TARGETED DRUG DELIVERY SYSTEMSHIPRA MALIKPHARMACEUTICS

CONTENTS

• INTRODUCTION• NEED OF TDDS• ADVANTAGES & DISADVANTAGES• IDEAL TDDS• CARRIERS• STRATEGIES• SYSTEMS• MICROSPHERES: MAGNETIC MICROSPHERE• NANOPARTICLES

INTRODUCTION

• Targeted drug delivery(Smart Drug Delivery) means selective and effective localization of drug into the target at therapeutic concentrations with limited access to non target sites .

• The drug can be targeted to an organ particular tissue or cell intracellular sites virus or bacterial cells

GOAL - prolong ,localize, target, and have a protected drug interaction with the diseased tissue.

NEED OF TARGETED DRUG DELIVERY

Advantages and Disadvantages

ADVANTAGES• Reduction of drug side-effects• Reduced frequency of drug

intake• Reduced dose of drug • Uniform blood level of drug• Maximizes the therapeutic

index

DISADVANTAGES• Rapid clearance of targeted

systems• Immune reaction against

carrier systems• Insufficient localization of

targeted systems in tumor cells• Diffusion and redistribution of

released drug• High cost

PROPERTIES OF IDEAL TDDS

• It should be -o Non-toxico Biocompatible o Biodegradable o Physicochemical stable both in-vivo & in-vitro

• Controlled and predictable drug release• Minimal drug leakage • Carrier should be readily eliminated without causing any change in

diseased state • Preparation should be easy, reproductive and cost effective • Drug release should not effect drug action

CARRIERS OR MARKERS

Engineered vectors which retain drug inside or onto them to delivery it within or vicinity of target.

PROPERTIES• Cross anatomical barriers; tumor vasculature• Linkage to be stable in biological fluids• Selectively and specifically recognize target cells

STRATEGIES OF DRUG TARGETING

Passive or Inverse

PASSIVE• DDS targets the systemic

circulation of body• Drug targeting occurs due to

body’s natural response to the physicochemical properties of drug or carrier system

• Example: uptake of some colloids by RES especially in liver or spleen => ideal substrate for passive hepatic targeting of drug

INVERSE• Uptake of the DDS like colloids by

RES is avoided, hence called INVERSE TARGETING

• Example: preinjection of large amount of blank colloidal carriers or macromolecules like dextran to saturate the RES system => drug targeting to NON-RES ORGANS

ACTIVE TARGETING

• Carrier system is modified on its surface to deliver drug to a specific site

• FIRST ORDER: distribution to the capillary bed of target site like lymphatic, cerebral ventricles etc.

• SECOND ORDER: delivery to special cells like tumor or kupffer cells in liver.

• THIRD ORDER: intracellular localization of dug carrier complex via endocytosis or ligand mediated entry where lysosomal degradation of carrier complex causes release of drug.

TARGETING STRATEGIES

DUAL TARGETING• CARRIER MOLECULE also has their own therapeutic activity and thus increases

therapeutic effect of drug• Net SYNERGISTIC EFFECT of drug conjugate

DOUBLE TARGETING• TEMPORAL & SPATIAL methodologies are combined in a delivery system • SPATIAL PLACEMENT : targeting drugs to specific organs, tissues or subcellular

compartments• TEMOPAL DELIVERY :controlling the rate of drug delivery

CARRIER SYSTEMS

• Colloidal carriers• Cellular carriers

: erythrocytes, platelets, antibodies• Supramolecular delivery system

:micelles, lipoproteins(VLDL,LDL)• Polymer based system• Macromolecular carrier

:MABS, polysaccharides

COLLOIDAL CARRIER SYSTEMS

• Vesicular systems Liposome Virosome Pharmacosome

• Microparticulate systems Nanoparticles Microspheres

MICROSPHERES

• Microspheres are small spherical particles, with diameters in the micrometer range (typically 1 μm to 1000 μm).

• Also called as -– Microparticles – Microbeads

MATERIALS USED

• NATURAL POLYMERS Proteins: albumin, gelatin, collagen Carbohydrates: starch, agarose Chemically modified carbohydrates: poly(acryl) dextran, poly(acryl)

starch

• SYNTHETIC POLYMERS Biodegradable: lactides & their gylcolides, polyanhydrides Non-biodegradable: polymethyl methacrylate,acrolein

TYPES OF MICROSPHERE

NATURE DESCRIPTION IMAGE APPLICATION

BIO ADHESIVE •Intimate contact with absorption site•Prolonged residence time

Nasal :gentamycin,insulinOcular:methylprednisolone

FLOATING(GRDDS)

•Bulk density less than gastric fluid•2 types : hollow : microballon

NSAIDS,antibiotics

TYPES OF MICROSPHERE

NATURE DESCRIPTION IMAGE APPLICATION

RADIO ACTIVEMICROSPHERES

Radionuclide tightly bound to microbeadAlpha:10cell layerBeta:Not more than 12mmGamma:several cm

Diagnostic(gamma):spleen,liver imagingTherapeutic(alpha/beta):radioembolization therapy

POLYMERIC MICROSPHERES

•Biodegradable•Non-biodegradable•Swell in aqueous medium

Vaccine :hepatitisLocal:protein,hormones

MAGNETIC MICROSPHERE

• Supramolecular particles small enough to circulate through capillaries without producing embolic occlusion

• But are to be captured in micro vessels

• Dragged into the adjacent tissue by magnetic field of 0.5-0.8 Tesla

• Magnetite(Fe3O4) : ferromagnetic material that is incorporated in microspheres to make them magnetically responsive

TARGETING OF MAGNETIC MICROBEAAD

REALEASE OF DRUG

• Freely moves through the capillaries • Application of external magnetic field result in accumulation of drug

at target site

APPLICATIONS OF MAGNETIC MICROBEADS

• Localization of therapeutic agent

• Bioengineering & biomedical trends like enzyme immobilization, protein purification, cell isolation

• DNA analysis

• Drug discovery

• Molecular targeting

PREPARATION OF MICROSPHERES

METHOD DESCRIPTION APPLICATIONEmulsion solvent evaporation

Drug+polymer sol=>to aqueous phase(PVP) = EMULSION(O/W) =>evaporate solvent = microsphere

•Aceclofenac microspheres•Hollow microspheres

Emulsion cross linking

Drug=+Gelatin sol=>add drops to liquid paraffin=emulsion(W/O)=>MICROBEADS washed with isopropyl alcohol=>add to glutaraldehyde sol

Gelatin A microspheres

PREPARATION OF MICROSPHERES

METHOD DESCRIPTION APPLICATIONCo-acervation Drug+Polymer sol=>phase

separation -change in T,pH-salt or non solvent addition

•Proteins•Steroids

Emulsion-solvent diffusion

Drug polymer mix+ethanol:dichloromethane(1:1)=>add dropwise to SLS sol=agitate at 40C => microbeads dried

Microballons

Ionic gelation Diclofenac sodium+ sodium alginate aq sol=>add to Ca2+ & chitosan sol in acetic acid = microsphere kept for 24 hrs for internal gellification

Diclofenac sodium=> drug release at pH6.4-7.2

COACERVATION METHOD

NANOPARTICLES

• 1-100 nanometer in size

• Also called ULTRAFINE PARTICLES

• NANOTECHNOLOGY defines particle as a small object that behaves as a whole unit with respect to its transport and properties

PROPERTIES

• High surface area- volume ratio

• Act as bridge between bulk materials and atomic/molecular structures

• Size dependent properties are observed

• Possess unexpected optical properties as they are small enough to confine their electrons and produce quantum effects

TYPES OF NANOPARTICLES

NANO-CARRIER

DESCRIPTION IMAGE APPLICATION

NANOSHELLS

Hollow silica spheres covered with gold

Targeting tumor cells

NANOWIRES

Metallic:Au,NiSemi conducting:Si, InPInsulating:SiO2

Detect tumor in brain,treatment of Parkinson's

TYPES OF NANOPARTICLESQUANTAM DOTS

Miniscule semiconductor particles

Targeting cancerous cells

GOLD NANOPARTICLES

Ultra sensitive detection system for DNA& proteins

Genetic engineering

DENDRIMERS Synthetic nanoparticle,510nm diameter

Medical imaging,gene transfection

PREPARATION OF NANOPARTICLES

• TOP DOWNAttrition : broad size distribution (10-1000 nm) : varied particle shape or geometry : impurities

• BOTTOMS UP METHODSo Vapor phase fabrication: pyrolysiso Liquid phase fabrication: sol gel method

Fabrication

Marketed drugs

BRAND GENERIC NAME

INDICATION COMPANY

Tricor® Fenofibrate Hypercholesterolemia

Abbott Laboratories

Avinza® Morphine sulphate

Psycho stimulant Elan nano systems

Rapamune® Rapamycin immunosuppresant

Elan nano systems