SISTEM PENGHANTARAN OBAT

COLON –DRUG DELIVERY SYSTEM

SEMESTER GANJIL 2020-2021

Anatomy of Colon
 LAYERS OF COLON

Major part

MAJOR FUNCTIONS OF COLON External coat of large intestine

✓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

 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
• reduce dosing frequency
• delay delivery to the colon to achieve high local concentrations in the treatment
of diseases of the distal gut,
• delay delivery to a time appropriate to treat acute phases of disease
(chronotherapy),
• 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.
 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.
 GIT disease state.
➢IBD (Inflammatory Bowel Disease)
• Crohn’s disease
• Constipation
• Diarrhea
• Gastro Enteritis
10
Target site Diseases conditions Drug and Active Agents

Topical action Inflammatory bowel disease, Hydrocortisone,

irritable bowel disease, Crohn’s budenoside,
Disease prednisolone,
sulfasalazine, olsalazine

Local action Chronic pancreatitis, Digestive enzyme

pancreatectomey cystic fibrosis, supplements,
colorectal cancer 5-Fluorouracil

Systemic action Preventive of gastric irritation and NSAIDs

first-past mebaolism of orally Steroids
ingested drugs
Oral delivery peptides Insulin
Oral delivery vaccine Thypoid
 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: pH fasting= 1-2; after eating , in feed pH =6
• RIGHT COLON-6-4.
• MID COLON- 6.6.
GI TRACT SEGMENT pH
• LEFT COLON -7
STOMACH 1-3

SMALL INTESTINE 5-7.5

LARGE INTESTINE 6.8-7.8

RECTUM 7.8-8
 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
 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
 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

DRUG CORE Colonic pH

 Polymer Threshold pH
Eudragit® L 100 6.0

Eudragit® S 100 7.0

Eudragit® L –30D 5.6

Polymer of
methacrylic
Eudragit® FS 30D 6.8 acid are mostly
used
Eudragit® FS 30D 5.5

Polyvinyl acetate phthalate 5.0

Hydroxy propyl methyl cellulose phthalate 4.5-4.8

Cellulose acetate trimelliate 4.8

Cellulose acetate phthalate 5.0

 Drug Trade Name Coating Polymer / Formulation

Budesonide Entrocort® Eudragit® L 100-55, ethylcellulose

Budenofalk® Eudragit® S (Dissolution pH-7)
Targit® 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 (Dissolution pH-

Colo-Pleon® 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
Drug Concept of
Carrier Molecule
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
 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
Enteric coated coated matrix Solublization of Degradation of
matrix tablet tablet in enteric coat and swelled matrix
upper GI swelling of inner tablet and drug
matrix followed by release
degradation 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
hours. observed
 Osmotically Depend upon the osmotic pressure
exerted by osmogen on drug
Controlled Drug compartment with which drug get
Delivery Systems released slowly though the orifice

Relies on the relatively strong

peristaltic waves in the colon that lead
Pressure Dependent to an increased luminal pressure. In
Release Systems 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 ke dlm usus halus
▪ Pemelar berupa kap hidrogel yg dikeluarkan
dr dasar badan kapsul
▪ Metabolisme u/ pemisah paksaan
(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
CODE SYSTEM
PORT SYSTEM
The Chronotropic System
 TIME CLOCK® SYSTEM
Wax coating with
➢ Solid dosage form coated Enteric coating surfactant
with lipid barriers containing
carnauba wax and bees wax
along with surfactants.
➢ Further coated with enteric
coating polymer to prevent
premature drug release, but Drug core
the release is independent of
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 succesful 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
 ❖InteliSite® capsule

➢ The InteliSite® capsule is an

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
 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

#####

www.uhamka.ac.id info@uhamka.ac.id (021)73944451 uhamkaid Uhamka @UhamkaID

 TUGAS KELOMPOK
• Rangkuman artikel tentang materi berikut:
A.Sistem penghantaran sediaan oral terkendali melalui:
Kel. 1. disolusi terkontrol
2. difusi terkontrol
3. secara osmotic
4. menggunakan prodrug
B. Sistem penghantaran sediaan kolon
Kel. 5.pulsincap
6. OROS CT
7. CODE system
8. Chronotropic System
9. Enteriontm capsule
10. Intelisite®

www.uhamka.ac.id info@uhamka.ac.id (021)73944451 uhamkaid Uhamka @UhamkaID