP ACHIEVED BY
LE

Differenc
es in pH
in the
small
intestine
and
colon

Dissolution
salute the
pHdependent
polymer

EXAMPLE

Entericcoated,
polymer base

The
acrylic
expansion of polymer
the hydrogel
polymers are
pHdependent
Insulin +

DELIVERY
METHOD

PRINCIPLE

Degradati
ENZYME- on of
CONTROL componen
LED
ts of the
DRUG
preparatio
RELEASE n by
colonic
bacterial
enzymes
2.

ACHIEVED BY

degradation
prodrug
Bond coating
material that
can be
degraded by
the capsule
shell +
Hydrogel and
polymer
matrix
comprising
cross-lingked
and

EXAMPLE

Mono-, oligo, or
polymer with a
drug-carrier
bond
Azo polymers,
polymers with
glycoside bond

Cross-linked
guar gum,
pectin, dextran,
inulin, a
polymer azo

DELIVERY
METHOD
3. TIMECONTROLLED
DRUG
RELEASE

PRINCIPL
E
The transit
time in the
small
intestine is
relatively
constant
at around
3 hours

ACHIEVED
BY
The
development
of timedependent
polymer

EXAMPLE
Ether
cellulose,
Eudragitsust
ained-release
coating
COER-24 TM

Osmotic
pressure
which
emerged
slowly in the
preparation
The polymer
layer is
eroded or

Ehter
cellulose,
EudragitE,
chitosan (in

combination
with acid)

DELIVERY
METHOD

PRINCIPL
E

ACHIEVED
BY

EXAMPLE

PRESSURECONTROLLED
DRUG
RELEASE

The
disintegrati
on of the
preparatio
n in the
colon by
intralumina
l pressures
resulting
from
strong
peristalsis

thick coating
consisting of
waterinsoluble
polymers,
polymer
unexpands

Hard gelatin
capsules with
ethyl
cellulose
coated on
the inside

4.

OROS-CT TM (Oral Osmotic System for Colon

Targeting)
Micropore

Drug + Osmotic agent

Swelling agent
Enteric Coated
Semipermeable membrane

After the dissolution of the enteric coating, polymer

sswelling will push the fluid in the compartment osmotic out
through micropore due to water penetration.
This causes a combination of sustained release of drug

COER-24 TM
(Controlled Onset Extended Release)
Micropore

Drug Compartement

Osmotic Compartement

Semipermeable membrane
Polymer delay coat: plays on
delayed drug release

During the lag phase, osmotic compartment expands causing

increased pressure on drug compartment
By sustained release drug out via micropore on semipermeable
film coating on the outside after the dissolution and ekstrusilap
delay underneath.

Swelling-induced time controlled

drug delivery system
TIME-CLOCKTM
Lapisan surfaktan
hidrofobik (wax,
polysorbat 80,
HPMC)
Membran polimer
tak larut air

Drug layer

Salut Enterik
Drug core

CHRONOTROPICTM
Salut Enterik (Eudragit
EudragitS
(opsional)

Swelling agent layer Sucrose

Salut HPMC
(low substituted
bead
HPC)
(viskositas
E-CONTROLLED EXPLOSION SYSTEM (TES)

Drug

Lag time control:

Controlling

the speed of water penetration

through the coating or shell (pH-induced)

Controlling

the speed of liquid absorption

through the polymer layer (swelling induced)

Controlling

the osmotic activity of the salt or

osmotic polymer compounds (pressure-induced)

Controlling

the speed of erosion and dissolution

of the polymer coating (erosion induced)

Set

the coated layer thickness

CONCLUSION

Part of the colon of the gastrointestinal tract has

become an important site for drug delivery systems
and drug absorption
CDDS offers advantages for both patients for the
treatment of local and systemic
Specificity of the colon can be achieved with a
system that uses natural ingredients that can be
degradated by colonic bacterial enzymes.
Therefore complexity of the system CDDS and
uncertainties method of dissolution that already
exist in enforcing the relationship vitro and in vivo,
then it is still a challenge for the experts of
Pharmaceutical to develop and validate a method of
dissolution involving physiological properties colon

CONCLUSION
Colonic drug delivery are one of the major challenges.
Management of local pathologies requires efforts in
decreasing or eliminating side effects .
Drug delivery to specific site i.e. colon is a potential
alternative for improvement in therapy.
Colon provides favorable factors and conditions for
designing of delivery systems.
High
commercial viability. Increasing number of
international patents and research work in this particular
mode of drug delivery itself shows its potential for
pharmaceutical market.

References

Philip AK, et al. 2010. Colon Targeted Drug

Delivery Systems: A Review on Primary and Novel
Approaches. OMJ. 25: 70-78.
M. K. Chourasia, S. K. Jain. 2003. J Pharm
Pharmaceut Sci. 6(1):33-66.
Rajeev S. Raghuvanshi. 2007. Oral Controlled
Release Drug Delivery Systems (OCRDDS):
Recent Trends & Future Challenges
Prof V. R. Sinha. Site Specific Drug Delivery to
Colon: Approaches and Recent Developments