Shibu lijack
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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