Escolar Documentos
Profissional Documentos
Cultura Documentos
delivery system
Why?
Anatomy of colon
Functions of colon
The absorptive capacity is very high. The absorptive capacity is very high, each
about 2000 ml of fluid enters the colon through the ileocecal valve from which
more than 90% of the fluid is absorbed
Provides suitable environment for the growth of colonic microorganisms,
Absorption of water and Na+ from the lumen, concentrating the fecal content,
Secretion of K+ ions,
Absorption of water
Water absorption occurs
secondary to the
absorption of electrolytes
and short chain fatty
acids by solvent drag
Colon absorbs Na+ and Cland secrets HCO3- and K+
against potential gradient
HCO3- in lumen
neutralises the acidity
caused by fatty acid
production
Lag Phase
of 5 hrs.
observed
Emptying rates
Gastric emptying Fasted state
Gastric emptying - Fed
state
Small intestinal transit
10 min. to 2 hrs
Colonic transit
20-35 hours
EFFECT ON COLONIC
ABSORPTION OF DRUGS
IBD (Crohns
disease &
Ulcerative
colitis)
Diarrhoea
Constipation
Gastroenteritis
Reduction in bowel
movement & decreases the
avaibility of drug at
absorption site
Diarrhoea affects the
performance of formulations
Colonic microflora
Microflora
Aerobic
Enterobacteri
a
Staphylococc
i
Lactobacillus
Anaerobic
Fungi
Bacteroids
Bifidobacteri
a
Clostridia
Eubacteria
Reduction of C=C,
azo, nitro,
aldehydes,
ketones, alcohols,
N-oxides
Dehydroxylation
Decarboxylation
Dehalogenation
Desamination
Heterocyclic ring
fission
Acetylation
Esterification
Enzymes in colon
Reducing
enzymes
Hydrolyti
c
enzymes
Nitroreductas
e
Esterases
Azoreductase
Amidases
N-oxide
reductase
Glycosidases
Sulphoxide
reductase
Glucuronidas
e
Hydrogenase
Sulfatase
Applications
Advantages
Drug
directly
available at
the target
site
Decreased
dose to be
administere
d
Decreased
side effect
Improved
drug
utilization
Pharmaceutical
approaches for
colonic targeting
1. pH sensitive polymers
2. Microbially triggered systems
3.
4.
5.
6.
1.
Prodrug
2.
Polysaccharides
3.
Hydrogel
pH sensitive systems
Solid formulations for colonic delivery that
are based on pH-dependent drug release
mechanism are similar to conventional
enteric-coated formulations.
Utilize enteric polymers that have relatively
higher threshold pH for dissolution.
Polymers
Mechanism
pH sensitive polymer
Eg. Eudracol
Disadvantages
Lack of consistency in dissolution of the
polymer at desired site
Factors such as SCFA, fermentation products
reduce the colonic pH
1. Prodrugs
2. Hydrogel approach
3. Linking with polysaccharides
Prodrugs
I.
Azo conjugate
eg. Sulphasalazine for 5-ASA
V. Dextran conjugate
eg. Naproxen-dextran conjugation
Azo-bond conjugate
Azoreductase enzyme produced in colon by
colonic bacteria which degrades azo bond.
This principle is utilized in preparation of
prodrug derivative of active drug for
targeting in colon
Azo polymers
Azo-polymers used include:
Copolymers of styrene and 2-hydroxyethyl
methacrylate cross-linked by N,N`bis(bstyrene sulphonyl)-4,4`-diaminoazo-benzene
Poly (ether-ester) azopolymers
Glycoside conjugation
Certain drugs can be conjugated to different
sugar moieties to form glycosides
Glycosides are bulky and hydrophilic
They do not penetrate the biological
membranes upon ingestion
They are poorly absorbed from the small
intestine
When it reaches the colon, it will be cleaved
by colonic bacterial glycosidase
Dexamethasone-21--D-glucoside
(Arrow shows site of action of
glycosidase)
Glucuronide conjugation
Same as that of glycoside conjugation.
Here, glucuronide moiety is joined
Example: Dexamethasone is tried for
conjugation and the results were evaluated
in ulcerative colitis induced in the rates
Dexamethasone-b -D-glucuronide.
Cyclodextrin conjugate
Cyclodextrin metabolizing enzymes
produced by colonic bacteria degrades
Cyclodextrin particularly -CD. This principle
can be used for preparation of prodrug with
CD.
The -CD is practically resistant to gastric
acid and salivary and pancreatic amylases.
But they are complete degraded by the
colonic microflora.
Dextran conjugates
NASIDS ware directly coupled to dextran by
using carboxylic groups of drugs
Acted upon by dextranase
Eg. Dextran ester of naproxen
Polysaccharides as carriers
Natural polysaccharides such as pectin and
xylan are not digested by human stomach or
small intestine but are degraded by colonic
resident bacteria
The bacteria ferment the polysaccharides to
gases such as methane, CO2, hydrogen and
SCFA
Guar gum
Pectin
Inulin
Amylase
Cyclodextrin ()
Dextran
Chitosan
Eudragits
Rofecoxib , Tinidazole
Naproxen
Azathioprine
5-Amino salicylic acid
Albendazole
Ibuprofen
Satranidozole
5-fluorouracil
Hydrogels
Hydrogels contain acidic comonomers and enzymatically degradable azoaromatic
cross-links
In acidic pH, gels have low degree of swelling. Thus, drugs are protected against
degradation by digestive enzymes
On entering colon, the gels reach a degree of swelling such that crosslinks are
accessible to enzymes (azoreductase)
Time-dependent delivery
Difficult to predict in advance.
The strategy is to resist the drug release in
acidic & intestinal environment
In this approch, specific lag time is
previously determined.
Eg. Pulsincap
It consists of enteric coated capsule
containing water soluble cap and water
insoluble body.
The body is loaded with Hydrogel plug and
drug layer.
Enteric coat dissolves in small intestine and
the water soluble cap also dissolves.
The Hydrogel plug absorbs water and swell
and release drug at a predetermined lag
time of 4 hours.
Evaluation
Drug release
study in 0.1N HCL
for 2 hours (mean
gastric emptying)
Drug release
study in
phosphate buffer
for 3 hours (mean
small intestine
transit time)
Method
II
Suitable medium
containing colonic
bacteria (streptococcus
faecium or B.ovatus)
Amount of drug
released at different
time intervels
determined.
In vivo studies
Animal models
String technique
Endoscope technique
Radiotelemetry
Roentgenography
Gamma scintigraphy
Human models
Animal models
Guine
a pigs
Glucoside
prodrug of
dexamethasone
Other
animal Rats and pigs
s
String technique
Tablet is
attached to
piece of string
Subject
swallows the
tablet
Physically
examined for
signs of
disintegration
Endoscope technique
Optical technique
A fiber scope (gastroscope) monitors the
behavior of dosage form
This method requires administration of mild
sedative to facilitate the swallowing of
endoscopic tube
Radiotelemetry
Administration of capsule containing
a small pH probe interfaced with a
miniature radio transmitter which
sends signal indicating the pH of the
environment to an external antenna
attached to the subjects body
Dosage form is physically attached
to the capsule
The dosage form must contain
significant amount of buffers the
release of which produces a
detectable pH change. Most
formulations do not have such high
amounts of buffers. Hence this
technique has less spplications
Roentgenography (X-rays)
Involves inclusion of radio-opaque material
into the dosage form to be viewed by X rays
Eg. Barium sulphate
Use of X rays involves the exposure of
subject to high amount of radiations
Radio-opaque material has high density and
not suitable for most pharmaceuticals
Gamma scintigraphy
Most useful technique
-emitting radio isotope is present in the dosage form
Gamma rays detected by gamma camera
Advantages:
1. Very little radiation exposure to subjects
2. Gives both qualitative and quantitative results
3. Totally non-invasive
4. Allows for in vivo evaluation under normal
physiological conditions