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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

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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/1943/1132

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5)http:/www.aapspharmscitech.org

6)www.elsevier.com/international journal ofpharmaceutics/ 298(2005)91-97