Drug targating

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Drug Targeting

Mr. Sagar Kishor savaleMr. Sagar Kishor savale[[Department of Pharmaceutics] Department of Pharmaceutics]

[email protected] [email protected] 2015-0162015-016

Department of Pharmacy (Pharmaceutics) | Sagar savale

05/01/2305/01/23 Sagar SavaleSagar Savale

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CONTENTSCONTENTS Problems with CDDSProblems with CDDS Drug TargetingDrug Targeting Types of Drug TargetingTypes of Drug Targeting Approaches of Drug TargetingApproaches of Drug Targeting Levels of Drug TargetingLevels of Drug Targeting Factors affecting Drug TargetingFactors affecting Drug Targeting Targeted Drug Delivery SystemTargeted Drug Delivery System Problems with TDDSProblems with TDDS ReferencesReferences


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Problems Associated With Conventional Drug Problems Associated With Conventional Drug Delivery SystemDelivery System

Difficulty in assessing diseased site (RA, Diseases of CNS, Difficulty in assessing diseased site (RA, Diseases of CNS, Cancer, Interact able bacterial, fungal & parasitic infection)Cancer, Interact able bacterial, fungal & parasitic infection)

High dose & frequent administration of drugs leads to toxic High dose & frequent administration of drugs leads to toxic manifestationmanifestation

Inappropriate pharmacodepositionInappropriate pharmacodeposition Inactivation or decomposition of drug by GIT pH, by enzymes Inactivation or decomposition of drug by GIT pH, by enzymes

which digest food , metabolism by microbial florawhich digest food , metabolism by microbial flora In parentral route deactivation & metabolism of drug, dose In parentral route deactivation & metabolism of drug, dose

related toxicity frequently observed.related toxicity frequently observed.


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Ideal Characteristics of Targeted Drug Delivery SystemIdeal Characteristics of Targeted Drug Delivery System

It should be It should be Biochemically Inert ( Non-toxic)Biochemically Inert ( Non-toxic) NonimmunogenicNonimmunogenic Physically & Chemically stable Physically & Chemically stable in-vivo in-vivo & & in-vitro.in-vitro. The carrier must be biodegradable or readily eliminated from The carrier must be biodegradable or readily eliminated from

body without problemsbody without problems Preparation of the delivery system must be reproducible, cost-Preparation of the delivery system must be reproducible, cost-

effective & simpleeffective & simple

Drug Targeting Drug targeting means to deliver the drug only to its

site of action & not to the non-target organs, tissues or cells.


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Rational for Targeted Drug Delivery Rational for Targeted Drug Delivery SystemSystem

To supply drug selectively to its site of action to provide To supply drug selectively to its site of action to provide maximum therapeutic activitymaximum therapeutic activity

Preventing degradation or inactivation of drug Preventing degradation or inactivation of drug Prevention of inappropriate deposition of the drug Prevention of inappropriate deposition of the drug For the drugs that have low therapeutic indexFor the drugs that have low therapeutic index


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Types of Drug TargetingTypes of Drug Targeting

First Order TargetingFirst Order TargetingIt involves the delivery of a drug to specific organ or a tissueIt involves the delivery of a drug to specific organ or a tissue

Second Order TargetingSecond Order TargetingIt involves targeting towards the specific cell type within the It involves targeting towards the specific cell type within the tissue or organ (e.g. Tumor cells Vs Normal cell) tissue or organ (e.g. Tumor cells Vs Normal cell)

Third Order TargetingThird Order TargetingIt involves a delivery to a specific intracellular compartment in It involves a delivery to a specific intracellular compartment in the target cell ( e.g. Lysosomes)the target cell ( e.g. Lysosomes)


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Approaches of Drug TargetingApproaches of Drug TargetingFirst ApproachFirst Approach

It involves the use of biologically active agents that are It involves the use of biologically active agents that are both potent & selective to a particular site in the body both potent & selective to a particular site in the body

((Magic Bullet Approach of EhrlichMagic Bullet Approach of Ehrlich))Second ApproachSecond Approach

It involves the preparation of pharmacologically inert It involves the preparation of pharmacologically inert form of active drugs, which upon reaching the active sites form of active drugs, which upon reaching the active sites becomes activated by a chemical or enzymatic reaction becomes activated by a chemical or enzymatic reaction

( ( Prodrug ApproachProdrug Approach))Third ApproachThird Approach

Biologically inert macromolecular carrier system that Biologically inert macromolecular carrier system that directs a drug to a specific site in the body where it is directs a drug to a specific site in the body where it is accumulated & shows its effect ( accumulated & shows its effect ( Magic Gun or Missile Magic Gun or Missile Approach)Approach)


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Levels of Drug TargetingLevels of Drug Targeting

Followings are the levels of drug targetingFollowings are the levels of drug targeting

Passive TargetingPassive Targeting Inverse TargetingInverse Targeting Active Targeting ( Ligand Mediated Targeting & Physical Active Targeting ( Ligand Mediated Targeting & Physical

Targeting )Targeting ) Dual TargetingDual Targeting Double TargetingDouble Targeting Combination TargetingCombination Targeting


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Passive TargetingMeans targeting occurs because of the body’s natural

response to the physicochemical characteristics of the drug or drug carrier system

e.g.

The ability of some colloids to be taken up by the RES specially in the liver & spleen

Inverse TargetingThese process involves the reversion of the biodistribution

trend of the carrier & hence the process is referred as inverse targeting

e.g.

Suppression of the RES by the pre-injection of the large amount of blank colloidal carriers which leads to impairment of the host defense system.


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Active Targeting

The facilitation of the binding of the drug-carrier to target cells through the use of ligands or engineered homing devices to increase receptor mediated localization of the drug & target specific delivery of drug is referred as active targeting.

. Active Targeting

Ligand Mediated Targeting

Physical Targeting


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Ligand Mediated Targeting

Here the carrier for the drug is made specific for the certain cell or group of cells by incorporating ligands such as antibody, polypeptide, oligosaccharides etc. on the surface of the carrier.

e.g.apoprotein coat serves as ligand for the LDL receptors

Physical TargetingIn this mode of targeting ,some characteristics of the

bioenvironment are used either to direct the carrier to particular location or to cause selective release of its content.

e.g.

Application of the external magnetic stimuli has been suggested for the localization of the magno-responsive liposomes and microspheres within a preselective capillary bed.


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Dual TargetingThis classical approach of the drug targeting employs, carrier

molecules which have their own intrinsic anti-viral effect thus synergies the anti-viral effect of the loaded active drug.

Double Targeting

In this mechanism spatial targeting is combined with temporal control release .

Sustain release

Stimuli Responsive Release

Self-regulating Release

Active Targeting

Passive TargetingDouble

Targeting

Controlled Release of Drug

Drug Targeting


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e.g.

PEG coated liposomes (for selective release of drug in low pH medium) attached with MAb (for targeting specific target like tumor)

Combination Targeting

These targeting systems are equipped with carriers, polymers & homing devices of molecular specificity that could provide a direct approach to the target site.


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Factors affecting the Drug TargetingFactors affecting the Drug Targeting

Cellular Uptake & ProcessingCellular Uptake & Processing OpsonizationOpsonization

Phagocytosis carried out specialized cells of mononuclear Phagocytosis carried out specialized cells of mononuclear phagocyte system mediated by absorption of specific blood phagocyte system mediated by absorption of specific blood components (opsonins) is called as opsonization.components (opsonins) is called as opsonization.

Affected ByAffected By: Hydrophilic property of carrier system,: Hydrophilic property of carrier system, Its molecular weight, size & conc. in extra-vascular Its molecular weight, size & conc. in extra-vascular fluid fluid

Transport Across the Epithelial BarrierTransport Across the Epithelial Barrier

Affected ByAffected By: pH of the site, enzymes present, surface area of target, : pH of the site, enzymes present, surface area of target, segment length, microbial flora, transit time segment length, microbial flora, transit time


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Extravasation

In many diseases drugs have to egress from the central circulation & interact with its extra vascular-extracellular or extra vascular-intracellular targets .This process of transvascular exchange is called as extravasation.

Affected By: permeability of the blood capillary walls, rate & flow of blood supply, physiochemical factors of the compound, presences of the anionic sites on the endothelium etc.

Lymphatic Uptake

Following extravasation, drug molecules either reabsorbed into the blood circulation or into lymphatic system & then return with lymph into blood circulation. This process is known as Lymphatic Uptake.

Affected By: size & surface characteristics of the particles, formulation medium, composition & pH of the interstitial medium05/01/2305/01/23 Sagar SavaleSagar Savale

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Targeted Drug Delivery System

Prodrugs Drug-Carrier Delivery System

LiposomesNiosomesNanoparticlesMicroparticlesErythrocytesNeutrophillsSpecialized EmulsionsVirosomes

ADPETPolymeric Prodrugs


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ProdrugsProdrugs

ConceptConcept : : Chemically modification of the drug, which following administration Chemically modification of the drug, which following administration in side the body under go suitable changes yielding active principles in side the body under go suitable changes yielding active principles at the target site in the body compartment avoiding unnecessary at the target site in the body compartment avoiding unnecessary exposure of drugs to the other parts of the body.exposure of drugs to the other parts of the body.

e.g. e.g. Delivery of L-Dopa (precursor of dopamine) to brain, in the corpus Delivery of L-Dopa (precursor of dopamine) to brain, in the corpus striatum converted to dopamine by an enzyme aromatic amino acid striatum converted to dopamine by an enzyme aromatic amino acid decarboxylasedecarboxylase

A prodrug is pharmacologically A prodrug is pharmacologically inert form of an active drug that undergo inert form of an active drug that undergo transformation to the parent compound in transformation to the parent compound in vivo either by a chemical or an enzymatic vivo either by a chemical or an enzymatic reaction to exert its therapeutic effects.reaction to exert its therapeutic effects.


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Prodrug

ADPET Polymeric Prodrugs

ADPET (Antibody Directed Enzyme Prodrug Therapy)

Polymeric Prodrugs

ProdrugProdrug

POLYMERPOLYMER


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Drug-Carrier Delivery Systems

Drug CarriersCarrier is the one of the most important entities

essentially required for the successful transport of the loaded drug(s). These are the drug vectors which sequester, transport and retain drug en route, while elute or delivery it within or in the vicinity of target.

Ideal Features of Drug Carrier

Must be specific & selective for target cells Must maintain avidity & identity of the surface ligands.It must be able to cross the anatomical barriers & in case of tumor, tumor vasculature.Should be stable in plasma, interstitial & other biofluids05/01/2305/01/23 Sagar SavaleSagar Savale

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It should be non-toxic, non-immunogenic & biodegradable, & after recognition, & internalization the carrier system should release the drug moiety inside the target

The biomolecules used for carrier navigation & site recognition should not be ubiquitous otherwise it may cross over the sites, defeating the concept of targeting


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Liposomes are microscopic vesicles composed of one or more lipid bilayers, separated by water or aqueous buffer compartments with a diameter ranging from 80nm-10µm.

Liposomes

As a Carrier for Targeted Drug Delivery

Mainly used to target the organs like liver & spleenprolonged circulating time & small size (easy for extravasation) Magnetic liposomes pH sensitive cationic liposomes & anionic liposomes MAb can be easily incorporated on their surfaceOstearlylamylopectin coated liposomes specific for lung targeting


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Niosomes Niosomes are essentially no n-ionic

surfactant based multi-lamellar or uni-lamellar vesicles in which an aqueous solution of solute is entirely enclosed by a membrane resulted from the organization of the surfactant molecules as a bilayers. Niosomes are chemically more stable compare to liposomesAs a Carrier for Targeted Drug Delivery System carrier for drug delivery to the sites other than liver & spleen.e.g. Niosomes containing muramic acid Like liposomes selectively taken up by liver & spleen Immunoglobulin can be easily coated on the lipid surface


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Nanoparticles

As a Carrier for Targeted Drug Delivery System

polyoxyethylene coated nanoparticles

Polysorbate 80 coated nanoparticles for drug delivery to brain

transferrin coated gelatin nanoparticles

for targeting the lymph nodes

easily cross the vasculature of the tumor cells

Nanoparticles include the colloidal particles ranging in size from 10-1000nm.


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Microparticles Microparticles

include particles larger than 1µm but small enough not to sediment when suspended in water & larger enough to scatter the incoming light.


For targeting inflammatory bowelsTo target specific blood cells.Magnetic microspheres for delivery of radiopharmaceuticals MAb can be easily attached


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VirosomesVirosomes are

reconstituted influenza virus envelopes. The membrane of these vesicles consists of a spherical, unilamellar lipid bilayer. Purified influenza envelope glycoproteins are inserted into the lipid bilayer. The mean diameter of the vesicles is in the range of 120 - 180 nm.


Can be easily conjugated to the antibody against the antigen present on the tumor cells.


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Specialized EmulsionsEmulsions are the dispersion of one liquid

inside the other liquid


For liver targeting

Polyoxyethylene as an emulsifier

Conjugating antibodies to the distal end of polyoxyethylene


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Released RBCsThe membrane of

RBCs can be temporarily broken by changing tonicity or applying current to load drug inside them & this can be repair to gate intact RBCs. These RBCs can be used as targeted drug delivery


In liver cancer tumors, in Gaucher’s disease, in case of iron overload

Magnetic RBCs05/01/2305/01/23 Sagar SavaleSagar Savale

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NeutrophillsNeutrophills are one of

the WBCs present inside the blood.


Mainly in the pyrogenic diseases like acute arthritis, ulcerative colitis


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Problems Associated With Targeted Drug Problems Associated With Targeted Drug Delivery SystemDelivery System

Rapid clearance of targeted systems Rapid clearance of targeted systems Immune reactions against i.v. administered carrier systemImmune reactions against i.v. administered carrier system Target tissue heterogeneityTarget tissue heterogeneity Problems of insufficient localization of targeted systems into Problems of insufficient localization of targeted systems into

tumor cellstumor cells Down regulation & slugging of surface epitopesDown regulation & slugging of surface epitopes Diffusion & redistribution of released drug leading to non-Diffusion & redistribution of released drug leading to non-

specific accumulationspecific accumulation


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REFERENCESREFERENCES

Banker G S, Rhodes T R, Modern Pharmaceutics, Marcel Banker G S, Rhodes T R, Modern Pharmaceutics, Marcel Dekker, 4Dekker, 4thth ed, 529-586 ed, 529-586

Shargel L, Wu-pong S, Andrew B, Applied Biopharmaceutics Shargel L, Wu-pong S, Andrew B, Applied Biopharmaceutics & Pharmacokinetics, Mc Garw Hill, 567-573& Pharmacokinetics, Mc Garw Hill, 567-573

Kulkarni J S, Pawar A P, Shedbalkar V P, Biopharmaceutics Kulkarni J S, Pawar A P, Shedbalkar V P, Biopharmaceutics & Pharmacokinetics, 1& Pharmacokinetics, 1stst ed, CBS publishers, 159-164 ed, CBS publishers, 159-164

Ali J, Khar R, Ahuja A, Textbook of Biopharmaceutics & Ali J, Khar R, Ahuja A, Textbook of Biopharmaceutics & Pharmacokinetics,1Pharmacokinetics,1stst ed, Birla Publication, 226-234 ed, Birla Publication, 226-234


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Vyas S P, Khar R K, Targeted & controlled Drug Delivery Vyas S P, Khar R K, Targeted & controlled Drug Delivery Novel Carrier Systems, CBS Publishers, 1Novel Carrier Systems, CBS Publishers, 1stst ed;2004, 38-80 ed;2004, 38-80

Brahmankar D M, Jaiswal S B, Biopharmaceutics & Brahmankar D M, Jaiswal S B, Biopharmaceutics & Pharmacokinetics A Treatise, Vallabh Prakashan, 1Pharmacokinetics A Treatise, Vallabh Prakashan, 1stst ed;2006,336-340ed;2006,336-340

Shaji J, Chhatwani D, Liposomes: Biomedicines of The Shaji J, Chhatwani D, Liposomes: Biomedicines of The Future, ijper, Vol 41 (3), Jul-sep-2007,180-194Future, ijper, Vol 41 (3), Jul-sep-2007,180-194

http://www.pharmainfo.net/reviews/niosome-unique-drug-http://www.pharmainfo.net/reviews/niosome-unique-drug-delivery-system delivery-system

www.pathology.unibe.ch/.../virosomes/drug_tg.htmwww.pathology.unibe.ch/.../virosomes/drug_tg.htm


Drug targating

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