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
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