Targeted Drug Delivery Systems
Dr. Gajanan S. Sanap M.Pharm.,Ph.D
Department of Pharmaceutics
Ideal College of Pharmacy and Research
Kalyan 421- 306
COLON TARGETED DRUG DELIVERY
Anatomy of colon
Criteria of drug selection
Approaches of colon targeting
Targeted drug delivery systems:
The major goal of any drug delivery system is to supply a therapeutic
amount of drug to a target site in a body.
Targeted drug delivery implies selective and effective localization of
drug into the target at therapeutic concentrations with limited access
to non target sites.
A targeted drug delivery system is preferred in drugs having
instability, low solubility and short half life,
Colon drug delivery system refers to targeted delivery of drug in to the
lower parts of GI tract , mainly large intestine.
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
To deliver to a region that is less hostile metabolically, e.g., to
facilitate absorption of acid and enzymatically labile materials,
Oral route is considered to be most convenient for administration of
drug to patient.
Colon is used as site of Targeted drug delivery.
Colon was considered as a BLACK-BOX , as most of the drug are
absorbed from the upper part of the GI tract.
Prime objective-Beneficial in the treatment of colon diseases.
Increase the pharmacological activity.
Reduce dosing & side effects.
Prevent drug from degradation.
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
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
a)Delivery of drug in its intact form as close as possible to the target
b)The ability to cut down the conventional dose.
c) Reduced incidence of adverse side effects.
WHY COLON TARGETED DRUG DELIVERY IS NEEDED?
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.
The site specific delivery of drug to lower part of GIT, for
localized treatment of several colonic diseases. (ulcerative
colitis, Chron's disease, carcinomas and infections)
Prevent drug from degradation
Ensure direct treatment at disease site.
Suitable absorption site for Protein & Peptide drug.
Used to prolong the drug therapy.
Improved drug utilization.
Multiple manufacturing steps.
Microflora affects activity of drug via metabolic degradation of the
Bioavailability of drug may be low due to potentially binding of
drug in a nonspecific way to dietary residues, intestinal secretions,
mucus or faecal matter.
Non availability of an appropriate dissolution testing method to
evaluate the dosage form in-vitro.
Drug should be in solution form before absorption and there for
rate limiting step for poor soluble drugs.
Limitations / Challenges/Difficulties
Substantial variation in gastric retention time may
affect drug delivery.
Diseased condition may affect the colonic transit
time and drug release profile.
pH level of colon may vary between individuals
due to disease, state and temperature of food
In local colonic pathologies
Systemic delivery of protein and peptide
Potential site for the treatment of diseases sensitive to
circadian rhythms (asthma, angina and arthritis)
For the drugs that are absorbed through colon such as
For the treatment of disorders like IBS, colitis, crohn’s
disease (…where it is necessary to attain high concentration
Table 1. Colon targeting diseases, drugs and sites
Targetsites Disease conditions Drugand activeagents
Topical action Inflammatory Bowel
Diseases, Irritable bowel
disease and Crohn’s disease.
Local action Pancreatactomy and cystic
fibrosis, Colorectal cancer
Systemic action To prevent gastric irritation
To prevent first pass
metabolism of orally
Oral delivery of peptides
Oral delivery of vaccines
Colon and rectum cancer - 10% in men and 11% women
>55,000 Total Colorectal Cancer Deaths
Anatomy & physiology of colon
The GI tract is divided into stomach, small intestine & large
The colon itself is made up of the caecum, ascending colon,
hepatic flexure, transverse colon, splenic flexure, descending
colon, sigmoid colon.
It is about 1.5 m long.
Although it varies in diameter from approx 9 cm in caecum
& 2 cm in sigmoid colon.
The wall of colon is composed of 4 layers: serosa,
muscularis externa, sub mucosa & mucosa.
Serosa consists of areolar tissue, muscularis externa
composed of an inner circular layer of fibers, sub mucosa is
layer of connective tissue, mucosa is divided into epithelium
lamina propria & muscularis mucosae
Function of colon
Formation of suitable environment for colonic
Act as storage reservoirs of waste matter.
Removal of content of colon at proper time.
Absorption of potassium ion & water from
lumen, concentrating fecal content & secretion
& excretion of potassium & bicarbonates.
Gastrointestinal Transit --
Gastric emptying of various dosage form is highly
inconsistant & depends primary on whether the subject is
fed or fasting & properties of dosage form.
The arrival of dosage form in colon is determined by
rate of gastric emptying & intestine transit time.
Intestinal transit time
Organ Transit time (hrs)
Stomach <1 (fasting)
Small intestine 3-4
Large intestine 20-30
Factors to be considered for colonic drug delivery
1. pH in the colon:
pH of the GI tract is subjected to both inter & intra subject
On entry in to the colon, the pH dropped to 6.4 . The pH in
the mid colon & the left colon is 6.0- 7.6
Oral cavity 6.2-7.4
Stomach Fasted condition 1.5-2.0
Fed condition 3.0-5.0
Small intestine Jejunum 5.0-6.5
Large intestine Right colon 6.4
Mid & left colon 6.0-7.6
2. Gastrointestinal transit:
Gastric emptying of dosage forms is highly variable &
depends primarily on whether the subject is fed or fasted.
The arrival of an oral dosage form at the colon is determined
by the rate of gastric emptying & the small intestinal transit
The transit time of dosage form in GIT:
Organ Transit time (hrs)
Stomach <1 (fasting), >3 (fed)
Small intestine 3-4
large intestine 20-30
3. Colonic microflora:
Many compounds taken orally are metabolized by gut
Drug release depends on enzymes that are derived from
microflora present in colon.
These enzymes are used to degrade coatings/matrices as well
as to break bonds between an inert carrier and an active agent
resulting in the drug release from the formulation.
Important metabolic reactions carried out by intestinal
bacteria : hydrolysis, reduction, dehydroxylation,
decarboxylation, dehalogenation, deamination, acetylation,
Drug absorption in the colon
Drugs are absorbed passively by either paracellular or
Transcellular absorption involves the passage of drugs through
Paracellular absorption involves the transport of drug through
tight junction between cells. ( Hydrophilic drug)
The colon may not be the best site for drug absorption since the
colonic mucosa lacks well defined villi as found in the small
The colon contents become more viscous with progressive
absorption of water as one travels further through the colon. This
causes a reduced dissolution rate, slow diffusion of drug through
Role of absorption enhancers
The permeability of drugs can be modified by the use of
These enhancers increase transcellular & paracellular
transport through one of the following mechanism:
1. By modifying epithelial permeability via denaturating
2. By reversibly disrupting the integrity of lipid bilayer of
Calcium ion chelating agent EDTA
Surfactants Polyoxyethylene lauryl ether
Bile salts Glycocholate
Fatty acids Sodium caprylate
Mixed micelles Oleic acid glycocholate
Drugs used for local effects in colon against GIT diseases.
Drugs poorly absorbed from upper GIT.
Drugs for colon cancer.
Drugs that degrade in stomach and small intestine.
Drugs that undergo extensive first pass metabolism.
Drugs for targeting.
Criteria of drug selection
Pharmaceutical Approaches for Targeting Drugs
pH sensitive systems
Microbially triggered system
◦ Polysaccharide based systems
Timed release systems
Osmotically controlled drug delivery systems
Pressure dependent release systems
An oral colonic delivery system should retard drug release in the
stomach and small intestine but allow complete release in the
A variety of strategies has been used and systems have been
developed for the purpose of achieving colonic targeting .
Approaches to colon specific drug delivery
1. Coating with pH dependent polymers:
The underlying principle of this approach has been employment of
polymers that are able to withstand the lower pH values of the
stomach, but that disintegrate and release the drug as the pH in the
small bowel increases.
Selection of enteric polymer dissolving at pH 7 is likely to cause
drug release in terminal small bowel.
The pH in the transverse colon is 6.6 and 7.0 in the descending
colon. Use of pH dependent polymers is based on these differences in
The polymers described as pH dependent in colon specific drug
delivery are insoluble at low pH levels but become increasingly
soluble as pH rises.
These processes distribute the drug throughout the large intestine
and improve the potential of colon targeted delivery systems.
Examples: Cellulose Acetate Phthalate (CAP)
CAP is a white free-flowing powder. It is insoluble in water, alcohols,
and chlorinated hydrocarbons, but soluble in acetone and its mixtures
with alcohols, ethyl acetate–IPA mixture.
Enteric polymers Optimum pH for dissolution
Polyvinyl acetate phthalate (PVAP) 5.0
Cellulose acetate trimelitate (CAT) 5.5
Hydroxypropyl methyl cellulose phthalate
Methacrylic acid copolymer, Type C
Cellulose acetate phthalate (CAP)
Table. pH of commonly used enteric polymers.
Cellulose Acetate Phthalate:
Methacrylic Acid Copolymers:
These are anionic copolymers and are very commonly utilized for
enteric coating, including application in colonic delivery.
Shellac is a material of natural origin used for enteric coatings. It is
a purified resinous secretion of the insect Laccifer lacca.
Hydroxypropyl Methylcellulose Phthalate (HPMCP):
HPMCP is a white powder or granular material. It is a more
flexible polymer than CAP. Commercially, the available forms are
HPMCP-50 and HPMCP-55.
The microflora of the colon is in the range of 1011 -1012 CFU/ mL,
consisting mainly of anaerobic bacteria, e.g. bacteroides,
bifidobacteria, eubacteria, clostridia, enterococci, enterobacteria and
Microflora produces a vast number of enzymes like glucoronidase,
xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase,
deaminase, and urea dehydroxylase.
Presence of the biodegradable enzymes only in the colon, the use of
biodegradable polymers for colon-specific drug delivery.
These polymers shield the drug from the environments of stomach and
small intestine, and are able to deliver the drug to the colon.
Microbially Triggered Drug
Delivery to Colon
A Prodrug is a pharmacologically inactive derivative of a parent
molecule that require some form of transformation in vivo to release the
active drug at the target site.
This approach involves covalent linkage between the drug and its carrier.
Biotransformation is carried out by a variety of enzymes, mainly of
bacterial origin, present in the colon. The enzymes that are mainly
targeted for colon drug delivery include azoreducatase-galactosidase, β-
xylosidase, nitroreductase, glycosidase deaminase, etc.
For colonic delivery , prodrug is designed to undergo minimal
hydrolysis in upper tracts of GIT & undergo enzymatic hydrolysis in
colon there by releasing the active drug moiety from drug moiety.
Metabolism of azo compound by intestinal bacteria is one of most
extensively studied bacterial metabolic process.
The azo linkage exhibits a wide
range of thermal, chemical,
photochemical and pharmaceutical
The azo compounds are
extensively metabolized by the
Sulphasalazine, which was used
for the treatment of rheumatoid
arthritis. This compound has an
azo bond between 5-ASA and
Include naturally occurring
polysaccharides obtained from
plant (guar gum, inulin), animal
(chitosan, chondrotin sulphate),
algal (alginates) or microbial
The polysaccrides can be broken
down by the colonic microflora to
simple saccharides. Therefore,
they fall into the category of
“generally regarded as safe”
Of the multitude of bacterial enzymes that are produced in colon, 2
main classes are:-
Drug Carrier Molecule
Enzymatic stimuli in the biological
environment of the GIT breaks the bond
Drug Carrier Molecule
Drug Carrier Molecule
Drug Carrier Molecule
Hydrolysis of sulphasalazine (A) into 5-aminosalicylic acid (B) and
Sulfasalazine is mainly used for the treatment of inflammatory
Chemically it is 5-amino salicylic acid (5-ASA) coupled with
sulphapyridine by azo bonding.
On reaching the colon, the azo bond is reduced by
azoreductases to 5-ASA & sulphapyridine.
The active moiety is 5-ASA & sulphapyridine acts as carrier
to deliver 5-ASA in colon.
Azo polymeric new drug
In which use of polymers as drug carriers for drug
delivery to colon .
Synthetic, naturally, sub-synthetic polymers used form
colon targeted polymeric prodrug with azo linkage
between polymer & drug moiety.
The various azo polymers are evaluated for coating
materials over drug core. These are susceptible to
cleavage by azo reductase enzyme.
Coating of protein & peptide drug capsules
crosslinked with azoaromatic group Polymer to
protect drug from degradation in stomach & small
intestine. In colon azo bonds reduced & drug is
1)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.
Sulphasalazine(SASP) is prodrug of 5-ASA. It is conjugated
with sulphapyridine through azo bond.
Sulphasalazine was introduced for the treatment of rheumatoid
arthritis and anti-inflammatory disease.
Carrier moiety conjugated
with 5-amino salicylic acid
Prodrug of 5-amino
p- 4-amino benzoyl-β-
a dimer representing two
molecules of 5-ASA that are
linked via an azo bond
Polysaccharide based delivery system
Polysaccharides offer an alternative substrate for the
bacterial enzymes present in the colon.
Most of them are hydrophilic in nature.
Natural polysaccharides are either modified or mixed
with water insoluble polymers.
Polysaccharides as carriers:
The colonic microflora secretes a number of enzymes that are
capable of hydrolytic cleavage of glycosidic bonds.
These include β-d-glucosidase, β-dgalactosidase, amylase,
pectinase, xylanase, α-d-xylosidase, and dextranases.
Natural polysaccharides like pectin & inulin are not digested in
stomach & small intestine but are degraded in colon by resident
The bacteria converts polysaccharides to gases such as methane,
carbon dioxide, hydrogen & to short chain fatty acids.
These polysaccharides thus have the potential as non-toxic
carriers for colon specific drug delivery.
Time release dosage forms:
Nonbiodegradable polymers are used.
They are generally nonspecific with respect to pH-solubility characteristics and
the employment of these polymers as carrier matrices for colonic delivery often
utilizes a time-dependent mechanism.
This provides an initial lag phase of low or no release during transit through
the upper gastrointestinal tract.
The lag time usually starts after gastric emptying because most of the time-
controlled formulations are enteric coated.
The enteric polymer coat prevents drug release in the stomach.
Drug release from these systems is not pH dependent.
Various polymers used are: polyacrylates, methylcellulose, HPMC, CMC etc.
This system, first described by Shah & co-workers, uses lag time to
achieve colon delivery.
System consist of 3 main parts: An outer enteric coat, inner
semipermeable polymer membrane, and a central core having swelling
excipients and an active component.
The outer enteric coating prevents drug release until the tablet reaches
the small intestine.
In the small intestine, the enteric coating dissolves allowing
gastrointestinal fluids to diffuse through the semipermeable membrane
into the core.
The core swells until after a period of 4–6 h, when it bursts, and releases
the active component in the colon.
TIME CLOCK® SYSTEM
TIME CLOCK® SYSTEM
Solid dosage form coated
with lipid barriers containing
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
pH or digestive state of the
Wax coating with
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.
Patient compliance and treatment efficacy
Useful in treatment of ulcerative colitis, crohn's disease,
irritable bowel syndrome and carcinomas
Low dose is required ,so less side effect
Used for local and systemic action
Gastric irritation can be avoided
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.
Some micro flora may degrade the drug.
Small luminal surface area and relative tightness of
tight Junctions in colon, delay the systemic absorption.
Onset of action is slow.
1. Ulcerative colitis.
2. CHRON'S disease.
3. Irritable bowel syndrome.
4. Metastatic human colon cancer.
1. Molecules degraded/poorly absorbed from upper G.I.T
such as peptides and proteins are better absorbed from
2. For achieving chemotherapy for diseases that are
sensitive to circadian rhythm such as Asthma, angina,
The OROS-CT (Alza corporation) can be used to target the drug
locally to the colon for the treatment of disease or to achieve systemic
The OROS-CT system can be a single osmotic unit or may
incorporate as many as 5-6 push-pull units, each 4 mm in diameter,
encapsulated within a hard gelatin capsule.
For treating ulcerative colitis, each push pull unit is designed with a
3-4 h post gastric delay to prevent drug delivery in the small intestine.
Drug release begins when the unit reaches the colon.
OROS-CT units can maintain a constant release rate for up to 24
hours in the colon or can deliver drug over a period as short as four
Osmotic Controlled Drug Delivery (ORDS-CT)
Depend up on the osmotic pressure
exerted by osmogens on drug
compartment with which though drug
get released slowly through the
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
Disease Drug content
1) Mesacol tablet Sun pharma,
2) SAZO Wallace , India Ulcerative
3) BUSCOPAN German
4) Entofoam Cipla, India Ulcerative
For evaluation, not any standardized evaluation technique is available
for evaluation of CDDS because an ideal in vitro model should posses
the in-vivo conditions of GIT such as pH, volume, stirring, bacteria,
enzymes, enzyme activity, and other components of food.
These conditions are influenced by the diet, physical stress, and these
factors make it difficult to design a standard in-vitro model.
1. In vitro dissolution study
2. In vitro enzymatic degradation test
3. Relative colonic tissue exposure
4. Relative systemic exposure to drugs
6. Magnetic moment imaging study
7. Drug delivery index
8. High frequency capsule
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,
• Drug release study in 0.1 N HCl for 2 hours (mean gastric emptying
• Drug release study in phosphate buffer for 3 hours (mean small
intestine transit time PH 6.8)
These dissolution studies can be carried out by using paddle or basket
or flow through dissolution apparatus.
Dissolution of CDDS is usually complex, dissolution
Describe in USP
Disso. Carried out by conventional basket method.
Dissolution tests for CDDS in different media simulating pH
condition & times likely to be encountered at various
location in GI tract.
Following media were used-
pH 1.2 to simulate gastric fluid.
pH 6.8 to simulate jejunal region of small intestine.
pH 7.2 to simulate ileum segment.
Enteric coated CDDS studied in gradient disso. Study in 3
buffer systems. 2 hr at pH 1.2, then 1 hr at pH 6.8& finally
at pH 7.4
BioDis-III (Apparatus III)
• Ideal for the dissolution profiling of extended release
• It is designed to meet or exceed current USP specification.
• It used a reciprocating motion to dip the inner tube into
• At the designated time, the entire row of inner tubes
raises and moves to the next row of media.
• Capable of running unattended upto 6 days and can store upto 25
• 7 sample tubes which automatically traverse upto 6 rows of
corresponding outer tubes filled with different media.
• With accessories, the appropriate media volume can vary from 100,
300 ml (USP) or 1000 ml.
In vitro enzymatic degradation test
Drug release in buffer medium containing enzymes(e.g.pectinase, dextranase) or
rat or guinea pig or rabbit decal contents
Amount of drug release in particular time directly proportional to the rate of
degradation of polymer carrier.
Incubating carrier drug system in fermenter
Suitable medium containing colonic bacteria (streptococcus faecium or B.ovatus)
Amount of drug released at different time intervels determined.
B R Nahata College of Pharmacy
2 In vivo methods:
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.
Techniques which are used for monitoring the in vivo behavior of
colon targeted drug delivery are
String technique : In these studies, a tablet was 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 was withdrawn from the stomach
by pulling out the string and physically examining the tablet for the
signs of disintegration.
It is an optical technique in which a fiber scope (gastro scope) is
used to directly monitor the behavior of the dosage form after
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.
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.
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.
The most useful technique, to evaluate the in vivo behavior of dosage
forms in animals and humans is external scintigraphy or gamma
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
neutron activation methods.