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Colon Targeted DrugDelivery
System
WELLA AFRIANI
1111012041Kelas C
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introduction
Colon drug delivery system refers to
targeted delivery of drug in to the lower
parts of GI tract, mainly large intestine
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Anatomy of colon
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Application
In local colonic pathologies
Systemic delivery of protein andpeptide
Potential site for the treatment ofdiseases liike asthma,arthritis & angina
For the drugs that are absorbedthrough colon such as steroids
For the treatment of disorders like IBS,colitis,crohnsdisease where it is
necessary to attain high concentrationof drugs in colon
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Limitation and Challenges
Dissolution in luminal fluid.
Stability of drugs.
Binding of drugs to dietary residues,intestinal secretions, mucus or fecal
matter.
Metabolic degradation by colonicmicroflora.
Wide range of pH values
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Lower surface area and relative tightness of
the tight junctions in the colon restrict drugtransport.
Longer residence time
Requires protection against variety of thegastric enzymes.
Cytochrome P450 3A class of drugmetabolizing enzymes have lower activity incolon
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Target sites Diseaseconditions
Drugs used
Topical/local
action
Inflammatory
bowel disease,Irritable bowel
syndrome&crohndisease
Hydrocortisone,
Budenoside,Prednisolone,Sulphasalazine,Olsalazine,Infliximab
Mesalazine,Balsalazide, 6-Mercaptopurine,Azathiorprine,Cyclosporine,etc
Introduction to colonic
drug delivery system
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Amoebiasis Metronidazole,Ornidazole,Tinidazole,Mebandazole, etc
Chronicpancreatitis,Pacreatactomyand Cystic fibrosis
Digestive enzymesupplements
Colorectal cancer 5-Fluoro uracil
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Systemicaction
To prevent gastricirritation NSAIDS
To prevent first pass
metabolism of orallyingested drugs
Steroids
Oral delivery of
peptides
Insulin
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MECHANISM OF ACTION:
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Factor affecting
Colonicdrug Delivery
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A. Gastric emptying
Fasted state 10 min. to 2 hrs
Fed state Higher than 2 hrs
Small intestinal transit 3-4 hours
Colonic transit 20-35 hours
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DISEASE EFFECT ON COLONIC
ABSORPTION OF DRUGS
IBD (Crohnsdisease &
Ulcerative
colitis)
Malabsorption lipophilic drugsMucosa & submucosa gets thick & so
reduces surface area, reduces
diffusion
Diarrhoea Retention time reduces.
Reduces drug absorption & release
from dosage form
B.Gastrointestinal disease state
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Constipation Reduction in bowel movement &
decreases the avaibility of drug
at absorption site
Gastroenteritis Diarrhoea affects the
performance of formulations
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Stomach
Fasted state
Fed state
1.52
2 - 6
Small intestine 6.6
7.5
Ascending colon
Transverse colonDescending colon
6.4
6.67.0
c.Gastric and intestinal pH
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Pharmaceutical
approaches for CDDS
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Approaches1. Prodrug
2. Osmotically controlled drug delivery
3. Redox-sensitive polymers
4. pH dependent system
5. Time dependent system6. Microflora activated system7. Pressure controlled system8. Bioadhesive systems9. Micro particulate system
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A. PRODRUG APPROACH (Drug is conjugated with
carrier)I. Azo conjugate
eg. Sulphasalazine for 5-ASA
Drug is conjugated with an azo bond.
II. Glycoside conjugate
eg. Dexamithasone
Drug is conjugated with glycoside
III. Glucuronide conjugate Drug is conjugated with Glucuronide
IV. Cyclodextrin
conjugate(CD)
Drug is conjugated with cyclodextrin
V. Dextran conjugate
eg. Naproxen-dextran
conjugation
Drug is conjugated with dextran
1. Prodrug approach
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VI. Polymeric conjugate Drug is conjugated with polymer
VII. Amino acid conjugate
eg. Proteins.
Drug is conjugated with aminoacid
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1)Azo bond conjugate:-
Azoreductase enzyme produced in colon by
colonic bacteria which degrades azo bond.
This principle is utilized in preparation ofprodrug derivative of active drug for targeting in colon.
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Sulphasalazine(SASP) is prodrug of 5-ASA. It is
conjugated with sulphapyridine through azo bond.
Sulphasalazine was introduced for the treatmentof rheumatoid arthritis and anti-inflammatory
disease.
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Carrier moiety conjugated with
5-amino salicylic acid
Prodrug of 5-amino
salicylic acid
p-aminohippurate (4-amino
benzoyl glycine)
ipsalazine,
p- 4-amino benzoyl--alanine balsalazine
p-aminobenzoate HB-313
nonabsorbable sulphanilamide
ethylene polymer
poly-ASA
a dimer representing two
molecules of 5-ASA that are
linked via an azo bond
olsalazine (OSZ)
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2)Glycoside conjugation:-Certain drugs can be conjugated to different
sugar moieties to form glycosides
Glycosides are bulky and hydrophilic
They do not penetrate the biologicalmembranes upon ingestion
They are poorly absorbed from the smallintestine
When it reaches the colon, it will be cleaved bycolonic bacterial glycosidase
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Dexamethasone-21- D-glucoside(Arrow shows site of action of glycosidase)
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3)Glucuronide conjugations:-Same as that of glycoside conjugation.
Here, glucuronide moiety is joined
Example: Dexamethasone is tried for conjugationand the results were evaluated in ulcerative colitisinduced in the rates.
Dexamethasone- b -D-glucuronide.
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4)Cyclodextrin conjugate:- Cyclodextrin metabolizing enzymes produced by
colonic bacteria degrades Cyclodextrin particularly -CD. This principle can be used for preparation ofprodrug with CD.
The -CD is practically resistant to gastric acid and
salivary and pancreatic amylases. But they are completedegraded by the colonic microflora.
5)Dextran conjugate:-NASIDS ware directly coupled to dextran by usingcarboxylic groups of drugs
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6)Amino acid conjugation:-In the amino acid, acid group
increase hydrophilicity and chain length of carrieramino acid,
decrease the permeability of amino acids and proteins.So the amino acid conjugate showed more enzymatic
specificity for hydrolysis by colonic enzyme.
Glycine and glutamic acid conjugates of salicylic acid.
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2)Osmotic controlled drug deliveryOROS-CT (Alza corporation)
Immediately after the OROS-CT is swallowed, thegelatin capsule containing the push-pull units dissolve
Because of its enteric coating, each push-pull unit isprevented from absorbing water in the acidic environment.
As the unit enter the small intestine, the coatingdissolve in this higher pH (pH >7), water enters the unit,
causing the osmotic push compartment to swell andconcomitantly creates a flowable gel in the drug
compartment.
Swelling of the osmotic push layer forces drug gel outof the orifice.
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3)Redox-sensitive polymers
Novel polymers that are hydrolysed nonenzymatically byenzymatically generated FLAVIN
For azo bond cleavage,mainly 2 approches1. Intracellular enzymatic compartment,
2. Extracellular reduction by flavin.
Under anaerobic conditions, bacterial azo reduction byenzymatically generated reduced flavins requires the
presence of NADPH as its electron source.
As NADPH oxidized, the electron mediator (reducedflavins) acts as an electron shuttle from the NADPH
dependent flavoprotein to the azo compound.
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NADPH
(OXIDIZED) FLAVIN(REDUCED)
ACT AS ELECTRONE SHUTTLE
FLAVOPROTEINAZO COMPOUND
HYDROZO INTERMEDIATE
e-
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Co-polymers of methacrylic acid and methylmethacrylate are widely used.
Eudragit L: pH 6
Eudragit S: pH 7
Premature drug release observed. To overcome this problem Eudragit FS has been
developed.
Eudragit FS: pH 7-7.5: Slow dissolution rate
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4. pH dependent approach
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POLYMER THRESHOLD PH
Eudragit L 100 6.0
Eudragit S 100 7.0Eudragit L-30D 5.6
Eudragit FS 30D 6.8
Eudragit L 100-55 5.5
Poly vinyl acetate phthalate 5.0Hydroxypropylmethylcellulose phthalate 4.5-4.8
Hydroxypropylmethylcellulose phthalate 50 5.2
Hydroxypropylmethylcellulose phthalate 55 5.4
Cellulose acetate trimellate 4.8
Cellulose acetate phthalate 5.0
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EudracolTM
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EudracolTM
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Marketed formulations
delivery of olsalazine
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delivery of balsalazine
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5.Time dependent
delivery Difficult to predict in advance.
The strategy is to resist the drug releasein acidic & intestinal environment
In this approch, specific lag time ispreviously determined.
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Pulsincap
It consists of enteric coated capsule containingwater soluble cap and water insoluble body.
The body is loaded with Hydrogel plug and drug
layer.
Enteric coat dissolves in small intestine and thewater soluble cap also dissolves.
The Hydrogel plug absorbs water and swell andrelease drug at a predetermined lag time of 4hours.
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Time clock
The Time Clock system consists of a solid dosage
form coated with l ip id ic barr iers con tain ing
carnuba wax and bees wax along with surfactants,
such as polyoxyethylene sorbitan mono oleate.
This coat erodes or emulsifies in the aqueous
environment in a time proportional to the thickness
of the film, and the core is then available fordispersion.
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Technique
employed
Polymer used Drug used
Bacteria
dependent/Polysaccharide based
Chitosan Diclofenac
Sodium
Pectin
Chondroitin salphate
Guar gum
Indomethacin
Indomethacin
Doxamithacin
Amylose
Alginate
5 ASA
5 ASA
6. Bacterial based approach
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Microbial
flora
Enzymes
produced
Chiefly applied for:
Majority ofthem
Azoreductase Release of 5- ASA fromvariety of prodrugs
Lactobacilli Glycosidase,Glucuronidase
Glycosides &glucuronides
Bacteroides Glycosidase,Glucuronidase
Glycosides &glucuronides
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7. Pressure-controlled
drug-delivery systems Muscular contraction of the gut wall generatepressure
Colon has higher luminal pressure
System can be developed which withstand thepressure in intestine and ruptures in responseto raised pressure in colon.
Ethyl cellulose capsules have been used forthis purpose.
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8. Bioadhesive systems:- Oral administration of some drugs requires high
local concentration in the large intestinefor
optimum therapeutic effects.
Bioadhesion is a process by which a dosageform remains in contact with particular organ for an
augmented period of time.
This longer residence time of drug wouldhave high local concentration or improved absorption
Various polymers including polycarbophils,polyurethanes and polyethylene oxide-polypropylineoxide copolymershave been investigated for colon.
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9. Multiparticulate system
Pellets
Granular matrixBeads
Microspheres
Nano particles
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Microbially controlled system
Microsphere containing different
natural polysaccharide Chitosan
Guar gum Pectin
Dextran
Chondroitin sulphate
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Evaluation
1. In vitro dissolution study
2. In vitro enzymatic degradation test
3. Relative colonic tissue exposure
4. Relative systemic exposure to drugs
5. -Scintigraphy
6. Magnetic moment imaging study
7. Drug delivery index8. High frequency capsule
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Invitro test for intactness of coatings andcarriers in simulated conditions of stomach andintestine
Drug release study in 0.1 N HCl for 2 hours (meangastric emptying time)
Drug release study in phosphate buffer for 3
hours (mean small intestine transit time PH 6.8)
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Method 1
Drug release in buffer medium containing enzymes(e.g. pectinase, dextranase) or cecal contentsof rat or guinea pig or rabbit
Method 2 Suitable medium containing colonic bacteria
(Streptococcus faecium or B. ovatus)
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BioDis-III (Apparatus III) Ideal for the dissolution profiling of extended
release dosage forms.
It is designed to meet or exceed current USPspecification.
It used a reciprocating motion to dip the innertube into media.
At the designated time, the entire row of innertubes raises and moves to the next row ofmedia. 54
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Bio-Dis III
Capable of running unattended upto 6 days and canstore upto 25 programms.
7 sample tubes which automatically traverse upto6 rows of corresponding outer tubes filled withdifferent media.
With accessories, the appropriate media volumecan vary from 100, 300 ml (USP) or 1000 ml.
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BioDis III
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References
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1)http://www.pharmainfo.net/pppc05/colon-specific-drug-delivery-recent-techniques
2) http://jpronline.info/article/view/1943/1132
3)http://www.ncbi.nlm.nih.gov/pubmed/12753729
4)http://www.ualberta.ca/~csps/JPPS6(1)/S.Chourasia/colon.htm
http://jpronline.info/article/view/1943/1132http://jpronline.info/article/view/1943/11328/11/2019 1111012041 Wella Afriani
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5)http:/www.aapspharmscitech.org
6)www.elsevier.com/international journal ofpharmaceutics/ 298(2005)91-97