Colon: Colon Drug Delivery System

COLON DRUG DELIVERY SYSTEM
COLON
INTRODUCTION
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The colon is the last portion of the digestive system in most vertebrates; it extracts water
and salt from solid wastes before they are eliminated from the body.
In mammals, the colon consists of four sections: the ascending colon, the transverse
colon, the descending colon, and the sigmoid colon. The colon, cecum, and rectum make
up the large intestine.
ANATOMY
The location of the parts of the colon are either in the abdominal cavity or behind it in the
retroperitoneum. The colon in those areas is fixed in location.
Arterial supply to the colon comes from branches of the superior mesenteric artery
(SMA) and inferior mesenteric artery (IMA). Flow between these two systems
communicates via a "marginal artery" that runs parallel to the colon for its entire length.
Historically, it has been believed that the arc of Riolan, or the meandering mesenteric
artery (of Moskowitz), is a variable vessel connecting the proximal SMA to the proximal
IMA that can be extremely important if either vessel is occluded. However, recent studies
conducted with improved imaging technology have questioned the actual existence of
this vessel, with some experts calling for the abolition of the terms from future medical
literature.
Venous drainage usually mirrors colonic arterial supply, with the inferior mesenteric vein
draining into the splenic vein, and the superior mesenteric vein joining the splenic vein to
form the hepatic portal vein that then enters the liver.
Lymphatic drainage from the entire colon and proximal two-thirds of the rectum is to the
paraaortic lymph nodes that then drain into the cisterna chyli. The lymph from the
remaining rectum and anus can either follow the same route, or drain to the internal iliac
and superficial inguinal nodes. The pectinate line only roughly marks this transition.
ASENDING COLON
The ascending colon, on the right side of the abdomen, is about 25 cm long.[2] It is the
part of the colon from the cecum to the hepatic flexure (the turn of the colon by the liver).
It is secondarily retroperitoneal in most humans. In ruminant grazing animals the cecum
empties into the spiral colon.
Anteriorly it is related to the coils of small intestine, the right edge of the greater
omentum, and the anterior abdominal wall. Posteriorly, it is related to the iliacus, the
iliolumbar ligament, the quadratus lumborum, the transverse abdominis, the diaphragm at
the tip of the last rib; the lateral cutaneous, ilioinguinal, and iliohypogastric nerves; the
iliac branches of the iliolumbar vessels, the fourth lumbar artery, and the right kidney.
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The ascending colon is supplied by parasympathetic fibers of the vagus nerve (CN X).
Arterial supply of the ascending colon comes from the ileocolic artery and right colic
artery, both branches of the SMA. While the ileocolic artery is almost always present, the
right colic can be absent in 5–15% of individuals.
TRANSVERSE COLON
The transverse colon is the part of the colon from the hepatic flexure to the splenic
flexure (the turn of the colon by the spleen). The transverse colon hangs off the stomach,
attached to it by a wide band of tissue called the greater omentum. On the posterior side,
the transverse colon is connected to the posterior abdominal wall by a mesentery known
as the transverse mesocolon.
The transverse colon is encased in peritoneum, and is therefore mobile (unlike the parts
of the colon immediately before and after it). Cancers form more frequently further along
the large intestine as the contents become more solid (water is removed) in order to form
feces.
The proximal two-thirds of the transverse colon are perfused by the middle colic artery, a
branch of superior mesenteric artery, while the latter third is supplied by branches of the
inferior mesenteric artery. The "watershed" area between these two blood supplies, which
represents the embryologic division between the midgut and hindgut, is an area sensitive
to ischemia.
DESENDING COLON
The descending colon is the part of the colon from the splenic flexure to the beginning of
the sigmoid colon. The function of the descending colon in the digestive system is to
store food that will be emptied into the rectum. It is retroperitoneal in two-thirds of
humans. In the other third, it has a (usually short) mesentery. The arterial supply comes
via the left colic artery.
SIGMOID COLON
The sigmoid colon is the part of the large intestine after the descending colon and before
the rectum. The name sigmoid means S-shaped (see sigmoid). The walls of the sigmoid
colon are muscular, and contract to increase the pressure inside the colon, causing the
stool to move into the rectum.
The sigmoid colon is supplied with blood from several branches (usually between 2 and
6) of the sigmoid arteries, a branch of the IMA. The IMA terminates as the superior
rectal artery.
Sigmoidoscopy is a common diagnostic technique used to examine the sigmoid colon.
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REDUNDANT COLON
One variation on the normal anatomy of the colon occurs when extra loops form,
resulting in a longer than normal organ. This condition, referred to as redundant colon,
typically has no direct major health consequences, though rarely volvulus occurs
resulting in obstruction and requiring immediate medical attention.[3] A significant
indirect health consequence is that use of a standard adult colonoscope is difficult and in
some cases impossible when a redundant colon is present, though specialized variants on
the instrument (including the pediatric variant) are useful in overcoming this problem.[4]
COLONIC TECHNOLOGY
COLONIC DRUG DELIVERY
Targeted delivery of drugs to the colon has been employed to achieve one or
more of four objectives. The desired outcomes can be
1. sustained delivery to reduce dosing frequency
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2. To delay delivery to the colon to achieve high local concentration on the

treatment of diseases of the distal gut.
3. to delay delivery to a time appropriate to treat acute historically
4. to deliver to a region that is less hostile metabolically e.g. to facilitate absorption
of acid and enzymatically labile materials especially peptides.
If a colonic system functioned perfectly it would not release drug in the upper and mid
GIT, but open at the beginning of the large bowel where conditions are more favorable
for the drug dispersion and absorption. More distally low dispersive forces restrict
spread of the formulation. The significant feature of the colon as far as drug delivery is
concerned is that the colon is folded but is devoid of villi an micro villi so the effective
surface area is much less than the small intestine. The mucous thicknesses gradually
increase when moving from proximal to distal end and which reduce to permeability.
The colon is moist rather than wet as it absorbs about 99% of the secreted or swallowed
fluids.
Access to the lower colon is possible via the rectum. However, aesthetic consideration
rules out rectal administration of drugs, at least in most western countries. Is the colon
accessible to insulin via the oral route? To reach the colon after oral ingestion, insulin
would have to make a long trek through the stomach and the small intestine. Protection
must be provided for insulin during the passage to prevent destruction by proteolysis.
Once in the colon, insulin would be exposed to the resident microflora in the colon.
These have been estimating as about 1011or more microorganisms per gram of colonic
contents. Not only is there a possibility that bacterial peptidases would hydrolyze the
insulin, but the intensely anaerobic environment in the colon may reduce the disulfide
bonds in insulin.
The colon does not seem to have a specific absorption mechanism for substances other
than water and electrolytes. The colon functions to recapture the water and sodium
chloride secreted into the upper gut along with enzymes and other intestinal secretory
components. Of the 1.5 to 2.1 of water and the 200 to 250 mmol of sodium chloride
entering the upper intestine in 24h all but 40ml of water and 1mmol of NaCl are
reabsorbed In the colon. 1- deamino-8- D-arginine vasopressin (DDAVP), directly in to
various regions of the rabbit intestine and measured the appernce of the peptides in the
blood. Absorption was greatest from the ileocecal junction between the small intestine
and the colon, and least from other parts of the colon. The duodenum also exhibit
efficient absorption of DDAVP. Kidron etal injected about 45U/kg insulin from the colon
was followed by a greater and longer lasting fall in blood glucose than from the ileum. In
both sites, deoxychoalte enhanced absorption; the soybean typsin inhibitor enhanced the
effect of insulin only in the ileum. Such studies should be done in other species to map
the sites of best absorption of insulin from the GI tract. The available evidence points to
the cecal region of the gut, which is the junction between the small intestine and the
colon, as a likely site for delivery of peptide drugs.
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BASIC REQUIREMENT OF DD TO THE COLORECTAL AREA ARE AS

FOLLOWS:
1. The drugs should be delivered to the colon either in a slow release or targeted
form ingested orally or introduces directly by an enema or rectal suppository.
2. The drugs must overcome the physical barrier of the colonic mucosa.
3. Drug must survive metabolic transformation by numerous bacterial species
resident in the colon which are mainly anaerobes and posses a wide range of
enzymatic activities.
FACTORS THAT INFLUENCE DRUG DELIVERY TO COLORECTAL AREA.

1. The rate of absorption of drugs from the colon is influenced by the rate of
blood flow to and from the absorptive epithelium.
2. Dietary components such as complex carbohydrates trap molecules within
polysaccharide chains.
3. Lipid soluble molecules are readily absorbed by passive diffusion.
4. The rate of gastric emptying and small bowel transit time.
5. Motility pattern of the colon determine the rate of transit through the colon
and hence the residence time of a drug and its absorption.
6. Drug absorption varies according to whether the drug is targeted to the upper
colon, lower colon or the rectum.
GASTROINTESTINAL TRANSIT TO THE COLON
The estimation of the transit time of a dosage form through the various parts of
the GI tract would appear to be simple task. However there are thousands of paper in the
literature dealing with GIT transit time, with differing results.
A simple delivery device to the ileocecal region would consist of a capsule of tablet
coated with an erodible material of a thickness calculated to erode completely in the
transit time from mouth to cecum. Because the transit time has a large range of
variability, there is a finite chance of premature or late exposure may lead to entrapment
of the drug by the formed feces in the colon, with subsequent interference with the free
diffusion of the drug to the luminal wall and diffusion into the blood. In addition, if the
data of Lundin and Vilhardt hold for the human, the drug load would be released into the
region of poor absorption. Because of the variability in transit time, a subtler orocecal
delivery system is needed.
The odds of delivery to the ileocecal region can be increased by taking advantage of two
factors:
1. The high acidity of the stomach and
2. The relative constant time in the small intestine.
The dosage form is coated with an enteric substance that is insoluble in the stomach pH.
But that begins to erode away in the neutral pH of the small intestine. By adjusting the
thickness of erodible layer to be completely gone in 4h the start of the erosion process is
triggered by leaving the acid stomach for the neutral small intestine and is completed by
the means time of arrival of the drug at the ileocecum. Such a system has been tested
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with some success for the oral delivery of drugs of the colon, although the author suggest
that the acrylic coating only dissolves off in the more alkaline of the human colon. This
method relies on a constant transit time through the small intestine and is therefore
subject to uncontrolled factors ranging from the amount and kind of food to the
psychological state of the subject. Moreover the rate of erosion of the polymer is pH
dependent ;changes In the composition of the diet can affect the pH of the intestinal tract
with the risk of premature release of the drug In an alkaline intestine, and of late delivery
in the case of an acidic colon. The pH of the human colon is far from constant.
The colon by virtue of favorable pH and reduced motility, is home to a dense
population of micro organism (over 400 species (1), numbering1011-1012 colony forming
unit per ml of colonic material(2). The presence of a resident micro flora is a highly
specific to environment feature of the colon contrasting markedly with the sparsely
populated upper GIT this difference can be exploited in order to affect site specific drug
release in the colon. The consistently high levels of bacteria in the colon mean that it is
much more reliable than the more variable pH or transit time which have been
investigated for colonic delivery. Prodrugs eg sulphasalzine, which rely on the action of
colonic bacteria to break down an inactive precursor and release the active drug moiety
(mesalazine or 5- aminosalicylic acid), have been in use for many years but are highly
drugs specific and there is a need for the development of a universal system which can
be adapted to a variety of drugs for local and systemic treatment. An amylose based
bacterially triggered system has been developed to fulfill this need .
DEVELOPMENT OF A UNIVERSAL COLONIC DRUGS DELIVERY

SYSTEM
The colonic micro floras reliant on undigested polysaccharides as their energy

source are the producers of large quantity of polysaccharidase enzymes. This has lead to
the identification of polysaccharides as good candidate for colonic drug delivery. A wide
variety of polysaccharides have been shown to be digested by human colonic bacteria but
of these amylose one of the main polysaccharides from starch has shown the most
promise and progress for colonic delivery.
In order to effect colon specific release an amylose based dosage form must first reach
the colon intact. Amylose must therefore resist digestion by the endogenous enzymes of
the pancreas and a proportion of amylose termed “resistant starch” is capable of doing
this digestion of resistant starch by colonic bacteria can still occur due to greater
efficiency of colonic bacterial enzymes. Amylose in its glassy form is a form of resistant
starch and the properties which lend it to colonic drugs delivery.
Amylose due to its tendency to swell in contact with water, cannot be used alone
to control drug delivery. Mixing amylose with a water insoluble polymer such as ethyl
cellulose allows intermingling of polymer chains sufficient to cause a reduction in the
swelling properties of amylose films.
DESCRIPTION OF THE AMYLOSE /ETHYL CELLULOSE

TECHNOLOGY
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Amylose and ethyl cellulose (as an aqueous suspension ) can be mixed and used
as a film coat. This technology is versatile and using conventional fluid bed coating can
be adapted to coat tablets capsules and pellets. Amylose and ethyl cellulose are not
completely miscible and the result Is a heterogeneous film coating In which the amylose
exists interspersed within the polymer. Thus, the film coat is a matrix system in which
the amylose Is behaving as a pore forming agent in that it provides areas within a water
insoluble film that are subject to swelling of enzymatic degradation and drug release will
occur by this route.
RESEARCH AND DEVELOPMENT

In vitro
Through in vitro investigation the system of film coating with amylose
and ethyl cellulose proved capable of controlling drugs release in stimulated gastric and
small intestinal conditions. Through optimization of variables primarily
TABLE 1.
PROPERTY OF GLASSY AMYLOSE THAT ENABLE ITS USE AS A
COLONIC SPECIFIC COATING
Good film forming property
Non toxic
Resistant to pancreatic enzyme digestion
Susceptible to fermentation by bacterial enzymes in the colon
Coating thickness and amylose/ ethyl cellulose ratio, a coating with appropriate
controlled- release characteristics could be development for a variety of drugs glucose 5-
amino salicylic acid propranolol 4- amino Salicyclic acid and prednisolone sodium
metasulphobenzoate
After successful retardation of drugs release in simulated upper GI conditions it

was necessary to establish whether release would occur in the presence of colonic
bacteria. This was done in vitro using human fecal material as a model for the colonic
contents. Colonic bacteria are mainly anaerobic an the anaerobic environment was
provided by batch fermenters in which inoculums of human fecal material(10% w/v on
pH 7.2 buffer media under an atmosphere of nitrogen ) were introduced and drug-
loading dosage form were then added to this. Any amylose present in the film was then
available for digestion by the colonic bacteria and drug release into the fecal media
brought about by permeation through the pores left by amylose was assessed.
Rapid release of drugs in to simulated colonic condition was shown using several
drugs fig below shows the release of 5- amino salicylic acid into control dissolution
systems and colonic conditions thus the amylose/ethyl cellulose coating shows the
desired formulation characteristic for colonic drug delivery.
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Although amylose/ ethyl cellulose coating for pellets or tablets performed well in vitro
the in vivo performance cannot always be predicted. Therefore these systems were
investigated in man by coupling drugs release with gamma scintigraphic methods of
following transit. Since glassy amylose is present in many food stuffs and ethyl cellulose
is generally regarded as safe the clinical trials did not require preclinical safety data.
APPROACHES TO COLONIC DRUG DELIVERY

THROUGH ORAL ROUTE
Oral route generally preferred by the patient than the rectal route. Colon is the most distal
segment of G.I.T. that’s why orally administered drug must retard drug release in the
upper G.I.T. but must release promptly on entry into the distal colonic part. In colon due
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to presence of low fluid volume & viscous nature of luminal content, the drug dissolution
& release from the formulation may vary. Colonic microflora also shows impact on the
stability of released drug. Inspite of these difficulties various approaches & systems have
been developed to target the drug to the colon.
1. pH DEPENDENT DELIVERY – In G.I.T. there is presence of pH gradient which

approximately ranges from 1.2 in stomach, 6.6 in proximal small intestine, 7.5 in
distal intestine & pH of colon is about 6.4. Generally Eudragit S is used for the colon
delivery it dissolves at pH greater than 7.0, which results in premature drug release
from the system. It is concluded that pH of G.I.T. was not a reliable criteria for
colonic targeting. Problem of premature drug release can be overcomes by the use of
Eudragit FS.
Mesalazine tablets coated with Eudragit® L-100 are commercially available as

Claversal®, Salofalk®, Mesasalβ, and Rowasa®. These tablets can effectively
deliver mesalazine to the terminal ileum and proximal colon in patients with
inflammatory bowel disease. Delayed-release tablets containing mesalazine and
coated with Eudragit® S-100 are marketed in a number of countries (Asacol® ). These
tablets dissolve at a pH level of 7 or greater, releasing mesalazine in the terminal
ileum and beyond for topical inflammatory action in the colon. Although this
formulation is generally successful in achieving site-specific delivery of mesalazine,
failure of the coating to dissolve has been reported, with patients observing intact
tablets in their feces.
2. PRESSURE DEPENDENT DELIVERY – The pressure controlled colon delivery

capsule utilizes the increase in pressure of the luminal contents of the colon. Increase
in luminal pressure is due to reabsorption of water in this region. The drug is
dispersed in suppository base & coated with ethyl cellulose for the preparation of
such system. Temperature of body is responsible for suppository base to melt &
increases the volume which forms balloon of ethyl cellulose filled with liquid. This
balloon can withstand with the contraction of small intestine (peristalsis) but ruptures
when subjected to intensive contraction in the colon & contents of thicker viscosity.
This system is used for the production of single unit system.
3. BACTERIA DEPENDENT DELIVERY – In these system colonic bacteria are

utilized to degrade the substrate. The bacterial amount has been estimated about 10 11
per gram in the colon & having around 400 species (anaerobic in nature). Earlier
polymer cross linked with azo aromatic groups was used but due to potential
carcinogenic activity now a days natural polysaccharides are used. Natural
polysaccharides generally undergo premature drug release so they are chemically
modified or mixed with hydrophobic polymers. This polymer shows good film
forming properties, resistant to pancreatic enzymes but they will undergo degradation
due to bacterial enzyme.
4. TIME DEPENDENT DELIVERY (PULSATILE DRUG DELIVERY) - Pulsatile

release systems are formulated to undergo a lag-time of predetermined span of time
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of no release, followed by a rapid & complete release loaded drugs(s). The approach
is based on the principle of delaying the time of drug release until the system transits
from mouth to colon. A lag-time of 5 hours is usually considered sufficient since
small intestine transit is about 3-4 hours, which is relatively constant and hardly
affected by the nature of formulation administered. This system offers many
advantages over conventional oral drug delivery systems like patient compliance,
reduced dosage, and reduced dosage frequency, avoidance of side effects, avoidance
of peak & valley fluctuation, nearly constant drug level at the target site.
PULSATILE SYSTEM –
“A tool to increase therapeutic efficacy of drug”
In recent years considerable attention has been focused on the development of pulsatile
drug delivery system. Delivery system with pulsatile release pattern has gained most
popular form of controlled drug delivery system because conventional systems with a
continuous release are not ideal. Oral controlled drug delivery systems are generally used
due to convenient dosage form & it also releases drug in constant or variable rates. In
these system drug release generally occurs within therapeutic window for prolong period
of time. Hence these systems show sustained release of drug from dosage form.
Advantages of pulsatile drug delivery system
1. Extended daytime or nighttime activity

2. Reduced side effects
3. Reduced dosage frequency
4. Reduction in dose size
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5. Improved patient compliance

6. Lower daily cost to patient due to fewer dosage units are required by the
patient in therapy.
7. Drug adapts to suit circadian rhythms of body functions or diseases.
8. Drug targeting to specific site like colon.
9. Protection of mucosa from irritating drugs.
10. Drug loss is prevented by extensive first pass metabolism.
The oral controlled drug delivery system with continuous release does not show
suitability in various conditions of the body which require pulsatile release of drug
defined as “a pulsatile release profile” & is characterized by a time period of no release
(lag time) followed by a rapid & complete drug release of drug from dosage form.
Conditions requiring pulsatile release includes – A number of hormones like rennin,
aldosterone & cartisole which shows daily fluctuation in their blood levels. These
changes are generally known as circadian rhythm which is responsible for changes in
many functions of the body like activity of liver enzyme, blood pressure, intra-ocular
pressure etc. PH, gastric acid secretion in stomach, gastric emptying & gastric intestinal
blood transfusion . Various diseases are also dependent on the circadian rhythm for
example acute myocardial insufficiency occurs most commonly around 4.00 P.M. &
Epileptic seizures have the highest incidence in the morning, such conditions demands
consideration of diurnal progress of disease rather than maintaining constant plasma drug
level. In these conditions delivery system should be administered at night but it should
release drug at morning time. Some other diseases are bronchial asthma, angina pectoris,
rhumatic disease, ulcer & hypertension also required time dependent delivery. Drugs
responsible for producing biological tolerance also require pulsatile release. These
systems prevent their continuous presence at the biophase. It releases drug after lag time
(time at which drug is required by the body). For drugs required to be targeted in colonic
region (distal organ) the delivery system should prevent release of drug in the upper two
third portions in g.i.t. Drug with idiosyncratic pharmacokinetics or pharmacodynamics or
drugs with extensive first pass metabolism or which show potential food interaction
require pulsatile release of the drug. Some drugs induce nausea or vomiting or some
cause gastric irritation or some undergo degradation in gastric acid medium, all such drug
requires drug release after lag time. Pulsed fashion can be achieved by the enteric coating
of delivery system.
All above conditions are required chronotherapeutics (i.e. precisely time therapy). To
accomplish the objectives & advantages of chronotherapeutics, time controlled pulsatile
drug delivery devices are required they show releasing the right amount at the right time.
Ideal Pulsatile Drug Delivery System
The first pulsatile drug delivery formulation, which released active substance at a
precisely defined time point was formulated in the early 1990s. The aim of the research
was to obtain sigmoidal release pattern. Below drug release profile is for the single pulse
release system.
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Classification of Pulsatile or Time Controlled System
In this review attempt is made to review various time controlled drug delivery system
based on rupturing of membrane or erosion of membrane. Time dependent dosage forms
are formulated to release their drug load after a predetermined lag time. Alternative terms
used are pulsatile release, delayed or sigmoid release. Besides one-pulse systems,
multiple systems release the drug in subsequent pulses. The application of pulsatile
release systems can be advantageous to adapt a drug therapy to chronopharmacological
needs or to target a drug specific site in the gastrointestinal tract, e.g. to the colon . Lag
time of 4-6 hours generally considered sufficient, since small intestine transit is about 3-4
hours, which is relatively constant. Formulation in which drug release is independent of
the environmental factors like PH, enzymatic activity, intestinal motility, pressure etc.
can be achieved by incorporating a lag-time into the formulation equivalent to mouth to
colon transit time. The pulsatile drug delivery systems are of two types –
• Single unit system

• Multiple (pellet system) unit system
Single Unit System
1. Capsular system – Architecture of these systems generally consists of an

insoluble capsule body housing, a drug & a plug. After a predetermined lag-time
plug was removed because it undergoes swelling, erosion or dissolution.
Example: pulsincap R system – In this system a water insoluble body containing
the drug formulation, system is closed with a swell able hydrogel. Plugged
(insoluble but permeable & swellable) at open end . Upon contact with, gastro-
intestinal fluid or dissolution medium the plug swells pushing itself out of the
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capsule after lag-time. Position & dimensions of plug control lag-time. For rapid
release of water insoluble drug effervescent or disintegrating agents are added.
No gastrointestinal irritation can be observed in both human & animal. Plug
material is generally made up of following –
1.
o Swellable materials coated with insoluble but permeable polymer
(polymethacrylates)
o Erodible compressed polymer (HPMC, polyvinyl alcohol, polyethylene
oxide)
o Congealed melted polymer (glyceryl monooleate)
o Enzymatically controlled erodible polymer (pectin)
Disadvantages: These systems show variable gastric residence time & this problem is
overcome by enteric coating.
1. Pulsatile delivery by osmosis – The Port R system consists of gelatin shell filled
with osmotically active ingredient along with drug & also having an insoluble
lipidic plug. Shell is coated with semi permeable membrane (cellulose acetate)
then plugged with insoluble plug as well as system comes in contact with aqueous
medium the water moves across semi-permeable membrane & exert pressure
which remove the plug after lag-time . System shows good in-vivo & in-vitro
correlation in humans & used to deliver methylphenidate to schoolage children
for the treatment of attention deficit hyper activity disorder (ADHD) .
Another system is also based on expendable orifice that contain capsular system in which
liquid drug is absorbed on highly porous particles. Drug releases through orifice of a
semipermeable capsule supported by an expending osmotic layer after the barrier layer is
dissolved.
Still another system is based on delivery by a series of stop. In this system the capsule
contains a drug & water absorptive water engine that are placed in compartment
separated by a movable partition. These stops obstruct the movement of partition but are
overcome in succession when osmotic pressure rises above threshold level.
1. Pulsatile delivery by erosion or solublization of coating – Most of the pulsatile

drug delivery systems are reservoir devices coated with a barrier layer. This
barrier erodes or dissolves after specified lag period & drug is subsequently
released rapidly. The lag time depends on the thickness of the coating layer.
Example: The Time Clock system consists of solid dosage form coated with lipid
barriers such as carnauba wax & beeswax along with surfactants like
polyoxyethylene sorbitan monooleate . When this system comes in contact with
the aqueous medium the coat emulsifies or erodes after the lag-time depending on
the thickness of coat. The lag time of system is independent of the gastrointestinal
motility, PH, enzyme & gastric residence time.
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Advantage: Ease of manufacturing.
Disadvantages: In-vivo variability (food effects which is present in G.I.T.).
In another example the Chronotropic R system consists of solid dosage form coated with
hydrophilic swellable hydroxy propyl methyl cellulose which releases drug after lag-time
depending on thickness of coat & viscosity grade of hydroxypropyl methyl cellulose. The
system is suitable for both tablet & capsule dosage form, both in-vivo & in-vitro lag
times shows good correlation with the applied amount of the hydrophilic retarding
polymer.Multi layered tablet – with the three layered tablet release pattern with two
pulses was obtained, two drug layers are separated by a drug free gellable polymeric
barrier layer (like HPMC, methacrylic & acrylic polymers or polyalcohols).
4. Pulsatile delivery by rupture of membrane – The other class of the reservoir type
pulsatile system is based on rupturable coatings. The drug release from the core occurs
when sorrounding polymeric membrane undergo ruptured due to inbuilt pressure within
system. The effervescent excipients produces gas or osmotic agent produces osmotic
pressure or swelling agent cause swelling, one of these is necessary for rupture of
coating. Citric acid & sodium bicarbonate is incorporated as effervescent mixture in
tablet core coated with ethyl cellulose, when system comes in contact with water it
produces carbon dioxide gas which exerts pressure & after lag time rupture the
membrane & rapid release of drug occurs. A reservoir system with a semi permeable
coating is proposed especially with drugs with high first pass effect in order to obtain in-
vivo drug pattern similar to the administration of several immediate release doses
croscarmellose sodium starch glycollate or low substituted hydroxy propyl cellulose were
used as swelling substances, which resulted in complete film rupture followed by rapid
drug release. The lag time is controlled by composition of outer polymeric membrane
(HPMC water soluble polymer increased permeability decreased lag-time).
Multiparticulate System
Multiparticulate systems are reservoir type of devices with a coating, which either
ruptures or changes its permeability. Drug is coated over sugar seeds these granules may
then be packaged in a capsule or compressed with additional excipients to form a tablet.
The active pharmaceutical ingredient may also be blended or granulated with polymers
before coating to provide an additional level of control. However, drug loading in this
type of system is low due to higher need of excipients.
These systems show various advantages over single unit systems, which includes –
• Short gastric residence time

• Reproducible gastric residence time
• No risk of dose dumping
• Flexible to blend pellets with different composition or release pattern
• Lowest transit time variability
• Unique profiles
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• Amenable to capsule & tablets

• Capable of pulsatile release
Disadvantages –
• Multiple manufacturing steps

• Low drug load
• Incomplete release
1. Pulsatile release by rupturing of membrane – In these multiparticulate system

drug is coated on sugar seeds & then coated with insoluble & swellable top layer
. The swelling agent includes superdisintegrents like carboxy methylcellulose,
sodium starch glycollate, L-hydroxy propyl cellulose. Polymers like polyacrylic
acid, polyethylene glycol etc. alternatively comprising of a mixture of tartaric
acid & sodium bicarbonate that used as effervescent agent. Water ingress to
system causes the coating to swell, rupture & release of drug occurs. Release of
drug is independent of pH or solubility of drug. Lag-time can be varied by
varying thickness of coating or by changing amount of plasticizers in the
outermost layer. If concentration of osmotic agent increases rapid release of drug
after lag-time can be observed. In-vivo studies of time controlled explosion
system with an in-vitro lag-time of three hours showed appearance of drug in
blood after 3 hours, and maximum level after 5 hours.
1. Rupturable coating with osmosis – These system contains core having drug (low
bulk density solid or liquid lipid material) & disintegrant. Core is coated with
cellulose acetate polymer. System is combination of swelling & osmotic effect,
upon immersion in aqueous medium, water penetrates the core, displaces the lipid
material, after depletion of lipid material internal pressure increases until a critical
stress is reached, which causes rupture of coating.
Another type of system is one in which tablet or capsule is composed of large number of
pellets (two or more pellets). Single pellet of this system contains drug plus osmotic
agent & coated with water permeable, water insoluble polymer. In film hydrophobic
agent (water insoluble) is incorporated which alters permeability. The rate of water influx
& drug efflux causes the film coating of each population to differ from any other pellet
coating in the dosage form. Pellet gets swelled due to dissolution of osmotic agent as it
comes in contact with water resulting in regulation of diffusion & release of drug content
from pellet. Each pellet population of system shows this effect. The coating thickness
may vary & this system is used for antihypertensive drug diltiazem. Osmotically active
compound don’t undergo swelling, the use of osmotic active agent was reported by
Shultz & Kleinbudde. The pellet core made up of drug, sodium chloride & coated with
semipermeable cellulose acetate polymer (permeable to water & not to drug). Varying
thickness of coating & amount of plasticizer in coating can vary lag-time of system.
Sodium chloride provides fast release of drug if it is absent in core then a sustained
release was observed after lag-time due to lower degree of swelling & generation of
16 LNCP
small fissures in core. Chen has also reported a system-containing core of drug &
osmotically active agent coated with insoluble permeable membrane.
3. Change in membrane permeability based pulsatile release – The permeability & water
uptake of acrylic polymers with quaternary ammonium groups can be influenced by the
presence of different counter ions. Several delivery system with sigmoidal or pulsatile
release based on these ion exchange have been developed Eudragit RS 30D is polymer of
choice, it contains positively polarized quaternary ammonium group in the polymer side
chain & also negative hydro chloride counter ions. The ammonium group is hydrophilic
causes interaction with water & changes in permeability of it in controlled manner. In
these system core containing drug & sodium acetate coated with four different layer of
Eudragit RS30D. Small amount of sodium acetate dramatically change the permeability
of eudragit film. After lagtime permeability increases due to increase in interaction
between eudragit & acetate, resulting in entire drug release within few minutes. Increase
in lag-time occurs as thickness increases but it has no effect on release.
Sigmoidal release system consists of drug & succinic acid core coated with ammonio-
methacrylate copolymer USP/NF TYPE B. The lag-time is controlled by the rate of water
influx through polymer membrane. Succinic acid dissolves by the water causes increase
in permeability of hydrated polymer film that increases free volume. These findings were
used to design acid containing core that is coated by polymeric membrane.
DRUG METABOLISM IN THE COLON

Metabolism rection in the liver and the small intestine are well documented.
However only sparse information is available on drug metabolism in the colon. Drug
metabolism is the colon can be brought about by the host enzymes in the epithetical cells
or by the microbial enzymes in the gut flora. Metabolic activates in the wall of the colon
can be attributed to cytochrome P450 esterase amidase and various transferse. Reductive
drug metabolism does not appear to be important at this site.
17 LNCP
The colonic mucosa resembles the small intestinal mucosa with respect to the
spectrum of metabolizing enzymes. However the total metabolic capacity of the colonic
wall is inferior because the mucosal mass in the lower part. This may be more than offset
by the high metabolic capacity found in the gut flora in the large intestine.
The GIT contains a variety of micro organism that participate in the metabolism
of ingested material. The upper part contains only a small number of primarily GM
+TIVE bacteria whereas the colon contain a vast amount of primarily anaerobic bacteria
with Bacteriods, Bifidobacterium And Eubacterium beign the most common species
found. Gram positive cocci such as clostridium enterococci and various species of
enterobacteriaceae are also present. The growth of the bacteria is regulated by gastric
acids peristaltic activity and microbial interaction including bacterial metabolic
byproduct administration of antibiotic as well as onset of disease and age can affect the
metabolic activity of the intestinal microflora. Redox reaction and hydrolysis are the
predominant metabolic conversion triggered by the intestinal microflora are
nitroreductase deaminase urea dehyroxylase and azoreductase. The hydrolytic enzymes
are β -glucuronidase and xylosidase and galactosidase and arabinosidase.
The unique enzymatic features of the microbial flora present in the colon make it
conducive for drug targeting. Active metabolites intended for local therapy can be
liberated from poorly absorbed parent molecules by microbial processes. An advantage
can also be taken for release of drugs from delivery system disintegration only by the
action of microbial enzyme as a means for targeted delivery. This approach is suitable for
drugs molecules that are unstable in the upper part of the GIT but can be absorbed from
the lower part.
Amino acids consisting of polar groups like -NH2 and -COOH have been used as
carriers for colon-targeted drug delivery. These prodrugs were designed to be bulky and
hydrophilic to remain unabsorbed in the upper GIT. However, the intestinal microflora of
the colon hydrolyzed the drug-amino acid conjugate and the drug was released free into
the lumen of the colon. . Another type of conjugates is that the glucuronide conjugates
where glucuronic aid is conjugated to the drug moiety. These conjugates were stable in
the upper GIT and glucuronidase in the colon hydrolyze this linkage releasing the free
drug in the colon. An example for drugs, which are involved in such glucuronide linkage
includes Nalaxone/Nalmefene, Budenoside, and Dexamethasone. Sugar moieties like
glucose, galactose, and cellobiose have also been conjugated to drug moieties to form
glycosides. These linkages were found to be selectively hydrolyzed by glucosidase,
galactosidase, and cellobiosidase enzymes of bacteria in the cecum and colon. Dextran
ester prodrugs were prepared by covalently attaching methylprednisolone and
dexamethasone to dextran by the use of a succinate linker.
ENZYMES MICROORGANISM REACTION CATALYZED
Reduces AR and hetronitro cyclic

Nitroreductase E.coli, Bacteroids
compounds.
18 LNCP
Clostridia, Lactobacilli, E.
Azoreductase Reductive cleavage of azo compound.
coli
N-oxide reductase,
E. coli Reduce N-oxide and sulpoxides
sulfoxide reductase
Reduce carbonyl groups and
Hydrogenase Clostridia, Lactobacilli
aliphatic double bonds
Esterase and E.coli P. vulgaris, B. Cleavage of ester or amidases of
amidase subtilis, B. mycoides COOH acids
Cleavage of β -gylcosidase of
Glucosidase Clostridia, Eubacteria
alcohols and phenols.
Cleavage of β -glucuronidase of
Glucuronidase E. coli A. aerogenes
alcohols and phenols
Eubacteria clostridia, Cleavage of O-sulfates and
Sulfatase
strptococci sulphamates
BIOPOLYMER FOR COLONIC DELIVERY

Conventional controlled release products for oral administration normally lack
any unique property which would facilitate drug targeting to a specific location in the
19 LNCP
GIT. In view of the time course of GI transit, any slow release system having a drug
release time profile extending beyond 6-8 hrs is likely to be present in the colon for
release of a high proportion of the drugs payload. If the formulation has the appropriate
dissolution control the colon capable of absorbing the drugs and the half life sufficient to
achieve therapeutic concentrations the plasma concentration can be maintained for longer
following each dose. Biopolymer is mainly plant based polysaccharides which are
digested by the gut wall. As a consequence such materials particularly those which have
pronounced swelling properties have been frequently employed in the formulation of
controlled drug release products and are especially valuable as the basis for colonic drug
delivery systems.
GUAR GUM
Guar gum is a galactomannan polysaccharide [β -1,4 D-mannose,α -1,6 D-

galactose] having (1 4 ) linkages. It has a side branching unit of monomeric D-
galactopyranose joined at alternate mannose unit by (16) linkage. It has low water
solubility but hydrates and swells in cold water forming viscous colloidal dispersion or
sols. Rubinstein and gliko-kabir reported cross linking of gaur gum with borax to
enhanced its drug retaining capacity. The gum is susceptible to bacterial galatomannases
present in the large intestine an the viscosity of a gaur gum solution incubated with a
homogenate of faeces was shown to reduce by 75% over 40 mins.
Guar gum is commonly used with other biopolymer. Sinha and kumria used
xanthan gum an guar gum as a compression coat with a XG:GG ration of (20:10) and
10:20 ration to deliver 5- fluorouracil to the colon. Further studies followed the GI
behavior of these mixtures XG:GG (10:20) mixture by incorporation of 99mTc-DTPA into
solid dosage form. Following administration to six volunteer the tablet were found to
disintegrate on the ascending colon disintegration of the tablet started between 4-6 hrs
post dose in the entire volunteer with a further spread of tracer into the ascending
transverse and descending and sigmoid colon.
CHONDROITIN SULFATE
20 LNCP
Chondroitin sulfate is a souble mucopolysaccharide consisting β -13,D-glucuronic acid

linked to N-acetyl –D-galactosamide. It is a substrate for the bacteroides sp in the large
intestine. Natural chondrotin sulfate is readily water souble and may not be able to
sustain the release of most drugs from the matrix. Rubinstein and co-worker has reported
the use of cross linked chondroitin sulfate as a carrier for indomethacin specifically for
the large bowel. Since natural chondroitin sulfate is readily water soluble it was cross
linked with 1-12- diaminodocane. The cross linking reaction was between the carboxyl
group in chondrointin and the amino group in diaminodocane resulting in formation of a
dimmer of chondrotin sulfate. The cross linked polymer was blended with indomethcin
and compressed into tablet.
PECTIN
It is a heterogeneous polysaccharide composed mainly of galacturonic acid and its

methyl ester. In human nutrition it is one of the most important sources of dietary fiber
and is a constitute of fruit and vegetable cell walls. It is composed mainly of long linear
chains α -1,4 Dgalactose an L-arabinose side chain. It remains intact in stomach and
small intestine but is degraded by colonic bacterial enzyme which appear to work in
concert. Pectin with high degree of methoxylation can be employed for colonic drug
delivery however the material is poorly compactable on its own with a high degree of
fragmentation some elastic but little plastic deformation. Mura and colleagues overcame
these limitation in the formulation of a theophylline matrix tablet by combination of the
pectin with a hydrophilic direct compression agent a coated the tablet with EUDRAGIT
21 LNCP
S100. At high conc. Of EMDEX the tablet increase in hardness but dissolution rate
increases suggestion that the EMDEX acts as a channeling agent through the gel.
Pectin with low degree of methoxyltion can be cross linked with a carefully controlled
amount of a divalent cation typically calcium. In common with many other polymers,
calcium or zinc stabilizes pectin an other linear polysaccharides by bridging across the
molecule in a conformation often refer to as an “EGGBOX”. These prevent chain
repulsion. Calcium appears to have the ideal elemental dimension for this type of
interaction which occurs In plants walls. If the pectin is heavily methoxylted this
interaction cannot occur.
Pectin is a poor film former and other polymers including HPMC chitosan and ethyl
cellulose are often used in combination.
DEXTRAN
22 LNCP
It is a polysaccharide consisting of α -1,6 D-glucose and α -1,4- D glucose units Dextran

hydrogels are stable when incubated at 370C with the small intestinal enzymes
amyloglucodase invertase and pancreatine. However they are degraded by dextrananses
which is a microbial enzyme found in the colon. Gels have been prepared with
diisocayante. These hydrogel are characterized by equillubrium degree of swelling and
mechanical strength. Release of entrapped hydrocortisone was found to depen on the
presence of dextranases in the release medium.
Researcher have oxidized dextran using sodium periodate and coupled the Aldehyde
product with the alpha amino group of 5- amino salicylic acid. It was reported that
dextran having 93% of degree of oxidation yielded the maximum 5-ASA which were
resistant to dextranase hydrolysis.
INULIN
Inulin is a naturally occurring glucofructan which
can resist hydrolysis and digestion in the upper
GIT. It is fermented by colonic microflora. Inulin
with a high degree of polymerization was
formulated as a biodegradable colon specific
coating by suspending it in eudragit RS films. The
films withstand gastric and intestinal fluids but
were degraded by the fecal degradation medium.
``
OTHER MATERIAL
23 LNCP
STARCH
CHITOSAN
NONBIODEGRADEABLE SWELLING POLYMERS
Non biodegradable polymers are more frequently employed In controlled release

system rather than in targeted colonic delivery. These polymers are frequently synthetic
and undergo dissolution or disintegration in the GIT without undergoing significant
absorption or degradation. They are generally nonspecific carriers systems employment
of these polymers as carriers matrices for colonic delivery may require a pH or time
dependent coat for colon specificity. Hence products have been commonly formulated
contain such polymers in a drug core, followed by application of an enteric polymer coat
for controlling drug release in the stomach and the upper intestine.
The solubility characteristic of the active substance can also play an important
role. If a drug has high and pH dependent solubility profile the selection of polymer
system for targeted drug delivery, particularly to the colon is an extremely challenging
task. Such matrices tend to release the drug, partially or significant in the stomach and
the small intestine increased application of the polymer may cause incomplete drug
release in the colon. Drugs having poor solubility may have intrinsic problems in
absorption from the water deficient colon.
Nonbiodegradable swelling polymer do not undergo any cleavage by enzymes of

microbes present in the lumen. The prominent example include the cellulose ethers and
24 LNCP
the cross linked polysaccharides. Among the cellulose loses there are various grades of
HPMC based on upon viscosity which are commercially marketed under the trade name
METHOCEL®
FORMULATION
Drug Trade Name Coating Polymer / Formulation
Budesonide Entrocort® Eudragit® L 100-55, ethylcellulose

Budenofalk® Eudragit® S (Dissolution pH-7)
Targit® Coated Starch Capsule
Claversal®
Mesalazine Asacolitin® Eudragit® L100 (Dissolution pH-6)
Salofalk® Eudragit® S (Dissolution pH-7)
Pentasa® Eudragit® S (Dissolution pH-6)
Mesazal® Ethyl cellulose coated pellets
Calitofalk® Eudragit® L100 (Dissolution pH-6)
Asacol ® Eudragit® L100 (Dissolution pH-6)
Eudragit® S (Dissolution pH-7)
Sulfasalazine Azulfidine® Cellulose acetate phthalate (Dissolution pH-
Colo-Pleon® 6.2-6.5)
Eudragit ® L100-55 (Dissolution pH-5.5)
PLATFORM TECHNOLOGIES FOR CTDDS
25 LNCP
PULSINCAP
OROS-CT
CODESTM
PORT® SYSTEM
TIME CLOCK® SYSTEM
CHRONOTROPIC® SYSTEM
COLAL-PRED™
TARGIT™TECHNOLOGY
ENTERIONTM CAPSULE
TICKING CAPSULE
26 LNCP
27 LNCP
28 LNCP
CONCLUSION
29 LNCP
Colonic drug delivery is one of the major challenges.
Management of Local pathologies requires efforts in decreasing or

eliminating side effects.
Conventional dosage forms need to be drastically improved in

their design.
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
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30 LNCP
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33 LNCP

Colon: Colon Drug Delivery System

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COLON DRUG DELIVERY SYSTEM

Sigmoidoscopy is a common diagnostic technique used to examine the sigmoid colon.

2. To delay delivery to the colon to achieve high local concentration on the

BASIC REQUIREMENT OF DD TO THE COLORECTAL AREA ARE AS

FACTORS THAT INFLUENCE DRUG DELIVERY TO COLORECTAL AREA.

GASTROINTESTINAL TRANSIT TO THE COLON

DEVELOPMENT OF A UNIVERSAL COLONIC DRUGS DELIVERY

The colonic micro floras reliant on undigested polysaccharides as their energy

DESCRIPTION OF THE AMYLOSE /ETHYL CELLULOSE

RESEARCH AND DEVELOPMENT

After successful retardation of drugs release in simulated upper GI conditions it

APPROACHES TO COLONIC DRUG DELIVERY

1. pH DEPENDENT DELIVERY – In G.I.T. there is presence of pH gradient which

Mesalazine tablets coated with Eudragit® L-100 are commercially available as

2. PRESSURE DEPENDENT DELIVERY – The pressure controlled colon delivery

3. BACTERIA DEPENDENT DELIVERY – In these system colonic bacteria are

4. TIME DEPENDENT DELIVERY (PULSATILE DRUG DELIVERY) - Pulsatile

Advantages of pulsatile drug delivery system

1. Extended daytime or nighttime activity

5. Improved patient compliance

Ideal Pulsatile Drug Delivery System

Classification of Pulsatile or Time Controlled System

• Single unit system

Single Unit System

1. Capsular system – Architecture of these systems generally consists of an

1. Pulsatile delivery by erosion or solublization of coating – Most of the pulsatile

Advantage: Ease of manufacturing.

Disadvantages: In-vivo variability (food effects which is present in G.I.T.).

• Short gastric residence time

• Amenable to capsule & tablets

• Multiple manufacturing steps

1. Pulsatile release by rupturing of membrane – In these multiparticulate system

DRUG METABOLISM IN THE COLON

ENZYMES MICROORGANISM REACTION CATALYZED

Reduces AR and hetronitro cyclic

BIOPOLYMER FOR COLONIC DELIVERY

Guar gum is a galactomannan polysaccharide [β -1,4 D-mannose,α -1,6 D-

Chondroitin sulfate is a souble mucopolysaccharide consisting β -13,D-glucuronic acid

It is a heterogeneous polysaccharide composed mainly of galacturonic acid and its

It is a polysaccharide consisting of α -1,6 D-glucose and α -1,4- D glucose units Dextran

NONBIODEGRADEABLE SWELLING POLYMERS

Non biodegradable polymers are more frequently employed In controlled release

Nonbiodegradable swelling polymer do not undergo any cleavage by enzymes of

Budesonide Entrocort® Eudragit® L 100-55, ethylcellulose

PLATFORM TECHNOLOGIES FOR CTDDS

Colonic drug delivery is one of the major challenges.

Management of Local pathologies requires efforts in decreasing or

Conventional dosage forms need to be drastically improved in

Drug delivery to specific site i.e. colon is a potential alternative for

High commercial viability. Increasing number of international

1.Micheal J. Rathbone, Jonathan Hadgraft, Micheal S. Roberts , Majella E. Lane;”

 Magruder PR, Barclay B, Wong PSL, Theeuwes F. Composition Comprising a

5. http://www.jyoungpharm.in/article.asp?issn=0975- 1483;year=2009; volume=1;

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