COLON SPECIFIC DRUG DELIVERY SYSTEM

• Targeted drug delivery implies selective and effective localization of drug into the target
at therapeutic concentrations with limited access to no-target sites.
• A targeted drug delivery system is preferred in drugs having instability, low-solubility and
short half-life.
• Colon is used as site of Targeted drug delivery.
• Colon was considered as a BLACK-BOX, as most of the drugs are absorbed from the upper
part of the GI tract.
• Definition: -Colon drug delivery system refers to targeted delivery of drug into the lower
parts of GI tract, mainly large intestine.
• Inflammatory bowel diseases including irritable bowel syndrome, ulcerative colitis and
Crohn’s disease are considered as serious colonic disorders.

Advantages of colon targeting drug delivery system

➢ Colon is an ideal site for the delivery of agents to cure the local diseases of the colon.
➢ Local treatment has the advantage of requiring smaller drug quantities.
➢ Reduces dosage frequency. Hence, lower cost of expensive drugs.
➢ Possibly leading to a reduced incidence of side effects and drug interactions.
➢ The colon is an attractive site where poorly absorbed drug molecules may have an
improved bioavailability.
➢ Reduce gastric irritation caused by many drugs (e.g. NSAIDS).
➢ Bye pass initial first pass metabolism.
➢ Extended daytime or night-time activity.
➢ Improve patient compliance.
➢ Targeted drug delivery system.
➢ It has a longer retention time and appears highly responsive to agents that enhance the
absorption of poorly absorbed drugs.
➢ It has low hostile environment, less peptidase activity so peptides, oral vaccines, insulin,
growth hormones, can be given through this route
Limitations of colon targeting drug delivery system
➢ Multiple manufacturing steps.
➢ The resident microflora could also affect colonic performance via metabolic degradation
of the drug.
➢ Incomplete release of drug.
➢ 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.
➢ Drug should be in solution form before absorption and there for rate limiting step for poor
soluble drugs.
➢ Non-availability of an appropriate dissolution testing method to evaluate the dosage
form in-vitro.
➢ An important limitation of the pH sensitive coating technique is the uncertainty of the
location and environment in which the coating may start to dissolve. Normal in patients
with ulcerative colitis

Why to target colon?

➢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 appropriate concentration.

➢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 include, a) Delivery of
drug in its intact form as close as possible to the target site. b) The ability to cut down the
conventional dose. c) Reduced incidence of adverse side effects.

➢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 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.

Factors to be considered in the design of CSDDS:

➢Anatomy and physiology of colon.
➢PH in the colon. ➢Gastrointestinal transit. ➢Colonic microflora
Anatomy and Physiology of Colon
Structure of Colon
Colon is the lower part of the gastrointestinal tract and runs from ileocecal junction to the anus.
It includes proximal part (ascending colon), transverse colon, descending colon, sigmoid colon,
rectum and anus
In contrast with small intestine surface area of colon is low but effective absorption take place
due to presence of villi, microvilli and long residence time. The colon is cylindrical tube which is
lined by moist, soft pink lining called mucosa and it is 2 – 3 inches in diameter. The colon and
rectum have an anatomic blood supply. Lymph nodes are also present with blood vessels.

Blood supply
➢For proximal colon it is from superior mesenteric artery and inferior mesenteric artery supplies
blood to distal colon. ➢The venous drainage is via superior veins for proximal colon and inferior
veins for distal colon.

Functions of Colon
1.Suitable site and environment for the growth of colonic microorganism.
a. These bacteria are very rich in cytochrome. The normal flora of the large intestine prevents
the growth of other pathogenic bacteria and serves a useful purpose.
b. Some bacteria can breakdown cellulose. it has been concluded that people suffering from
constipation can breakdown cellulose more than normal ones, thus reducing the bulk
2.Formation of stool and storage reservoir of facial contents.
3.Absorption of potassium and water from lumen resulting in formation of facial content. Saline,
glucose, some anaesthetics, amino acid are better absorbed here.
4.Secretion and excretion of potassium and bicarbonate, bismuth, mercury, arsenic, etc.
5.Synthesis function: microorganism in colon synthesizes vitamin k, folic acid

pH of Various Area of Gastrointestinal Region

➢Radio telemetry has been used to measure the gastro-intestinal pH in healthy subjects.
➢On entry into the colon, the pH drops to 6.4±0.6. The pH in the mid colon is 6.6±0.8 and in the
left colon 7.0±0.716.

➢There is a fall in pH on entry into the colon due to the presence of short chain fatty acids arising
from bacterial fermentation of polysaccharides. For example; Lactose is fermented by the colonic
bacteria to produce large amounts of lactic acid resulting in pH drop to about 5.0.
DRUG ABSORPTION FROM COLON
Drugs are absorbed passively by either paracellular or transcellular route. Transcellular
absorption involves the passage of drugs through cells and this is the route most lipophilic drugs
takes, where paracellular absorption involves the transport of drug through the tight junction
between cells and is the route most hydrophilic drug takes. The poor paracellular absorption of
many drugs in the colon is due to the fact that epithelial cell junctions are very tight. The slow
rate if transit in colon lets the drug stay in contact with the mucosa for a longer period than in
small intestine which compensates the much lower surface area. The colonic 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 dissolved drug through the mucosa.
Theoretically, drug absorption can occur along the entire GI tract, while in actuality, most drugs
are absorbed in the duodenum and proximal jejunum

➢The colon mucosa lacks well defined villi as found in small intestine this reduces absorption
surface area. But the long transit time of compensate it. ➢However the factors like viscosity,
specific and nonspecific drug binding to dietary components and products released from colon
bacteria and lipid bilayer of the individual colonocyte and complex junction between the cells
are the physical barrier to the drug absorption. ➢To overcome absorption problems, absorption
enhancers are used.

Absorption enhancers: These are compounds which promotes absorption at colon. ➢They act
by: 1) disruption of intercellular junctional complex to open the paracellular route. 2)Modifying
epithelial permeability via denaturing membrane proteins or modifying lipid-protein
interactions. 3)Disrupting the integrity of lipid bilayer of colonic enterocytes. Examples:
a) Nonsteroidal Anti-inflammatory agents: Indomethacin, salicylates.
b) Surfactants: polyoxyethylene lauryl ether.
c)Fatty Acids: sodium caprate, sodium caprylate, sodium laurate.
d)Mixed micelles: Monoolein-taurocholate, oleic acid –taurocholate.
e) Other agents: Acylcarnitine, phenothiazines, dicarboxylic acids
APPROACHES FOR COLON TARGETED DRUG DELIVERY SYSTEM
1. PRIMARY APPROACHES
2. NEW APPROACHES
PH SENSITIVE POLYMER COATED SYSTEM
This system is based on solubility of different polymers at different PH range, as the PH varies at
different parts of GIT
Polymers are insoluble at lower PH & get solubilised as the PH increases i.e., colon So formulation
can be protected in stomach & to some extent in Small intestine

The intact molecule can be delivered to the colon without absorbing at the upper part of the
intestine by coating of the drug molecule with the suitable polymers, which degrade only in the
colon. The drug core includes tablets, capsules, pellets, granules, microparticles or nanoparticles.
The coating of pH-sensitive polymers to the tablets, capsules or pellets provide delayed release
and protect the active drug from gastric fluid. The polymers used for colon targeting, however,
should be able to withstand the lower pH values of the stomach and of the proximal part of the
small intestine and also be able to disintegrate at the neutral of slightly alkaline pH of the
terminal ileum and preferably at the ileocecal junction. The majority of enteric and colon
targeted delivery systems are based on the coating of tablets or pellets, which are filled into
conventional hard gelatin capsules
Disadvantages of this method are: a) Lack of consistency in the dissolution of the polymer at the
desired site. b) Lack of site specificity of pH dependent systems.

TIME DEPENDENT DELIVERY:

➢Time dependent/controlled release system (TCRS) such as sustained or delayed release dosage
forms are also very promising drug release systems.

➢Enteric coated time-release press coated (ETP) tablets, are composed of three components, a
drug containing core tablet (rapid release function). ➢The press coated swellable hydrophobic
polymer layer (Hydroxy propyl cellulose layer (HPC), time release function) and an enteric
coating layer (acid resistance function).

➢The tablet does not release the drug in the stomach due to the acid resistance of the outer
enteric coating layer.

➢After gastric emptying, the enteric coating layer rapidly dissolves and the intestinal fluid
begins to slowly erode the press coated polymer (HPC) layer➢. When the erosion front reaches
the core tablet, rapid drug release occurs since the erosion process takes a long time as there is
no drug release period (lag phase) after gastric emptying. ➢The duration of lag phase is
controlled either by the weight or composition of the polymer layer (HPC)
Microbially triggered system
These systems are based on the exploitation of the specific enzymatic activity of the microflora
(enterobacteria) present in the colon. The colonic bacteria are predominately anaerobic in
nature and secrete enzymes that are capable of metabolizing substrates such as carbohydrates
and proteins that escape the digestion in the upper GIT
For the fermentation, the micro flora produces a vast number of enzymes xylosidase,
arabinosidase, like glucoronidase, galactosidase, nitroreductase, azareducatase, deaminase,
and urea dehydroxylase. Because of the presence of the biodegradable enzymes only in the
colon, the use of biodegradable polymers for colon-specific drug delivery seems to be a more
site-specific approach as compared to other approaches. These polymers shield the drug from
the environments of stomach and small intestine, and are able to deliver the drug to the colon.
On reaching the colon, they undergo assimilation by micro-organism, or degradation by enzyme
or break down of the polymer back bone leading to a subsequent reduction in their molecular
weight and thereby loss of mechanical strength. They are then unable to hold the drug entity
any longer.
The majority of bacteria are present in the colon they are distributed throughout the GI tract.
Endogenous and exogenous substrates, such as carbohydrates and proteins, escape digestion in
the upper GI tract but are metabolized by the enzymes secreted by colonic bacteria.

➢This system includes:

a) coating with biodegradable azo-polymer.
b) prodrugs. c) hydrogels. d) polysaccharides as carriers
a. coating with biodegradable azo polymers:
The azo polymers are having high degree of hydrophilicity were degraded by colonic bacteria.
Examples: Divinyl azobenzene and substituted diamino benzene. Drugs used are insulin and
vasopressin.
b. Prodrug:
Prodrug is defined as an inert drug that becomes active only after it is transformed or
metabolized by the body. Covalent linkage is formed between drug and carrier, which upon oral
administration reaches colon without being absorbed from upper part of GIT. In the colon drug
release is triggered by high activity of certain enzymes in comparison to stomach and small
intestine.
A well-known colon specific prodrug, sulfasalazine used in ulcerative colitis & Crohn’s disease.

➢ Sulfasalazine is chemically 5-aminosalicylic acid coupled with sulfapyridine by azobonding

PRODRUG APPROACH
Prodrug is inactive form of parent drug that undergoes enzymatic transformation to release the
active drug Prodrugs are prepared by linking the active drug with hydrophobic moieties like
amino acids, glucose Most widely used prodrug approaches are

➢Azo prodrugs ➢Dextran prodrugs ➢Cyclodextrins prodrugs ➢Glycoside prodrugs

Hydrogels:
➢The hydrogels contain acidic co-monomers and enzymatically degradable azo-aromatic cross-
links.

➢In acidic pH gel has low degree of swelling which protects degradation of drug from stomach
enzyme.

➢On entering colon, gels reach the degree of swelling which makes crosslinks accessible to
enzyme.

➢Crosslinks are degraded and drug is released from disintegrating gels.

POLYSACCHARIDE BASED DRUG DELIVERY SYSTEM
The polysaccharide which is polymer of monosaccharide retains their integrity, because they are
resistant to digestive action of GI enzymes, matrices of polysaccharides are assessed to remain
intact in physiological environment of stomach and small intestine, as they reach colon, they are
acted upon bacterial polysaccharidases and results in degradation of the matrixes. Family of
natural polysaccharide has appeal to area of drug delivery as it comprised of polymer with large
number of derivitizable groups, with wide range of molecular weight, varying chemical
composition and form most low toxicity and biodegradability, yet a high stability
Polysaccharides naturally occurring in plant (e.g., pectin, guar gum, inulin), animal (e.g.,
chitosan, chondroitin sulfate), algal (e.g., alginates), or microbial (e.g., dextran) origins were
studied for colon targeting. These are broken down by the colonic microflora to simple
saccharides by saccharolytic species like bacteroides and bifidobacteria. Hydrolysis of the
glycosidic linkages on arrival in the colon triggers the release of the entrapped bioactive.
Although specifically degraded in the colon, many of these polymers are hydrophilic in nature,
and swell under exposure to upper GI conditions, which leads to premature drug release. To
overcome this problem, the natural polysaccharides are chemically modified and mixed with
hydrophobic water insoluble polymers, whereas in the case of formulations they are usually
coated with pH sensitive polymers.
Pressure controlled system
The digestive processes within the GIT involve contractile activity of the stomach and peristaltic
movements for propulsion of intestinal contents. In the large intestine, the contents are moved
from one part to the next, as from the ascending to the transverse colon by forcible peristaltic
movements commonly termed as mass peristalsis
These strong peristaltic waves in the colon are of short duration, occurring only three to four
times a day. However, they temporarily increase the luminal pressure within the colon, which
forms the basis for design of pressure-controlled systems. The luminal pressure resulting from
peristaltic motion is higher in the colon compared to pressure in the small intestine, which is
attributed to the difference in the viscosity of luminal contents
In the stomach and small intestine, contents are fluidic because of abundant water in digestive
juices, but in the colon, the viscosity of the content is significantly increased due to reabsorption
of water from the lumen and formation of feces
Osmotically controlled system
There are two OROS systems for colon drug delivery:
a. Osmet pump: It consists of an enteric coated semi-permeable shell which encloses an osmotic
layer along with a central impermeable and collapsible reservoir filled with drug. The interior of
this compartment is connected with the external environment through a delivery orifice at one
end. After dissolution of the gastric-resistant film, water is allowed to penetrate through the
semi-permeable membrane, thus raising the pressure inside the device. Which cause inner
reservoir to shrinks and drug formulation to pump out.
b. OROS CT: Immediately after ingestion, the hard gelatin capsule shell dissolves. The push and
pull unit are prevented from absorbing water in the acidic medium of stomach by enteric
coating. The osmotic pumping action results when the coating dissolves in the drug is delivered
out of the orifice at a rate controlled by the rate of water transport across the membrane.
Alza Corporation developed OROS-CT an osmotically controlled dosage form. It can be used to
target the drug locally to the colon for the management of diseases, which are not responding
to the systemically absorbed drug. It can be made up of single unit or may incorporate as many
as 5-6 push pull units, each with in 4 mm in diameter, encapsulated within hard gelatin capsule.
When it reaches to small intestine the enteric coating gets dissolved and water enters through
the semi-permeable membrane, causing osmogen to swell and the drug compartment gets
converted in to flow.
PULSINCAP:
Pulsincap was the first formulation developed based on time-release principle. It was similar in
appearance to hard gelatin capsule. It consists of water insoluble body water soluble enteric
coated cap. The contents are plased with in body plugged with hydrogel plug. When it is
administered, after predetermined time the enteric coat dissolves and the hydrogel plug starts
to swell.
PORT SYSTEM:
It consists of a gelatin capsule coated with a semi-permeable membrane (e.g., cellulose acetate)
housing an insoluble plug (e.g., lipidic) and an osmotically active agent along with the drug
formulation. When in contact with aqueous medium, water diffuses across the semi-permeable
membrane, resulting in increased inner pressure that ejects the plug after a lag time.
 EVALUATION
For evaluation, not any standardized
evaluation technique is available for
evaluation of CDDS because an ideal in
vitro model should possess 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
5.gamma Scintigraphy
6. Magnetic moment imaging study
7. Drug delivery index
8. High frequency capsule
IN-VITRO EVALUATION

➢ Invitro evaluation includes

i)in vitro dissolution study ii) in vitro enzymatic test
In vitro dissolution study

➢Dissolution is done using conventional basket method in different buffers to characterize the
behaviour of formulations at different PH levels
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 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
IN-VITRO EVALUATION
INVITRO ENZYMATIC TEST ➢ Includes two tests
I) Drug system is incubated in fermenter containing suitable media for bacteria, amount of drug
released at time intervals is determined ii) Drug release study is performed in different buffer
medium containing enzymes or caecal contents

➢ The amount of drug released in a particular time is directly proportional to the rate of
degradation of polymer

IN-VIVO EVALUATION AND CLINICAL EVALUATION

IN-VIVO EVALUATION

➢ It is done in rats, dogs as they resemble anatomical & physiological conditions and microflora
of human GIT
CLINICAL EVALUATION

➢Absorption of drugs from colon can be monitored by colonoscopy and intubations

Fermentation studies

➢For those formulations in which polymers which are specially degraded by the enzymes and
bacteria present in colon. ➢This method is carried out by,
i)By incubating drug delivery system in a buffer medium in the presence of enzymes (e.g.
pectinase).
ii)By incubating drug delivery system in a fermenter with commonly found human colonic
bacteria like streptococcus faecium or Bacteroide ovatus in a suitable medium under anaerobic
conditions

Animal models
➢Rats, mice, pigs and dog’s animal models were reported for colon targeted drug delivery
systems.

➢For simulating the human physiological environment of the colon, appropriate animal model
selection is depending 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 behaviour of colon targeted drug delivery
are String technique, Endoscopy, Radiotelemetry, Roentgenography, Gamma scintigraphy.

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. Endoscope technique:

➢It is an optical technique in which a fiber scope (gastro scope) is used to directly monitor the
behaviour of the dosage form after ingestion.

➢This method requires administration of a mild sedative to facilitate the swallowing of the
endoscopic tube. The sedative alters the gastric emptying and GI motility.

Radiotelemetry:
➢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 affect the
behaviour of the dosage form being studied.

Roentgenography:
➢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 point.

Gamma scintigraphy
➢The most useful technique, to evaluate the in vivo behavior of dosage forms in animals and
humans is external scintigraphy or gamma scintigraphy

➢It requires the presence of a gamma emitting radioactive 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.