Drug targeting is the ability of the drug to Drug targeting is the ability of the drug to accumulate in the target organ or tissue accumulate in the target organ or tissue selectively and quantitatively, independent selectively and quantitatively, independent of the site and methods of its administration. of the site and methods of its administration.

Drug targeting

The main problems currently associated with systemic drug administration are:

1.1. Even bio-distribution of drug throughout the body; Even bio-distribution of drug throughout the body;

2.2. The lack of drug specific affinity toward a The lack of drug specific affinity toward a

pathological site;pathological site;

3.3. The necessity of a large total dose of a drug;The necessity of a large total dose of a drug;

4.4. Non-specific toxicity and other adverse side-effects. Non-specific toxicity and other adverse side-effects. Drug Targeting May solve Many Of These Problems. Drug Targeting May solve Many Of These Problems.

Advantages of drug targeting:Advantages of drug targeting:

1.1. Drug administration protocols may be Drug administration protocols may be simplified; simplified;

2.2. Drug quantity may be greatly reduced as well Drug quantity may be greatly reduced as well as the cost of therapy;as the cost of therapy;

3. Drug concentration in the required sites can 3. Drug concentration in the required sites can be sharply increased without negative effects be sharply increased without negative effects on non-target compartments. on non-target compartments.

Drug Targeting

The concept of drug targeting allow the development The concept of drug targeting allow the development

of drugs which are of drugs which are potentpotent and and non-toxicnon-toxic and and

targeted targeted drugdrug to its particular site of action through:to its particular site of action through:

Use Cell-specific enzymes and ligands Use Cell-specific enzymes and ligands

Development of prodrug-based technologies Development of prodrug-based technologies

Use of smart polymeric systems Use of smart polymeric systems

Strategy for drug targeting

A prodrug is a pharmacologically inactive A prodrug is a pharmacologically inactive

compound which undergo chemical or enzymatic compound which undergo chemical or enzymatic

metabolism to give the active compound. metabolism to give the active compound.

Most chemically designed prodrugs consist of Most chemically designed prodrugs consist of

two components, which are the two components, which are the active drug active drug

chemically linked to a chemically linked to a pharmacologically inert pharmacologically inert

moiety moiety ..

After administration or absorption of the After administration or absorption of the prodrug, the active drug is usually released by prodrug, the active drug is usually released by either chemical or enzymatic hydrolytic or either chemical or enzymatic hydrolytic or reductive processes. reductive processes.

The prodrug must be sufficiently stable to The prodrug must be sufficiently stable to withstand the pharmaceutical formulation while withstand the pharmaceutical formulation while permitting chemical or enzymatic cleavage at permitting chemical or enzymatic cleavage at the appropriate time or site. the appropriate time or site.

1.1. The prodrug must be readily transported to The prodrug must be readily transported to

the site of action, rapid uptake and the site of action, rapid uptake and

essentially perfusion rate limited.essentially perfusion rate limited.

2.2. Once at the site, the prodrug must be Once at the site, the prodrug must be

selectively cleaved to the active drug selectively cleaved to the active drug

relative to its conversion at other sites.relative to its conversion at other sites.

3.3. Once selectively generated at the site of Once selectively generated at the site of

action, the active drug must be retained by action, the active drug must be retained by

the tissue. the tissue.

Factors for optimizing site-specific drug delivery:

Prodrug used to solve a wide range of Prodrug used to solve a wide range of pharmaceutical problems including:pharmaceutical problems including:

Un palatabilityUn palatabilitygastric irritationgastric irritationpain on injectionpain on injectioninsolubilityinsolubilityinstability.instability.poor drug adsorption and drug distribution poor drug adsorption and drug distribution by increasing the lipophilicity of the drug by increasing the lipophilicity of the drug molecule.molecule.

Overcome biological & pharmaceutical barriers Overcome biological & pharmaceutical barriers

which separate the site of administration from the which separate the site of administration from the

site of action of drug.site of action of drug. Enhance efficacy of drug. eg, the administration Enhance efficacy of drug. eg, the administration

of the of the methoxy methyl ester of hetacillin methoxy methyl ester of hetacillin

(derivative of ampicillin) gaiv more distribution of (derivative of ampicillin) gaiv more distribution of

ampicillin in the tissues than occurs on ampicillin in the tissues than occurs on

administration of ampicillin itself. administration of ampicillin itself. Prodrugs are decreases toxic side-effects by Prodrugs are decreases toxic side-effects by

restricting the action of a drug to a specific target restricting the action of a drug to a specific target

site in the body. site in the body.

Advantages Advantages

Are prodrug designed to ensure the release of the Are prodrug designed to ensure the release of the

active drug only at its site of action by utilizing active drug only at its site of action by utilizing

enzyme or chemical activity of a particular cell.enzyme or chemical activity of a particular cell.

For example, the prodrug For example, the prodrug cyclophosphamidecyclophosphamide is is

initially activated by initially activated by hepatic cell enzymes hepatic cell enzymes to to

generate generate 4-hydroxycyclophosphamide4-hydroxycyclophosphamide which is then which is then

specifically converted to the specifically converted to the alkylating cytotoxic alkylating cytotoxic

phosphoramide phosphoramide mustard in the hepatic target cells.mustard in the hepatic target cells.

SITE-SPECIFIC ENZYME-SITE-SPECIFIC ENZYME-BASEDBASED

DELIVERY SYSTEMSDELIVERY SYSTEMS

can used for site-specific delivery to tumor can used for site-specific delivery to tumor

cells.cells.As the blood supply to large solid tumors is As the blood supply to large solid tumors is

disorganized, the internal regions are often non-disorganized, the internal regions are often non-

vasculated and the cells termed vasculated and the cells termed hypoxic cell hypoxic cell

( poor O( poor O22))

The absence of molecular oxygen enhances the The absence of molecular oxygen enhances the

reductasereductase activity in hypoxic tissues providing activity in hypoxic tissues providing

means of targeting the internal regions of solid means of targeting the internal regions of solid

tumors using a selective chemical prodrug-delivery tumors using a selective chemical prodrug-delivery

system. system. For example, the For example, the 2-nitro-imidazole2-nitro-imidazole compound is compound is

selectively cytotoxic to cultured hypoxic cells. selectively cytotoxic to cultured hypoxic cells.

Use of Use of lipophilic prodrugs overcome the lipophilic prodrugs overcome the

impenetrability impenetrability of some barriers as of some barriers as blood-brain blood-brain

barrier barrier to highly polar drugs, however the to highly polar drugs, however the

increased lipid solubility may enhance uptake in increased lipid solubility may enhance uptake in

other tissues with a result in increase drug other tissues with a result in increase drug

toxicity. toxicity.

SITE-SPECIFIC REDOX-SITE-SPECIFIC REDOX-BASED DRUG DELIVERY BASED DRUG DELIVERY

SYSTEMSSYSTEMS

These problems overcome by utilizing a drug These problems overcome by utilizing a drug

delivery system which delivery system which "trapping" "trapping" a prodrug in the a prodrug in the

brainbrain by by oxidizing the prodrug oxidizing the prodrug to a to a less membrane less membrane

permeable derivative. permeable derivative.

This approach used to enhance the CNS penetration This approach used to enhance the CNS penetration

of a of a non-polar prodrug non-polar prodrug which crosses the blood-brain which crosses the blood-brain

barrier but is then rapidly oxidized to the active form barrier but is then rapidly oxidized to the active form

and trapped in the CNS.and trapped in the CNS.

Dihydropyridine-pyridiniumDihydropyridine-pyridinium salt redox systems of salt redox systems of

phenylethylaminephenylethylamine and and dopaminedopamine illustrate this illustrate this

technology. technology.

Dihydropyridine-pyridinium salt redox system for Dihydropyridine-pyridinium salt redox system for site-specific delivery to the brain. site-specific delivery to the brain. The 1,4 dihydro-prodrug is delivered directly to the The 1,4 dihydro-prodrug is delivered directly to the brain, where it is oxidized and trapped as the brain, where it is oxidized and trapped as the prodrug of quaternary ammonium salt. prodrug of quaternary ammonium salt. The quaternary ammonium salt is slowly cleaved by The quaternary ammonium salt is slowly cleaved by chemical/enzymatic action with the release of the chemical/enzymatic action with the release of the biologically active biologically active phenylethylamine .phenylethylamine .

It is also possible to target drugs to specific cells It is also possible to target drugs to specific cells thth use specific cell surface ligands – prodrug use specific cell surface ligands – prodrug that that use use antibody-directed enzyme for cleavage to antibody-directed enzyme for cleavage to active drug.active drug. The approach has been used to The approach has been used to target drugs to target drugs to tumor cellstumor cells by employing an by employing an enzymeenzyme, not normally , not normally present in the extracellular fluid or on cell present in the extracellular fluid or on cell membranes, membranes, conjugated only to an tumor antibodyconjugated only to an tumor antibody which which localizes in the tumor localizes in the tumor via an antibody-via an antibody-antigen interaction on administration. antigen interaction on administration.

SITE-SPECIFIC ANTIBODY-SITE-SPECIFIC ANTIBODY-DIRECTED ENZYME DIRECTED ENZYME PRODRUG THERAPY PRODRUG THERAPY

(ADEPT)(ADEPT)

Following clearance of any unbound Following clearance of any unbound antibody antibody

conjugate enzyme conjugate enzyme from the systemic circulation, from the systemic circulation, a a

prodrug prodrug which is which is specifically activated by the enzyme specifically activated by the enzyme

conjugateconjugate, is administered. , is administered.

The bound enzyme-antibody conjugate ensures The bound enzyme-antibody conjugate ensures

that the prodrug is only converted to the that the prodrug is only converted to the cytotoxic cytotoxic

parent parent compound at the tumor site thereby reducing compound at the tumor site thereby reducing

systemic toxicity. systemic toxicity.

Example: Example: using using cytosine deaminase cytosine deaminase to generate to generate 5-fluorouracil5-fluorouracil

from the from the 5-fluorocytosine prodrug 5-fluorocytosine prodrug at tumor sites at tumor sites

increases the delivery to the tumor by 17 fold increases the delivery to the tumor by 17 fold

compared to that achieved on administration of 5-compared to that achieved on administration of 5-

fluorouracil alone.fluorouracil alone.

1

2

Gastrointestinal tractGastrointestinal tract TARGETING SYSTEMSTARGETING SYSTEMS

TARGETING SYSTEMSTARGETING SYSTEMS stomachstomachOrally administered controlled release dosage forms Orally administered controlled release dosage forms are subjected to 2 complications:are subjected to 2 complications:1- short gastric residence time 1- short gastric residence time 2- irregular gastric emptying rate2- irregular gastric emptying rate..Gastric emptying of dosage forms is valuable asset Gastric emptying of dosage forms is valuable asset for dosage forms, which need to be residence in the for dosage forms, which need to be residence in the stomach for a longer period of time. stomach for a longer period of time.

Advantages of Prolonged gastric retention Advantages of Prolonged gastric retention improves bioavailability of drugimproves bioavailability of drugreduces drug waste reduces drug waste improves solubility for drugs that are less soluble in a improves solubility for drugs that are less soluble in a high pH environment. high pH environment. It has a local drug delivery to the stomach and It has a local drug delivery to the stomach and proximal small intestines. proximal small intestines. The controlled gastric retention of solid dosage forms The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of :may be achieved by the mechanisms of :mucoadhesionmucoadhesion, , floating drug delivery systems (FDDS), floating drug delivery systems (FDDS), sedimentation,sedimentation, expansion,expansion, modified shape systems, modified shape systems, simultaneous administration of pharmacological agentssimultaneous administration of pharmacological agents that delay gastric emptying. that delay gastric emptying.

Factors affecting gastric residence time of solid Factors affecting gastric residence time of solid

dosage formsdosage forms : :

Size and shape of dosage unitSize and shape of dosage unit

Tetrahedron- and ring-shaped dosage have a Tetrahedron- and ring-shaped dosage have a

better gastric residence time as compared with better gastric residence time as compared with

other shapes. other shapes.

Dosage forms having a diameter of more than 7.5 Dosage forms having a diameter of more than 7.5

mm show a better gastric residencemm show a better gastric residence

Several formulation parameters can affect the Several formulation parameters can affect the

gastric residence time.gastric residence time.

The density of a dosage form also affects the The density of a dosage form also affects the

gastric emptying rate. gastric emptying rate.

A buoyant (floating) dosage formA buoyant (floating) dosage form

having a density of less than that of the gastric fluids having a density of less than that of the gastric fluids

and it and it

is floats. Since it is away from the is floats. Since it is away from the pyloric sphincterpyloric sphincter, ,

the the

dosage unit is retained in the stomach for a dosage unit is retained in the stomach for a

prolonged prolonged

periodperiod..

Applications of Floating Drug Delivery SystemsApplications of Floating Drug Delivery Systems

Floating drug delivery offers several applications:Floating drug delivery offers several applications:

For drugs having For drugs having poor bioavailability poor bioavailability because of the because of the

narrow absorption window narrow absorption window in the upper part of the in the upper part of the

gastrointestinal tract. gastrointestinal tract.

It It retainsretains the the dosage form dosage form at the at the site of absorption site of absorption

and thus and thus enhances the bioavailabilityenhances the bioavailability. .

Sustained Drug DeliverySustained Drug Delivery HBSHBS systems remain in the stomach for long systems remain in the stomach for long

periods and hence can release the drug over a periods and hence can release the drug over a

prolonged period of time. prolonged period of time.

These systems have a These systems have a bulk density of <1 bulk density of <1 as a as a

result of which they can float on the gastric contents. result of which they can float on the gastric contents.

These systems are relatively These systems are relatively large in size large in size and and

passing from the passing from the pyloric sphincter is prohibitedpyloric sphincter is prohibited..

Site-Specific Drug DeliveryThese systems are These systems are particularly advantageous particularly advantageous for drugs for drugs

that that are specifically absorbed from stomach or the are specifically absorbed from stomach or the

proximal part of the small intestineproximal part of the small intestine, eg, , eg, riboflavin and riboflavin and

furosemidefurosemide..

By targeting drugs to the stomach, By targeting drugs to the stomach, desired therapeutic desired therapeutic

levels achievedlevels achieved and and drug waste drug waste could be could be reducedreduced

FDDS serves as an excellent drug delivery system for FDDS serves as an excellent drug delivery system for

the the eradication oferadication of Helicobacter pyloriHelicobacter pylori, , which causes which causes

chronic gastritis and peptic ulcers. The treatment chronic gastritis and peptic ulcers. The treatment

requires high drug concentrations within the gastric requires high drug concentrations within the gastric

mucosa. mucosa.

Absorption EnhancementAbsorption EnhancementDrugs that have poor bioavailability because of site-Drugs that have poor bioavailability because of site-

specific absorption from the upper part of the specific absorption from the upper part of the

gastrointestinal tract are potential candidates to be gastrointestinal tract are potential candidates to be

formulated as floating drug delivery systems, formulated as floating drug delivery systems,

thereby maximizing their absorptionthereby maximizing their absorption..

As increase in the bioavailability of floating dosage As increase in the bioavailability of floating dosage

forms of forms of enteric-coated LASIX-long product enteric-coated LASIX-long product (42.9%) (42.9%)

could be achieved as compared with commercially could be achieved as compared with commercially

LASIX tablets (33.4%)LASIX tablets (33.4%)

On comparison of floating & nonfloating dosage

units,The floating dosage units remained The floating dosage units remained floating on the floating on the

gastric contentsgastric contents throughout their residence in the throughout their residence in the

gastrointestinal tract, gastrointestinal tract,

Floating units Floating units away from the gastro-duodenal away from the gastro-duodenal

junction junction were were protected from protected from the the peristaltic waves peristaltic waves

during digestive phase during digestive phase

While the non floating dosage units While the non floating dosage units sink and sink and

remained in the lower part of the stomach, And remained in the lower part of the stomach, And

stayed close to the pylorus stayed close to the pylorus and were subjected to and were subjected to

propellingpropelling and and retropellingretropelling waves of the digestive waves of the digestive

phasephase. .

Intragastric residence Intragastric residence positions of floating positions of floating

and nonfloating unitsand nonfloating units

Design Floating Dosage FormsDesign Floating Dosage Forms

Single-Unit Floating Dosage Forms:The globular shells withThe globular shells with popcornpopcorn, , popricepoprice, and , and

polystyrol polystyrol have been used as have been used as drug carriers,drug carriers,

having lower density than that of gastric fluid having lower density than that of gastric fluid

used for drug controlled release. used for drug controlled release.

Sugar polymeric materials such as Sugar polymeric materials such as methacrylic methacrylic

polymer polymer and and cellulose acetate phthalate cellulose acetate phthalate have have

been used to been used to coat these shellscoat these shells. .

These are coated with a These are coated with a polymer mixturepolymer mixture. .

The polymer of choice can be either The polymer of choice can be either ethyl celluloseethyl cellulose

or or hydroxy propyl cellulose hydroxy propyl cellulose depending on the type depending on the type

of release desired. of release desired.

Finally, the product floats on the gastric fluid while Finally, the product floats on the gastric fluid while

releasing the drug gradually over a prolonged releasing the drug gradually over a prolonged

periodperiod..

A buoyant dosage form can also be obtained by A buoyant dosage form can also be obtained by

using a fluid-filled system that floats in the using a fluid-filled system that floats in the

stomach. As Hydro dynamically balanced systems stomach. As Hydro dynamically balanced systems

(HBS)(HBS)

multiple-Unit Floating Dosage Forms:

This systems are classified depending on This systems are classified depending on

formulation :formulation :

Effervescent Effervescent

Non-effervescent systemsNon-effervescent systems..

Design Floating Dosage Forms

Effervescent Floating Dosage FormsEffervescent Floating Dosage Forms a) matrix types systems a) matrix types systems

prepared with the swellable polymers such as prepared with the swellable polymers such as

methylcellulosemethylcellulose and and chitosanchitosan and and various various

effervescent compounds effervescent compounds eg, eg, sodium bicarbonatesodium bicarbonate, ,

tartaric acidtartaric acid, and , and citric acidcitric acid. . They are formulated in a way that when in contact They are formulated in a way that when in contact with the acidic gastric contents, with the acidic gastric contents, CO2CO2 is liberated and is liberated and entrapped in swollen hydrocolloids, which provides entrapped in swollen hydrocolloids, which provides buoyancy to the dosage formsbuoyancy to the dosage forms..

(A)(A)Multiple-unit oral floating drug delivery system. Multiple-unit oral floating drug delivery system.

(B)(B)Working principle of effervescent floating drug delivery Working principle of effervescent floating drug delivery

systemsystem. .

Effervescent LayerEffervescent Layerinner & outer sublayerinner & outer sublayer

Conventional sustainedConventional sustained release pillrelease pill

Swelable membraneSwelable membrane layerlayer

methylcellulose methylcellulose && chitosanchitosan

Sublayers membrane

sodium bicarbonate sodium bicarbonate && tartaric acid tartaric acid

polyvinyl acetate polyvinyl acetate && purified purified shellacshellac

The effervescentThe effervescent layer layer containing containing sodium bicarbonate sodium bicarbonate and and tartaric acid tartaric acid was divided into 2 sublayers to avoid was divided into 2 sublayers to avoid direct contact between the 2 agents. direct contact between the 2 agents. These sublayers These sublayers were surrounded by were surrounded by a swellable a swellable polymer membrane containing polyvinyl acetate polymer membrane containing polyvinyl acetate and and purified shellacpurified shellac. . When this system was immersed in the When this system was immersed in the buffer at buffer at 373700CC, it settled down and the solution permeated into , it settled down and the solution permeated into the effervescent layer through the outer swellable the effervescent layer through the outer swellable membrane. COmembrane. CO 2 2 was generated by the was generated by the neutralization neutralization

reaction reaction between the between the 2 effervescent agents2 effervescent agents, producing , producing swollen pills with a density less than 1.0 g/mL. swollen pills with a density less than 1.0 g/mL. It was found that the system had good floating ability It was found that the system had good floating ability independentindependent of of pHpH and and viscosityviscosity..

b) ion exchange resin floating system b) ion exchange resin floating system Use resin that was loaded with Use resin that was loaded with bicarbonatebicarbonate by by mixing the mixing the resine beads resine beads with with 1 M sodium 1 M sodium bicarbonate solution. bicarbonate solution. The The loaded resine beads loaded resine beads were then were then surrounded by a surrounded by a semipermeable membrane semipermeable membrane to avoid sudden loss of to avoid sudden loss of

COCO22

Effervescent floating drug Effervescent floating drug

delivery systemdelivery system

based on ion exchange resinbased on ion exchange resin

Upon coming in contact with gastric contents an Upon coming in contact with gastric contents an exchange exchange of of chloridechloride and and bicarbonate bicarbonate ions took place ions took place

that that resulted in COresulted in CO22 generation generation thereby carrying beads thereby carrying beads

toward the toward the top of gastric contents top of gastric contents and producing a and producing a floating layer of resin beadsfloating layer of resin beads . . The gastric residence time was prolonged considerably The gastric residence time was prolonged considerably ((24 hours24 hours) compared with uncoated beads () compared with uncoated beads (1 to 3 1 to 3 hourshours))..

Effervescent floating drug Effervescent floating drug

delivery systemdelivery system

based on ion exchange resinbased on ion exchange resin

Non-Effervescent Floating Dosage Non-Effervescent Floating Dosage

FormsFormsNon-effervescent floating dosage forms use a Non-effervescent floating dosage forms use a gel gel

forming hydrocolloids of forming hydrocolloids of swellable cellulose type swellable cellulose type , ,

polysaccharidespolysaccharides, and , and matrix-forming polymers matrix-forming polymers like like

polycarbonatepolycarbonate, , polyacrylatepolyacrylate, , poly methacrylate , and poly methacrylate , and

polystyrene polystyrene and bioadhesion polymers like chitosan

and carbopols. .

The formulation method includes: The formulation method includes:

a simple mixing the a simple mixing the drug drug and the and the gel-forming gel-forming

hydrocolloidhydrocolloid. .

Working principle of non effervescent floating drug Working principle of non effervescent floating drug

delivery system:delivery system:

After oral administration in contact with gastric After oral administration in contact with gastric

fluids this dosage form swells and attains a bulk fluids this dosage form swells and attains a bulk

density of < 1. density of < 1.

The air entrapped within the swollen matrix imparts The air entrapped within the swollen matrix imparts

buoyancy to the dosage form. The formed swollen buoyancy to the dosage form. The formed swollen

gel-like structure acts as a reservoir and allows gel-like structure acts as a reservoir and allows

sustained release of drug.sustained release of drug.

Intragastric floating drug delivery device. The system composed of a drug reservoir encapsulated in a microporous compartment having pores on top and bottom surfaces. The peripheral walls of the reservoir compartment were completely sealed to prevent any physical contact of the undissolved drug with walls of the stomach.

Tablets of Tablets of 2 kg/cm2 kg/cm22 andand 4 kg/cm4 kg/cm22 hardnesshardness after after immersion into the floating media immersion into the floating media floated immediately floated immediately for 3 to 4 minutes for 3 to 4 minutes and then came to the surface. And and then came to the surface. And remained floating for 24 hours. The tablet with remained floating for 24 hours. The tablet with 8 8 kg/cmkg/cm22 hardnesshardness showed showed no floating capability. no floating capability.

Small intestinal transit time is an important

parameter for drugs that are incompletely absorbed. Intestinal target solid dosage forms (enteric coated

tablets) is intended to:

Prevent destruction of the drug by gastric juices.

To prevent irritation of the stomach lining by the drug.

To promote drug absorption

TARGETING SYSTEMSTARGETING SYSTEMS intestinalintestinal

Colon-specific diseases are inefficiently treated by

oral therapy, because most orally administered drugs

are absorbed before arriving in the colon.

Advantages of Colon-specific drug delivery

systems include:

used for the local treatment of colonic disorders

such as Crohn`s disease, ulcerative colitis and irritable

bowel syndrome

deliver drugs to the lower gastrointestinal tract

without releasing them in the upper GI-tract, with

expected decrease in the side-effects of the drugs.

TARGETING SYSTEMS Colon

colon is a preferable site for the absorption of

liable compounds such as peptides and proteins,

because the hydrolytic enzyme activities of the

colon are lower than that of the small intestine

thus improve the bioavailability of such drugs.

Disadvantages

colon is not suitable site for drug absorption as the

small intestine, because the water content in the

colon is much lower and the colonic surface area

for drug absorption is narrow in comparison with

the small intestine.

Methodologies For Colon Site-Specific Drug

Release: pH-sensitive delivery systems

Methods based on pH-Sensitive Polymer Coated Drug

Delivery to the Colon such as enteric coated dosage

forms

However failure of pH-dependent system may be

expected due to:

inter and intra subject variation of GI pH

pH variation due to pathological conditions and diet

composition.

such methods release the drug in the upper small

intestine after gastric emptying,

Delayed Release Drug delivery to Colon (Time

Controlled

Release System) (TCRS) :

In (TCRS) the location of drug release depends on the

transit time in GIT. such as sustained release dosage

forms.

Disadvantages

Due to the large variation in the gastric emptying time

due amount of food intake and peristalsis in the

stomach thus in this approach the colon arrival time of

dosage forms cannot be accurately predicted, resulting

in poor colonical availability.

The approach is affected by the changes in diet,

environmental conditions, and state of disease.

Colon microflora triggered system (CODESTM)

is considered as a preferable design of colon-specific

drug delivery systems, since the immediate increase

of the bacterial population and corresponding

enzymes activities in the colon represent a non-

continuous event independent of GI transit time.

Some synthetic polymers containing an aromatic azo group, which are degraded by the azoreducatase in the large bowel , can be used as coating materials for drug to form polymeric prodrug with azo linkage between the polymer and drug .However, they have demonstrated some toxicity in contrast to polysaccharides which are non toxic.

The colon contains over 400 distinct species of bacteria. The

primary sources of carbon and energy for these bacteria is the

fermentation of polysaccharides present in dietary residues.

Thus colon-specific drug delivery system is designed depending on the bacterial degradation of

polysaccharides.

Colon microflora triggered system (CODESTM) The system consists of a traditional tablet core containing lactulose , which is over coated with and acid soluble material, and then subsequently overcoated with an enteric material, Eudragit L

Schematics of conceptual design of Schematics of conceptual design of CODESCODESTMTM

During the passage of CODESTM through the GIT:CODESTM remain intact in the stomach due to the

enteric coat.In small intestine, where the pH is above 6, the

enteric coat will dissolve and acid soluble polymer coating becomes only slightly permeable and swellable.

Upon entry into the colon, the polysaccharide (HPMC) around the core tablet will dissolve and drug diffuse through the coating. Where The bacteria will enzymatically degrade the lactulos into organic acid.

This lowers the pH surrounding the system sufficiently to affect the dissolution of the acid-soluble coating and subsequent drug release.

Targeting the brain via nasal administration shown a

direct route of transport from the olfactory region to

the central nervous system (CNS) without prior

absorption to the circulating blood.

brain TARGETING SYSTEMSbrain TARGETING SYSTEMS

Advantages :

That the olfactory receptor cells are in contact with

the

nasal cavity and the CNS thus provides a target

route of drug entry to the brain

Therapeutically rapid specific targeting of drugs to

the brain would be beneficial for the treatment of

Parkinson’s disease, Alzheimer’s disease or pain.

One of the major difficulties in cancer therapy is to

achieve good specificity of antineoplastic agents for

their intended site of action in the body.

As a result of their toxicity towards healthy

tissues, many anticancer drugs are often

administered at doses that are subtherapeutic.

Thus, tumor targeting systems are used to altering

the pharmacokinetic and bio-distribution profiles of

these drugs.

tumor TARGETING SYSTEMS

This can be achieved by:This can be achieved by:1) Encapsulating antineoplastic drugs in 1) Encapsulating antineoplastic drugs in

nanoparticles as liposomes and polymeric nanoparticles as liposomes and polymeric

micelles. micelles.

These nanoparticles systems enhance drug

accumulation at the tumor site and reduce

distribution to healthy tissues. In this method drug

carriers achieve this selectivity by the enhanced

permeation and retention (EPR) depending on

difference in capillary structure between healthy and

cancerous tissues.

Neoplastic tissues generally have porous

vasculature and poor lymphatic drainage

allowing for enhanced permeation of

nanoparticles across the endothelium and

greater retention within the tumor

By the use of isopeptide-AcAASIK(L)VAVSADR-NH2 coated drug to which the attachment of blood cells is weaker than to peptide-AcAASIKVAVSADR-NH2 The isopeptide linkage in AcAASIK(L)VAVSADR-NH2 is enzymatically cleaved by proteases in tumors to give the bioadhesive peptide AcAASIKVAVSADR-NH2 thus bioadhesion becomes active only at the tumor site. Thus isopeptide AcAASIK(L)VAVSADR-NH2, can act as prodrug form for the bioadhesive peptide AcAASIKVAVSADR-NH2 that act as anticancer drug carrier for tumor targeting.

2) Use of Tumor Selective Bioadhesive 2) Use of Tumor Selective Bioadhesive PeptidesPeptides as Drug Carriersas Drug Carriers