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Colon specific D r u g D e l i v e r y

Seminar on

Prepared By:-Ashish Savaliya,

M.Pharm-II P’Ceutics,NIMS University,Jaipur

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milestonesIntroductionAnatomy of colon Disorders of colonP’Ceutical ApproachesPlatform TechnologiesInnovative DevicesAdvantages

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Disadvantage

s

Applications

Conclusion

References

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IntroductionTargeted delivery of drugs to the colon is usually to achieve one or more of four objectives. To reduce dosing frequencyTo delay delivery to the colon to achieve high local

concentrations in the treatment of diseases of the distal gut,

To delay delivery to a time appropriate to treat acute phases of disease (chronotherapy),

To deliver to a region that is less hostile metabolically, e.g., to facilitate absorption of acid and enzymatically labile materials, especially peptides.

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Anatomy of Colon

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Disorders of Colon

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Inflammatory bowels disease

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Ulcerative colitis

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Crohn’s disease

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Colon Cancer

Colon and rectum cancer - 10% in men and 11% women >55,000 Total Colorectal Cancer Deaths

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P’ceutical Approaches

Covalent linkage of drug with carrierspH sensitive systemsMicrobial triggered systems Timed release systemsOsmotic controlled systemsBioadhesive systemsPressure dependent release systems

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Covalent linkage of drug with carriers

Azo Conjugates (N = N)

Cyclodextrin Conjugates

Glycoside Conjugates

Dextran Conjugates

Polypeptide Conjugates

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pH sensitive systems

GI tract segments pH

Stomach 1 - 3

Small intestine 5 – 7.5

Large intestine 6.8 – 7.8

Rectum 7.8 - 8

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Drug core

pH sensitive polymer

Drug core

On Reaching to COLON

Drug release

Mechanism of pH dependent system

Drug in

Upper GIT

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Polymer Threshold pH

Eudragit® L 100 6.0

Eudragit® S 100 7.0

Eudragit® L-30D 5.6

Eudragit® FS 30D 6.8

Eudragit® L 100-55 5.5

Polyvinyl acetate phthalate 5.0

Hydroxy propyl methyl cellulose phthalate 4.5-4.8

Hydroxy propyl methyl cellulose phthalate 50 5.2

HPMC 55 5.4

Cellulose acetate trimelliate 4.8

Cellulose acetate phthalate 5.0

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Drug Trade Name Coating Polymer / Formulation

Budesonide Entrocort®Budenofalk®

Targit®

Eudragit® L 100-55, ethylcelluloseEudragit® S (Dissolution pH-7)

Coated Starch Capsule

Mesalazine Claversal®Asacolitin®Salofalk®Pentasa®Mesazal®Calitofalk®Asacol ®

Eudragit® L100 (Dissolution pH-6)Eudragit® S (Dissolution pH-7)Eudragit® S (Dissolution pH-6)Ethyl cellulose coated pellets

Eudragit® L100 (Dissolution pH-6)Eudragit® L100 (Dissolution pH-6)

Eudragit® S (Dissolution pH-7)

Mesalazine Azulfidine®Colo-Pleon®

Cellulose acetate phthalate (Dissolution pH-

6.2-6.5)Eudragit ® L100-55 (Dissolution pH-

5.5)

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Microbial triggered systems

Bacterial count in the colon is much higher around - CFU/ml.

400 species

Fundamentally anaerobic in nature.

Predominant species: Bacteroides, Bifidobacterium and Eubacterium.

Major metabolic processes occurring in the colon are hydrolysis and reduction.

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Colonic Microflora

Human intestinal microflora distribution in number (Log 10- scale) per gram faeces.

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Enzymes in Colon

Reducing enzymesNitroreductaseAzoreductaseN-oxide reductaseSulphoxide reductaseHydrogenase

Hydrolytic enzymes Esterases Amidases Glycosidases Glucuronidase Sulfatase

Azoreductases, which reduces azo-bonds selectively andPolysaccharidases which degrades the polysaccharides.

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Timed Release Systems

Releases the drug after a predetermined lag time.The lag time usually starts after gastric emptying

because most of the time-controlled formulations are enteric coated.

The enteric polymer coat prevents drug release in the stomach.

Drug release from these systems is not pH dependent.

Various polymers used are: polyacrylates, methylcellulose, HPMC, CMC etc.

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Lag phase of

~ 5 h isobserved.

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Platform Technologies

PULSINCAP

OROS-CT

CODES™

PORT® SYSTEM

TIME CLOCK® SYSTEM

COLAL-PRED™

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PULSINCAP

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OROS-CT

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CODES™

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PORT® SYSTEM

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TIME CLOCK® SYSTEM

Solid dosage form coated with lipid barriers containing carnauba wax and bees wax along with surfactants. Further coated with enteric coating polymer to prevent premature drug release, but the release is independent of pH or digestive state of the gut

Enteric coatingWax coating withsurfactant

Drug core

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COLAL-PRED™

Pellets containing the drug (prednisolone metasulphobenzoate) with a coating of ethylcellulose and a specific form of amylose (derived from starch).

After completion of succsesful phase I and II trials ‘Alizyme’ obtained approval for Phase III clinical trial of COLAL-PREDTM in maintenance of remission of ulcerative colitis.

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Innovative Devices

Philips’ Intelligent pill

Enterion Capsule

InteliSite® capsule

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Philips’ Intelligent pill

The ‘iPill’ is a capsule and it has been designed to be swallowed and to pass through the digestive track naturally. It can be electronically programmed to control the delivery of medicine according to a pre-defined drug release profile.

The iPill determines its location in the intestinal tract by measuring the local acidity (pH difference) of its environment.

Is device of ‘Philips research’ available in market from 2008

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The iPill releases medicine from its drug reservoir via a microprocessor controlled pump, allowing accurate programmable drug delivery.

The capsule is designed to measure local temperature, and report measurements wirelessly to an external receiver unit.

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It can be used in treatment of Crohn’s disease, Ulcerative colitis and Colon cancer.

Philips Ipill._(360p).flv

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The Enterion capsule has recently been developed by Phaeton Research, Nottingham, UK, for targeted delivery of a wide range of different drug formulations into any region of the colon.

The capsule can be loaded with either a liquid formulation (eg. solution, suspension) or a particulate formulation (eg. powder, pellets, minitablets, etc.)

The floor of the drug reservoir is the piston face, which is held back against a compressed spring by a high-tensile strength polymer filament. A radioactive marker is placed inside a separate sealed tracer port to allow real-time visualization of the capsule location using the imaging technique of gamma scintigraphy.

Enterion Capsule

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When the capsule reaches the target location in the gastrointestinal tract, the contents are actively ejected by the external application of an oscillating magnetic field.

This magnetic field induce power in a tuned coil antenna, embedded in capsule wall. This power is fed to a tiny heater resistor located in capsule.

This heater resistor increases temperature & releases the spring & drives the piston.

The resulting increase in pressure within the drug reservoir forces off the O-ring sealed cap and ejects the drug or drug formulation into the surrounding GI fluids.

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InteliSite® capsule

The InteliSite® capsule is an ingestible, radio-controlled device capable of delivering either liquid or powder drug formulations, on demand, to a specific region of the gastrointestinal tract.

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The InteliSite® capsule is loaded with a drug solution or powder formulation in a specially designed reservoir. When the capsule reaches the desired location in the gastrointestinal tract it is externally activated by remote control.

Activation is accomplished by exposing the capsule to a radio frequency magnetic field that induces a small amount of heat in the capsule's activation assembly. This causes two shape-memory alloy wires to straighten, rotating an inner sleeve of the capsule in relation to an outer sleeve.

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The rotation process aligns a series of slots in the sleeve surfaces permitting the contents to be released into the specific area of the GI tract. After activation, the InteliSite® capsule passes harmlessly through the body.

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Advantages

Patient compliance and treatment efficacy

Useful in treatment of ulcerative colitis, crohn's

disease, irritable bowel syndrome and carcinomas

Low dose is required ,so less side effect

Used for local and systemic action

Gastric irritation can be avoided

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DisadvantagesThere is less fluid in colon than in small intestine and

hence, dissolution is a problem for water soluble drugs.

Binding of drug to dietary residues, intestinal

secretions etc., reduce concentration of free drugs.

Some micro flora may degrade the drug.

Small luminal surface area and relative tightness of

tight Junctions in colon, delay the systemic absorption.

Onset of action is slow.

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ApplicationsLOCAL ACTIONS

1.    Ulcerative colitis.2.    CHRON'S disease.3.    Irritable bowel syndrome.4.    Metastatic human colon cancer.

SYSTEMIC ACTIONS1. Molecules degraded/poorly absorbed from upper G.I.T

such as peptides and proteins are better absorbed from colon.

2. For achieving chemotherapy for diseases that are sensitive to circadian  rhythm such as Asthma, angina, arthritis.

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ConclusionColonic drug delivery are 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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ReferencesModified-Release Drug Delivery Technology by Michael

J. Rathbone, Jonathan Hadgraft.Colonic Drug Delivery by Clive G. WilsonTime Dependent System For Colonic Drug Delivery by

Gour MukherjiPulsincap System For Colonic Drug Delivery by

HowardN.E.StevensThe Enterion Capsule by David V. Prior, Alyson L.

Connor, and Ian R. Wilding*InteliSite Capsule - Data courtesy of Scintipharma, Inc. -

Lexxington, Kentucky U.S.A.

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