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drug delivery implies selective and effective localization of drug into the
instability, low solubility and short half life, large volume of distribution,
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relevant bioavailability of poorly absorbed drugs from the upper parts of
intestine specifically for proteins and peptides 3. The colonic drug delivery
colon cancer, the third most widespread form of cancer in both women
and men5.
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3. It also provide opportunity to clarify the mechanism of action of some
get metabolized in the colon to the active moiety and interfere with the
mode.
small intestine.
ensures direct treatment at the affected area with lower dose and less
2. The colonic drug delivery can also be utilized as the threshold entry of
the drugs into blood for proteins and peptides which degraded or poorly
3. The colon targeted drug delivery can also be used for chronotherapy
the small intestine and colon which may allow drug release at undesired
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site. The pattern of drug release may differ from person to person which
2. The pH level in the small intestine and caecum are similar which
specificity.
4. Diet and diseases can affect colonic microflora which can negatively
affect drug targeting to colon. Nature of food present in GIT can affect
drugs.
system.
gastrointestinal regions.
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3. Colon has the low fluid environment and nature of luminal contents
are viscous which may hinder the dissolution and drug release from the
formulation.
The large intestine extend from the ileocaecal junction to the anus which
is divided into three main parts colon, rectum and anal canal. The colon
splenic flexture, descending colon and sigmoid colon (Fig 1.1). The
average size of colon is 1.5 m long, the transverse colon is the longest
and most mobile part and has an average diameter of about 6.5 cm,
(Table 1.1).
The wall of colon is consisting of four layers namely the serosa, the
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the mucosa lining the lumen of the colon. The mucosa has three parts
Superior mesenteric artery supply blood to the proximal colon and the
microorganisms.
and colon
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Surface
S. Length Transit
GIT segment area pH Microorganism
no. (m) time
(m2)
1 Stomach 0.2 0.1 1.5 102 Variable
Small
intestine
2.
i. Duodenum 0.3 0.1 6.9 10 2hr
ii. Jejunum 3 6.0 6.9 105 1.5hr
iii. Ileum 4 6.0 7.6 107 1.5hr
Large
3 1.5 0.3 8 1011 48hr
intestine
route. The epithelial cell junctions are very tight which may leads to poor
contact with mucosa in colon for a longer period than in small intestine
which compensates the much lower surface areas of colon for absorption
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Drugs reported to be well absorbed through colon include glibenclamide,
factors, these are pH level and the transit time. The other factors which
motility,
6. Disease state,
reported. Diet, diseased state and food intake influence the pH of the
the stomach and colon10. The size of the particles influences the colon
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transit when dosage forms reach the colon. Small particles exceed
through the colonic region more slowly than the larger unit, on the other
hand for larger single unit density and size of has no genuine effect on
colonic transit. It has been shown that pellets move faster than the
tablets through the ascending colon. So pellets are more favorable than
region of GI tract.
Location pH
time of dosage
Right colon : 6.4
Large intestine
forms in GI
Mild colon and left colon : 6-7.6
tract7, 17.
< 1 (fasting )
Stomach
> 3 ( fed )
Small intestine 3 to 4
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Large intestine 20 to 30
part of the tract, normally form fistulae. The Crohns disease was first
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Fig: 1. 2 Locations of IBD in colon
Etiology:-
Pathology:-
although the most common pattern is an ileocolits 57. The disease is often
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discontinuous, giving rise to so-called skip lesions. Isolated involvement
as against the case with Crohn's Disease where any part of the
to entire colon.
Etiology:-
The reasons of the disease are not clear. The proposed hypotheses
Pathology:-
but in about 40 percent of patients. Only 20 percent adults will have the
in children.
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Microscopic-The inflammation of ulcerative colitis is largely confined to
Mesalazine,
Colonic tumors are growths arising from the inner wall of the large
intestine. The large intestine may show benign tumors called polyps, and
do not spread to other parts of the body and can be easily removed
unlikely. The cancer of the colon and rectum is third major type of
factor, these are pH level and the transit time. The other factors which
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Degradation by bacterial enzymes and byproducts,
Disease state,
subject variations. Diet disease state and food intake influence the pH of
any particular segment of the colon. The transit time in the small
dosage forms reach the colon transit depend upon the size of the
particles.
It has been shown that pellets move faster than do the tablets
through the ascending colon so more favorable than tablet. The transit
DELIVERY:
absorption enhancer for the poorly absorbed drugs. Drugs that will
benefit from colon targeting include those for the treatment of colonic
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disease.Drugs that metabolite in upper gastrointestinal tract are also the
candidate for the colon drug delivery system. Drugs like theophyllin,
ibuprofen, and low molecular weight peptides and peptide like drugs
Example: ethlylacetoactate.
The approaches for colon specific drug delivery system are prodrug or
1. pH dependent
2. Time dependent
3. Pressure dependent
4. Bacteria dependent
The change in the pH along the gastrointestinal tract has been used
means of coating that are intact at lower pH of the stomach but that will
varies from 1.2 in the stomach, 6.6 in the proximal small intestine and
about 7.5 in the distal part of small intestine (Table 2). This pH variation
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in the stomach and small intestine has previously been used to deliver
polymer coats are recalcitrant to the acidic condition of the stomach but
The most commonly used polymer for this purpose is methacrylic acid
to colon12. But the pH of the distal is 6. This delivery system thus has a
patient with ulcerative colitis are known to have markedly low colon
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pH13. The lists of drugs delivered to colon based upon this approach
Approach
Sr.
Drug pH sensitive polymer
No.
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The average transit time in the stomach is 2 hr which may vary, while in
the small intestine it is relatively constant around 3hr. The typical transit
time varies from 20 to 30h 22.Time dependent drug delivery system allow
the drug release after a set time delay. For the colon targeted drug
release the lag time should similar to the time taken for the system to
the basis of relatively constant transit time in the small intestine (3hr);
Pulsicap was the first formulation developed based on this approach 23.
of a drug and out of this shellac showed promising result 24. Time
mixtures which release the drug in colon 25. Eudragit L100 along with
channeling agent like sodium chloride has been effectively confirmed for
achieving colon target drug delivery based on this approach 26. Hydroxy
propyl methyl cellulose has been used for colon specific drug delivery of
been used for time dependent colon specific drug delivery 28, 29.HPMC
along with pectin has also been shown to produce promising result for
purgative30. The hydrogel based capsule was reported which swells after
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definite time and allow drug release after lag time successfully in colon,
varied.31, 32.
result of colon targeting following oral administration 31. Akhgari A., et al,
delivery35.
The muscular contraction of the gut generate pressure for grinding and
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through the gastrointestinal tract , luminal pressure in the colon higher
system. The balloon doesnt get rupture in the luminal pressure of the
when in the colon due to more intense pressure of the contractions of the
Drug can be administered locally and selectively to the colon if they are
with biodegradable material for the colon targeting was reported for used
large amount of the drug. The drug release rate is dependent on of the
bacterial enzymes activity in the colon rather than on that of the host.
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compared to 104 per gram in upper part of gastrointestinal tract, 400
different anaerobic species are present. Azo bond based polymer for the
obtaining universal carrier systems was reported but the safety and
amylose, dextran, guar gum, insulin ,pectin 37, 38. Biodegradable polymers
produce products which are non toxic and biocompatible. The microflora
sulfasalazin (SAS) used for IBD 40and rheumatoid arthritis is the earliest
Only 12% drug was released in the small intestine after oral
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carrier molecule than in SAS. Balasalazide is 5-amino salicylic acid
total release of 5-amino salicylic acid in rats has been observed from SAS
and amino acid conjugates47 were successfully reported for colonic drug
delivery
dependent approach.
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5- amino salicyclic Combination of pectin and hydroxyl
1.
acid propyl methyl cellulose8
2.
paracetamol
pellets
4 Insulin Ca pectinate8
Vasopressin methacrylate48
fluorescein
galactomannan
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1.7. EVALUATION OF COLON SPECIFIC DRUG DELIVERY SYSTEMS:
A successful colon targeted drug delivery system is one that dont release
drug in the stomach and small intestine, but releases the drug in the
colonic region. Different in vitro in vivo methods are used to evaluate the
53. Yang L.et al in their review has given the different alternative method
The dissolution study for colon targeted drug delivery is also reported
The two fluids of pH 1.2 and 6.8 were reported as dissolution media 16, 54.
cylinder method (Type 3 USP apparatus) for enteric coated pellet with
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liquid i.e. simulated gastric fluid for 60 min, followed by 3-6 hrs in
6.8 , 7.2 with phosphate buffer 35,12 for time and pH dependent approach.
technique with human fecal bacteria and shown potential of system for
in vitro assessment.
carried out using the rat caecal matter or slurries of human fecal or
culture fermentation system 57. The rat fecal contents were favored
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.Anesthetized rats were used for this purpose and there caecal contents
were exteriorized for collecting the contents which was further diluted
with phosphate buffered saline. The human fresh fecal slurries have also
200 ml, and 280 ml, respectively magnetically stirred and kept at 37 oC
data of the drug and gamma scintigraphic analysis 60. For, CODESTM
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Gamma scintigraphic studies revealed to achieve target release in the
Rats58, mice59, pigs43 and dogs14 animal models were reported for colon
on its approach and design of system60. For example, guinea pigs have
that drug release delayed with increase in the hydrophilic content of the
polymer 61, -scintigraphic studies revealed the drug release in the colon.
Du.Qing et.al39 reported the pectin and ethyl cellulose coated pellet of 5-
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pellets of in rats 63. K. Mladenovska et.al presented microparticles of
for colon targeted drug delivery by Baljit Singh et.al 19. The psyllium husk
aminosalicylic acid as the drug which was covalently bounded to the poly
SYSTEM:
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Some of the patents granted for colon targeted drug delivery system are
No.
polymers67.
colonic polyps .
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carcinoma, which is coated with
ions72.
polysaccharides
generated by a saccharides by
gastrointestinal tract74.
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6,632,454 Multilayer pharmaceutical Core with an active ingredient
salt of pectin76.
flora77.
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