COLON DRUG DELIVERY

SYSTEM

By : Rahmah Elfiyani
 INTRODUCTION
 Definition:-Colon drug delivery system refers to targeted
delivery of drug in to the lower parts of GI tract , mainly large
intestine.
 Colon was considered as BLACK-BOX as most of the drugs are
absorbed from upper part of the GI tract
 Targeted delivery of drugs to the colon is usually to achieve
one or more of four objectives
 To reduce dosing frequency
 To delay delivery to the colon to achieve high local
concentrations in the treatment of diseases of the distal gut,
 To delay delivery to a time appropriate to treat acute phases
of disease (chronotherapy),
 To deliver to a region that is less hostile metabolically, e.g., to
facilitate absorption of acid and enzymatically labile
materials, especially peptides
 Advantages

• Drug directly available at the target site

• Decreased dose to be administered
• Decreased side effect
• Improved drug utilization
• Long time residence
•Patient compliance and treatment efficacy
•Used for local and systemic action
•Gastric irritation can be avoided
 DISADVANTAGES
 TIME DEPENDENT SYSTEMS:
 Substantial variation in the gastric retention times.
 Transit through colon is more rapid in the normal than in patients
with colon disease.
 PH DEPENDENT SYSTEMS:
 PH level in the small intestine & colon vary b/w & with in the
individuals.
 MICROFLORA ACTIVATED SYSTEM:
 Diet & disease can affect colonic microflora.
 There is less fluid in colon than in small intestine and hence,
dissolution is a problem for water soluble drugs.
 Binding of drug to dietary residues, intestinal secretions etc., reduce
concentration of free drugs
 Small luminal surface area & relative tightness of tight Junctions in
colon, delay the systemic absorption.
 Onset of action is slow
 APPLICATIONS OF CDDS
 Promising site for drug delivery
 Local disorders
 Systemic absorption
 Drugs unstable in upper GIT
 Drugs poorly absorbed from GIT
 Drugs that necessitate targeting at site

 Potential application :
 Chronotherapy.
 Prophylaxis of colon cancer.
 Treatment of nicotine addiction.
 Potential site for the systemic delivery of therapeutic proteins
& peptides.
 Potential side affects can be reduced.
 Drug instability problems also reduced.
 Rational for the Development of
Colon Targeted Drug Delivery
• Treatment of local pathologies, exp : inflammatory diseases (ulcerative
colitis), colonic diseases (ameobiasis)
• Chronotherapy (asthma, hypertension, cardiac arrhythmias, arthritis or
inflammation )
• Greater responsiveness to the absorption enhancers.
• Less enzymatic activity
• Site for delivery of delicate drugs (Proteins and Peptides)
•Colon targeting can also be done for drugs which are not suitable in the
acidic environment of the stomach.(Aspirin, Iron supplements
ANATOMY & PHYSIOLOGY OF CDDS

Longest & Most mobile part.

Diameter 6cm.
 LAYERS OF COLON

Contd…

Major part

External coat of large intestine

MAJOR FUNCTIONS OF COLON
Create suitable environment for colonic microorganisms.

Storage reservoir of faecal matter .

Expulsion of the contents of the colon.

Absorption of potassium & Water from the lumen

9
 Saat kandungen lumen mencapai descending  massa
menjadi terlalu padat  memungkinkan dispersi obat dr
bentuk sediaan pelepasan yg diperlama
 Permukaan segmen dlm kolon memiliki luas permukaan
yg kecil (karna tdk ada villi), adany lipatan & gerakan yg
kurang (sebagian besar bersifat mendorong) 
pemisahan menurut ukuran partikel (pemisahan
mikropartikulat & sistem matriks)  partikel halus berada
pd lipatan  retensinya 
 Lingkungan dgn kandungan air yg rendah & gas yg tinggi
pd transversum colon akan membatasi disolusi bahan
 Pd descending berisi 300g kandungan fekal, jk massa ini
tdk dikeluarkan  tdk akan ada absorpsi
 Penghantaran obat diarahkan pd bag proksimal kolon
yaitu bag ascending, karena memiliki sejml air u/ disolusi,
adany perubahan pH & metabolisme unik dr bakteri sekal
11
FACTORS GOVERNING THE COLON
DRUG DELIVERY SYSTEM
 Gastro intestinal transit time.

 PH along GIT .

 Colonic Micro Flora.

 Drug absorption in the colon.

 GIT disease state.

 Gastro intestinal transit time.
 The arrival of oral dosage form at the colon is determined by
the rate of gastric emptying & small intestinal transit time.

 Gastric emptying of dosage form is highly variable depends :

 Subject Fed / fasted.
 Properties of dosage form.(Size & Density).
 Food increases gastric residence, some cases with regular
feeding dosage forms residence in creases 12hrs.
PH along GIT .

 Large PH variation along GIT.

 STOMACH-1-2PH(During fasting) 6PH(After
eating , in feed)
 RIGHT COLON-6-4.
 MID COLON- 6.6.
 LEFT COLON -7
 pH sensitive systems

GI TRACT SEGMENT PH

STOMACH 1-3

SMALL INTESTINE 5-7.5

LARGE INTESTINE 6.8-7.8

RECTUM 7.8-8
Mechanism of action of a pH dependent
system for targeted drug delivery to the
colon
pH sensitive Release of drug in
polymer + Colon
drug core

Colonic pH
DRUG CORE
Sr. No. Polymer Threshold pH

1 Eudragit® L 100 6.0

Polymer of
2 Eudragit® S 100 7.0 methacrylic
acid are
3 Eudragit® L –30D 5.6 mostly used
4 Eudragit® FS 30D 6.8

5 Eudragit® FS 30D 5.5

6 Polyvinyl acetate phthalate 5.0

7 Hydroxy propyl methyl cellulose 4.5-4.8

phthalate

8 Cellulose acetate trimelliate 4.8

9 Cellulose acetate phthalate 5.0

 Colonic Micro Flora
 GIT –Aerobic & Anaerobic bacteria.
 Upper region – small number of bacteria (Gm+ve bacteria).
 Proximal areas –high concentration of energy sources.
 COLONIC MICRO FLORA
 Eubacterium.
 Peptococcus.
 Peptostreptococcus.
 Clostridium.
 E.coli
 Lactobasillus etc.,
 STOMACH-0-103CFU/ml
 JEJUNUM-0-105CFU/ml
 ILEUM-103-107CFU/ml
 COLON-1011-1012CFU/ml
 Colonic Microflora

Human intestinal microflora distribution

in number (Log 10 scale) per gram faeces.
 Drug absorption in the colon

Hydrophilic drugs Lipophilic drugs

Colon contents—More viscous with progressive absorption of water & delays the
diffusion of drug from the lumen to mucosa.
Colonic epithelial permeability modified by enhancers.
Ex:-Ca+2 EDTA, Saponins,Bile salts, Fatty acids  DISRUPTION.
MODIFICATION.
MODIFICATION & DISRUPTION
 Factors affecting drug absorption
 Physical characteristics of drug (pKa, degree of ionization)
 Colonic residence time as dictated by gastrointestinal tract motility
 Degradation by bacterial enzymes and byproducts
 Selective and non-selective binding to mucus
 Local physiological action of drug
 Disease state
 Use of chemical absorption enhancers, enzyme inhibitors, or
bioadhesives
GIT disease state.

 IBD.
Affect the release &
 Crohn’s disease. absorption properties of
CSDDS
 Constipation.
 Diarrhea.
 Gastro Enteritis.
Pharmaceutical Approaches for Targeting
Drugs to Colon

» Covalent linkage of drug with carriers

» pH sensitive system

» Microbially triggered systems

» Prodrugs & Polymer based approach.

Polysaccharide based systems
Time release systems

» Osmotically controlled drug delivery systems

» Pressure dependent release systems

Covalent linkage of drug with carriers

Azo Conjugates (N = N)
Cyclodextrin Conjugates
Glycoside Conjugates
Dextran Conjugates
Polypeptide Conjugates
  Mechanism of pH dependent system
pH sensitive
polymer

Drug
in
Upper
GIT On Reaching to COLON

Drug release
 Drug Trade Name Coating Polymer / Formulation

Budesonide Entrocort® Eudragit® L 100-55,

Budenofalk® ethylcellulose
Targit® Eudragit® S (Dissolution pH-7)
Coated Starch Capsule
Mesalazine Claversal® Eudragit® L100 (Dissolution pH-6)
Asacolitin® Eudragit® S (Dissolution pH-7)
Salofalk® Eudragit® S (Dissolution pH-6)
Pentasa® Ethyl cellulose coated pellets
Mesazal® Eudragit® L100 (Dissolution pH-6)
Calitofalk® Eudragit® L100 (Dissolution pH-6)
Asacol ® Eudragit® S (Dissolution pH-7)

Mesalazine Azulfidine® Cellulose acetate phthalate

Colo-Pleon® (Dissolution pH-
6.2-6.5)
Eudragit ® L100-55 (Dissolution
pH-5.5)
 Microbially Triggered Systems

» Bacterial count in the colon is much higher around 1010-

1011 CFU/ml.

» 400 species

» Facultative anaerobic in nature.

» Predominant species: Bacteroides, Bifidobacterium and

Eubacterium.

» Major metabolic processes occurring in the colon are

hydrolysis and reduction.
 Enzymes in Colon

Reducing enzymes Hydrolytic enzymes

» Nitroreductase » Esterases
» Azoreductase » Amidases
» N-oxide reductase » Glycosidases
» Sulphoxide reductase » Glucuronidase
» Hydrogenase » Sulfatase

» Azoreductases, which reduces azo-bonds selectively

and
» Polysaccharidases which degrades the polysaccharides.
 Prodrugs
Concept
Drug Carrier Molecule of
prodrugs

Enzymatic stimuli in the biological environment of the GIT

breaks the bond

 AzoBond Prodrug.
 EX:- sulphasalazine.( Anti-inflamatory & Rheumatoid
arthritis).
 Sulphasalazine =Sulphapyridine & 5-ASA
 Active Drug
 Pro drug
Azo reductase

•Lacto bacillus. Glycosidase.

•Bacteroids. Glucouronidase.
•Bifido bcteria

NORMAL CONDITIONS DISEASE STATE

Composition , function, population Varies its composition , function, population

are constant
 (
A
Bacteria in
)
colon

( (
B C
) )

Hydrolysis of sulphasalazine (A) into 5-aminosalicylic

acid (B) and
sulfapyridine (C).
Polymer based approach.
 PH SENSITIVE POLYMER SYSTEM

PH
SENSITIVE
LAYER

DRUG
CORE COLON PH
 Natural Polysaccharides as
Polymer for Colon Drug Delivery

» Inulin » Chitosan
» Guar gum » Chondroitin sulphate
» Pectin » Dextran
» Almond gum » Cyclodextrins
» Locust bean gum
» Khaya gum
» Boswellia gum
 Behavior of Enteric-coated Polysaccharide Matrix

Colonic
bacteria

Enteric Solublization of
Enteric coated coated matrix enteric coat and Degradation of
matrix tablet tablet in swelling of inner swelled matrix
upper GI matrix followed tablet and drug
by degradation release
by colonic
bacteria
 Compression Coated
Tablets
Colonic
bacteria

Intact
compression Swelling of coat in Swelled coat
coated tablet upper GI Degraded by Degradation of
Environment colonic bacterial coat and drug
enzymes release
 Mixed Film Coated
Tablets
Colonic
bacteria

Mixed film Intact tablet in

coated tablet upper GI tract Swelled coat Degradation of
Degraded by coat and drug
colonic bacterial release
enzymes
 Timed Release
Systems

» Releases the drug after a predetermined lag time

» The lag time usually starts after gastric emptying
because most of the time-controlled formulations are
enteric coated.
» Drug release from these systems is not pH dependent
Lag Phase of
5 hrs.
obeserved
 Depend upon the osmotic pressure
Osmotically Controlled exerted by osmogen on drug
Drug Delivery Systems compartment with which drug get
released slowly though the orifice

Pressure Dependent Relies on the relatively strong peristaltic

Release Systems waves in the colon that lead to an
increased luminal pressure. In response to
raised pressure of the colon, the dosage
form get ruptured and release the drug at
desired site
Platform Technologies for CTDDS

» PULSINCAP
» OROS-CT
» CODE STM
» PORT® SYSTEM
» TIME CLOCK® SYSTEM
» CHRONOTROPIC® SYSTEM
» COLAL-PRED™
» TARGIT™ TECHNOLOGY
» ENTERIONTM CAPSULE
» TICKING CAPSULE
PULSINCAP
Prinsip dlm memodulasi
penghantaran :
 Pengosongan k dlm usus
halus
 Pemelar berupa kap
hidrogel yg dikeluarkan dr
dasar badan kapsul
 Metabolisme sekal u/
pemisahpaksaan (cleavage)
scr reduktif & glikosidik
 pH rendah yg dihasilkan dr
fermentasi bakteri &
polimer larut
PULSINCAP
SYSTEM

PLUG MADE UP OF –Polymethacrylates, HPMC, PVA.

O
R
O
S
-
C
T
OROS –CT SYSTEM.

DRUG + EXCIPIENT

Phthalates, Keratin, Formalin treated protein oil, anionic polymers

CODES SYSTEM.
PORT SYSTEM
The Chronotropic System
 TIME CLOCK® SYSTEM

 Solid dosage form coated Wax coating with

with lipid barriers containing Enteric coating surfactant
carnauba wax and bees wax
along with surfactants.
 Further coated with enteric
coating polymer to prevent
premature drug release, but
the release is independent of Drug core

pH or digestive state of the

gut
 COLAL-PRED™

Pellets containing the drug (prednisolone

metasulphobenzoate) with a coating of
ethylcellulose and a specific form of amylose
(derived from starch).
After completion of succsesful phase I and II
trials ‘Alizyme’ obtained approval for Phase III
clinical trial of COLAL-PREDTM in maintenance
of remission of ulcerative colitis.
Philips’ Intelligent pill
Enterion Capsule
InteliSite® capsule
 Philips’ Intelligent pill
 Is device of ‘Philips research’ available in market from 2008
 The ‘iPill’ is a capsule and it has been designed to be swallowed
and to pass through the digestive track naturally. It can be
electronically programmed to control the delivery of medicine
according to a pre-defined drug release profile
 The iPill determines its location in the intestinal tract by measuring
the local acidity (pH difference) of its environment.
 The iPill releases medicine from its drug reservoir via a
microprocessor controlled pump, allowing accurate programmable
drug delivery.
 The capsule is designed to measure local temperature, and report
measurements wirelessly to an external receiver unit
 It can be used in treatment of Crohn’s disease, Ulcerative colitis
and Colon cancer.
 Enterion Capsule
 The Enterion capsule developed by Phaeton Research, Nottingham,
UK, for targeted delivery of a wide range of different drug formulations
into any region of the colon.
 The capsule can be loaded with either a liquid formulation (eg.
solution, suspension) or a particulate formulation (eg. powder, pellets,
minitablets, etc.)
 The floor of the drug reservoir is the piston face, which is held back
against a compressed spring by a high-tensile strength polymer
filament. A radioactive marker is placed inside a separate sealed tracer
port to allow real-time visualization of the capsule location using the
imaging technique of gamma scintigraphy.
 When the capsule reaches the target location in the gastrointestinal
tract, the contents are actively ejected by the external application of an
oscillating magnetic field.
 This magnetic field induce power in a tuned coil antenna, embedded in
capsule wall. This power is fed to a tiny heater resistor located in
capsule
 This heater resistor increases temperature & releases the spring &
drives the piston.
 The resulting increase in pressure within the drug reservoir forces
off the O-ring sealed cap and ejects the drug or drug formulation
into the surrounding GI fluids.
 The InteliSite® capsule is an InteliSite® capsule
ingestible, radio-controlled
device capable of delivering
either liquid or powder drug
formulations, on demand, to
a specific region of the
gastrointestinal tract.
 The InteliSite® capsule is loaded with a drug solution or powder
formulation in a specially designed reservoir. When the capsule
reaches the desired location in the gastrointestinal tract it is
externally activated by remote control.

 Activation is accomplished by exposing the capsule to a radio

frequency magnetic field that induces a small amount of heat in the
capsule's activation assembly. This causes two shape-memory alloy
wires to straighten, rotating an inner sleeve of the capsule in relation
to an outer sleeve.
 The rotation process aligns a series of slots in the sleeve surfaces
permitting the contents to be released into the specific area of the GI
tract. After activation, the InteliSite® capsule passes harmlessly
through the body
Mekanisme penglepasan obat kolonik
 Spesifik
 Penggunaan polimer peka thdp pH  melarut pd pH rendah
disertai metabolisme sekal polisakarida
 Reduksi azo dr polimer berdasarkan pemutusan scr reduksi
 Biopolimer yg dpt difermentasi menjadi as lemak rantai
pendek
 Nonspesifik
 Kombinasi salut enterik (pH 7 atau lebih) dgn salut enterik
konvensional (pH lebih rendah dr 7) melalui barier disolusi
tergantung waktu, ketebalan penyalut
 Sistem pemelaran (pulsincap) atau pemecahan salut
 Sistem erosi (egalet)
 Memperlambat transit d kolon (pelet), pelepasan sebagian
besar obat terjadi saat sediaan terperangkap pada
ascending
 Conclusions

» Colonic drug delivery is one of the major challenge.

» 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 favourable factors and conditions for designing of delivery

systems.

» High commercial viability. Increasing number of drug and research work in

this particular mode of drug delivery itself shows its potential for

pharmaceutical market