RECENT ADVANCES IN COLON TARGETED DRUG

DELIVERY

Presented byVarun M. GirmeM. PHARM (PHARMACEUTICS) SEM - III

CONTENTS• INTRODUCTION• ANATOMY & PHYSIOLOGY OF COLON• COLON ABSORPTION• PHARMACEUTICAL APPROACHES FOR

TARGETING DRUGS TO COLON• EVALUATION OF COLON TARGETED DRUG

DELIVERY SYSTEM• CASE STUDY• REFERENCES05/01/2023 2

Oral route is considered to be most convenient for administration of drug to patient.

Colon is used as site of Targeted drug delivery.

Colon was considered as a BLACK-BOX , as most of

the drug are absorbed from the upper part of the GI

tract.

Prime objective-Beneficial in the treatment of colon

diseases.

Increase the pharmacological activity.

Reduce dosing & side effects.

Prevent drug from degradation.

INTRODUCTION

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Layers:

• Serosa

• Muscularis

externa

• Submucosa

• mucosa

ANATOMY & PHYSIOLOGY OF COLON

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DRUG ABSORPTION IN THE COLON

Drug molecules pass from the apical to

basolateral surface of the epithelial cell by

1.Transcellular - Passing through colonocytes.

2. paracellular - Passing between adjacent

colonocytes.

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l. COVALENT LINKAGE OF DRUG WITH CARRIER

ll. APPROACHES TO DELIVER INTACT MOLECULE TO COLON

lll . CURRENT APPROACHES

PHARMACEUTICAL APPROACHES TO DELIVER A

DRUG TO COLON

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APPROACHESCovelent linkage

of drug with carrierAzo bond conjugatesGlycoside conjugatesGlucuroni

de conjugatesCyclode

xtrin conjuga

tesDextran

conjugates

Amino acid conjugates

Polymeric prodrugs

Deliver the intact molecules to colon

Coating with polymers

Coating with pH sensitive

polymersEmbedding in

matrices

Embedding in

biodegradable matrices and

hydrogels

Time dependentBioadesive systems

Osmotic

controlled drug delivery

Current Approaches

Pulsinicap

Port system

Chronotropic system

CODESCOLAL-PRE

D Syste

m

Multi

particulate

Ticking capsule

Enterion capsule technology

Probiotic approach

Nanoparticulate system

l. COVALENT LINKAGE OF DRUG WITH CARRIER

Prodrug approaches

1.Azo bond conjugate

2.Glycoside conjugation

3.Glucoronide conjugates

4.Cyclodextrin conjugate

5.Dextran conjugate

6.Amino acid conjugation

7.Polymeric prodrugs05/01/2023 9

1.Azo bond conjugate Complex and relatively stable community of microorganism.Show various metabolic reactions including reduction of azo and nitro group.

Hydrolysis of sulfasalazine by azo reductase into sulfapyridine and 5-aminosalicylic acid

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2.Glycoside conjugation Hydrophilic in nature so they are not absorbed by the small intestine.But when they reach in the colon they are hydrolyzed by the enzyme bacterial glycosidase.

Dexamethasone-21-Dglucoside (Arrow shows site of action of glycosidase)

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3.Glucoronide conjugatesThe major mechanism for the inactivation and preparation for clearance of a variety of drugs. Bacteria of the lower GIT however secrete β-glucuronidase and can deglucuronidate a variety of drugs in the intestine.

Utilized to improve certain properties of drugs such as solubility, stability and bioavailability.The interior of these molecules is relatively lipophilic and the exterior relatively hydrophilic, they tend to form inclusion complexes with various drug molecules.

4.Cyclodextrin conjugate

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5.Dextran conjugateThese linkages are hydrolyzed by moulds, bacteria, and mammalian cells.In the colon, dextran’s glycosidic bonds are hydrolyzed by dextranases to give shorter prodrug oligomers, which are further split by the colonic esterases to release the drug free in the lumen of the colon

6.Amino acid conjugationMade up by two hydrophilic groups like -NH2 and –COOH they reduce the cell membrane permeability.

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conjugates of salicylic acid. (a) Salicyluric acid. (b) Salicylglutamic acid conjugate (Dotted line shows the site of cleavage)

7.Polymeric prodrugs. Both synthetic as well as naturally occurring polymers are used for this purpose.

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ll. APPROACHES TO DELIVER INTACT MOLECULE TO COLON

1.Coating with polymers

2.Coating with pH-sensitive polymers

3.Coating with biodegradable polymers

4.Embedding in matrices

5.Embedding in biodegradable matrices and hydrogels

6.Time dependent approach

7.Bioadhesive systems

8.Osmotic controlled drug delivery05/01/2023

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1.Coating with polymers•The drug molecule is intact with the suitable polymer in that manner that the drug release only in the colon instead of other part like small intestine and stomach.

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2.Coating with pH-sensitive polymers

3.Coating with biodegradable polymerslarge number of microorganisms are present in the colon. they are involved in the reduction of the dietary components.The micro organisms present in the colon cause the cleavage of the polymer at the alkaline ph and in the colon.

4.Embedding in matricesThe polymers used for this technique should exhibit degradability in the colon for liberation of entrapped drug.

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5.Embedding in biodegradable matrices and hydrogelsThe matrices of polysaccharides remain intact in the physiological environment of stomach and small intestine.once they reach in the colon, they are acted upon by the bacterial polysaccharidases and results in the degradation of the matrices.

6.Time dependent approach•Drug release occur after a certain lag period which is related to the time spend by the drug in reaching from mouth to the colon. •The lag time is depend on the size of the drug and gastric emptying.

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7. Bioadhesive systems•Dosage form remains in contact with particular organ for an period of time. •Improved absorption characteristics in case of poorly absorbable drugs8. Osmotic controlled drug delivery•OROS-CT system can be single osmotic unit or may incorporate as many as 5-6 pushpull units, each 4 mm in diameter, encapsulated with in a hard gelatin capsule .• Each bilayer push pull unit contains an osmotic push layer and a drug layer, both surrounded by a semipermeable membrane.

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CURRENT APPROACHES1. Pulsincap 2. Port system3. Chronotropic system 4. CODESTM

5. COLAL-PRED system6. Multi particulates7. Ticking capsules8. Enterion Capsule Technology9. Probiotic approach10. Nanoparticulate system

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1. Pulsincap

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2. Port system

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3. Chronotropic system

Drug release after a particular lag time.Surrounding with a soluble barrier layer, which consists of hydrophilic polymer HPMC.The coating of additional enteric coating film outside that layer to overcome the gastric empting variability.

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4. CODESTM

Designed to avoid the inherent problems associated with pH or time dependent systems.Combined approach of pH dependent and microbially triggered CDDS.

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5. COLAL-PRED systemProprietary gastrointestinal product developed by Alizyme for the treatment of ulcerative colitis (US). Treatment for ulcerative colitis without the typical side effects of steroids.

COLAL-PRED has a coating that is broken down only in the colon by bacteria.

This leads to topical delivery of steroids to the colon without significant systemic exposure with minimizing steroid related side effects.

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6. Multi particulatespH-sensitive, time dependent and microbial control systems for colon targeting.

AdvantageFewer adverse effects than single unit dosage formMore predictable gastric emptying Frequency of dose required is less Increase patient convenience

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7. Ticking capsules

It is electronically programmed to control the delivery of medicine according to a pre-defined drug release profile.Determines its location in the intestinal tract by measuring the local acidity (pH difference) of its environment.releases medicine from its drug reservoir via a microprocessor controlled pump, allowing accurate programmable drug delivery.05/01/2023 27

8. Enterion Capsule Technology Developed by Phaeton Research, Nottingham, UK.The capsule can be loaded with either a liquid formulation or a particulate formulation 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.

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capsule reaches in the gastrointestinal tract 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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9. Probiotic approachIn this approach, three components are desirable namely probiotic strain, microbially digestable carrier and triggering temperature.Probiotic strains include inactive microflora like Bifidobacterium and Lactobacillus species.At body temperature, these strains triggered to be active and start digesting the carrier and ultimately release the drug at desired place.Success in colon drug delivery system because these conditions are only available in colon.

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10. Nanoparticulate system Size range : 10–100 nm.drugs given with nanoparticles shows enhanced solubility, permeability and bioavailability.The drug is dissolved, entrapped, encapsulated or attached to a nanoparticle matrix.Drug Loading is relatively high and drugs can be incorporated into the systems without chemical reaction.

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EVALUATION OF COLON TARGETED DRUG DELIVERY SYSTEM

• In vitro Dissolution test• In Vivo Evaluation• Gamma scintigraphy

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In vitro Dissolution test•Dissolution for colon-specific drug delivery areusually complex.•Methods described in the USP cannot completely vivo conditions such as pH, bacterial environment and mixing forces.•Dissolution studies in different buffers may be undertaken.•The media chosen are, for example, pH 1.2 to simulate gastric fluid, pH 6.8 to simulate the jejunal region of the small intestine, and pH 7.2 to simulate the ileal segment.

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•In Vivo Evaluation•A number of animals such as rats and guinea pigs are used to evaluate the delivery of drug to colon.• Resemble the anatomic and physiological conditions as well as the microflora of human GIT. •Eg. Guinea pigs are commonly used for experimental IBD model.

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Gamma scintigraphyTime of arrival of a colon-specific drug delivery system in the colon.Time of transit through the stomach and small intestine.Disintegration can be obtained.Regional permeability in the colon.

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5-Fluoro uracil: -active pharmaceutical ingredient.

Chitosan :- used as polymer.

Eudragit S100:- used for enteric coating

CASE STUDY

Method:- solvent emulsification evaporation techniqueDifferent ratios of drug: polymer (1:1, 1:2,1:3, 1:4)Pellets and Enteric coating of nanoparticles were prepared.Particle size:- 138 ± 1.01 nmEntrapment efficiency:- 69.18%In vitro drug release studies.5-FU enteric coated nanoparticles with drug: polymer ratio of 1:3 (5-FU E1) and1:2 (5-FU E2)Plain chitosan nanoparticles, which were non-enteric coated (5-FU NE).

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5-FU E1 nanoparticles has shown enhanced drug release 82 ±0.05% and 71± 1.02% at 24 h and 8 h.5-FU E2 nanoparticles have shown a slight decrease in the drug release 73± 0.89% at 24 h and 68± 0.25% at 8 h.5-FU E1 nanoparticles considered as a potential carrier, which can release and localize the drug at colonic pH.Chitosan leads to the sustained release and also benefitted by its tumor inhibiting property.Enteric coating with Eudragit-S100 was supported by preventing drug degradation at gastric pH and allowing it to release once it enters the neutral and alkaline medium.5-FU E1 nanoparticles released drug after 4 h once it enters intestinal fluid and enhancing its drug release at colonic region.

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Formulated nanoparticles improved localization of the drug at the colon area and also achieved sustained release over a prolonged period of 24 h.Decreased toxicity to healthy cells as more amount of drug is localized in the colon area. Benefit the patient in decreasing the dosing frequency and dose that can be administered.

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REFERENCESShashank Tummala , M.N. Satish Kumar, Ashwati Prakash (2015), “Formulation and characterization of 5-Fluorouracil enteric coated nanoparticles for sustained and localized release in treating colorectal cancer”, Saudi Pharmaceutical Journal, 308–314.Cherukuri Sowmya, Reddipalli Sandhya, Komaragiri Keerthi. (2012), “Colon specific drug delivery system: A review on pharmaceutical approaches with current trends”, International research Journal Of Pharmacy, 45-55.Asha Patel, Nilam Bhatt, Dr.K.R.Patel, (2011), “Colon Targeted Drug Delivery System: A Review System”, Journal Of Pharmaceutical Sciences And Bioscientific Research, Vol1, Issue 1, 37-49

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Sunena Sethi, SL Harikumar, Nirmala Rayat, (2012), “Review On advances in Colon Targeted Drug Delivery System”, International Journal Of Pharmaceutical Sciences and Research, Vol. 3, Issue 09, 2989-3000 Dinesh Kumar, Mankaran Singh, Sharma Deepak, (2012), “Emerging Techniques and Challenges in Colon Drug Delivery Systems”, Journal of Applied Pharmaceutical Science, 139-147Pawar Dhanashree G*, Darekar Avinash B, Saudagar Ravindra B, (2013), “Colon Targeted Drug Delivery System: Pharmaceutical Approaches with Current Trends”, Vol2, Issue 6, 6589-6612Sardarmal Yadav , Ashish Kumar Pareek, Dr.Shiv Garg, (2015), “Recent advances in Colon Specific Drug Delivery System”, World Journal of Pharmaceutical Research, Vol4, Issue 6, 1380-1394.

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