Various approaches to Targeted Drug Delivery Systems (TDDS) in its formuation and evaluation in a pharmaceutical industry and research is outlined in this presentation.

1. DIFFERENT APPROACHES
Presented by:
Muhammed Fahad

2.  Delivery of drugs to specific part of the body.
 Significantly reduce overall drug toxicity while
maintaining therapeutic benefits.
 Improve therapeutic index of drugs.
  eg. peptide drugs
 High dosing required due to transport factors
including widespread disposition, rapid metabolism
and excretion.
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3. Approaches to Drug Targeting
 3 different approaches:
1. Physical or Mechanical Approach
2. Biological Approach
3. Chemical Approach
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4. PHYSICAL OR MECHANICAL APPROACH
 Involves formulation of drug using particulate delivery
device  physical localization  differential release
of drug.
 Site specificity is due to higher drug concns at the site.
 Also called ‘passive targeting’  exploit natural fate of
particles.
 Carrier systems may be microspheres, nanoparticles or
liposomes.
 Crucial factors—size & surface of particles.
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5. Localization of particulate carriers
 Liver—main site for clearance; hence majority of drugs
concentrate in liver.
 Oral microspheres—taken up from GI by Peyer’s
patches.
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6. Targeting to the mononuclear
phagocytic system (MPS)
 iv administered liposomes—localize within MPS.
 MPS consists of connective tissues of mesenchymal
origin.
 Functions of MPS:
 Clearance of large variety of harmful substances from
plasma.
 Catabolism of macromolecules.
 Participation in immune response.
 Synthesis and secretion of various effector molecules.
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7.  Egs:
 Targeting of azidothymidine (AZT) to macrophages as
nanoparticle carriers by iv & oral routes—18 fold increase
in reticuloendothelial system.
 Liposomal delivery of certain compounds may provide
extended retention.
 Liposomal delivery of drugs systemically enhances drug
concn of antimicrobials.
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8.  Infections caused by bacteria, fungi, viruses & protozoa
 difficult to manage with conventional chemotherapy
due to limited permeation of drugs into cells.
 Administration of antimicrobial drugs in liposomes
solves this.
 Drug-loaded liposomes are readily taken up by
phagocytic cells  help drug delivery directly to site of
action.
 Used in the treatment of systemic fungal infections such
as candidosis.
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9. Targeting to the pulmonary region
 Liposomes 50 nm in size—retained for many hrs.
 iv administered microspheres of certain drugs tend to
localize in lungs—diagnostic purposes.
Extravascular delivery
 Extravasation—ability of particles to leave blood pool.
 Solid lipid nanoparticles on iv administration accumulate
in the brain.
 E.g.: anticancer drug camptothecin loaded in
nanoparticles  increase avg residence time.
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10.  pH sensitive nanoparticle suspension used for
targeting in the eye to prevent early drug wash out.
 intraarticular administration of liposomes of
cortisol—showed increased retention in joints.
 E.g. treatment of knee arthritis with such carrier drugs
required lower dose of drug than conventional therapy.
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11. Mucosal Delivery of Antigens
 Mucosal surface—main site for pathogenic entry.
 Production of IgA provide immunity for mucosal surface
against many pathogens.
 Orally administered microspheres are taken up by
Peyer’s patches—used for oral administration.
 Microspheres protect vaccine from acid pH of stomach.
 Cause induction of IgA Ab in gut mucosa as well as other
mucosal surfaces like respiratory & genitourinary tracts.
 E.g. microspheres of Staphylococcal enterotoxin B toxoid
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12.  Size of microspheres also determine the type of
immunity offered—systemic or mucosal.
 Experiments show that microspheres smaller than 5
μm passed onto systemic circulation; those greater
than 5 μm ramained in Peyer’s patch for upto 35 days.
Magnetic Drug Targeting
 Ferrofluids—magnetic fluids
 Anticancer drugs bound to ferrofluids are targeted to
tumours by magnetic fields placed outside pateints
body.
 E.g. Epidoxorubicin
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13. BIOLOGICAL APPROACH
 Involves delivery of the drug using carrier system with
targeting moiety either in-built (by virtue of the
structure of the carrier) or is chemically coupled.
 4 approaches:
1. Antibodies directed against specific cell surface
antigens,
2. Endogenous carbohydrate-binding proteins (lectins),
3. Glycoconjugates functioning as specific ligands for
receptors on specific cells that recognize particular
sugar residues, and
4. Hormones functioning as specific ligands for receptors
on specific targets.
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14. Antibodies for Antigen Targeting
 higher immune response—when antigens are directed
to antigen presenting cells (APCs) & lymphocytes.
 Done by coupling antigen with a ligand of strong
binding affinity for molecules of MHC.
 E.g. coupling of viral antigens to monoclonal
antibodies against a mouse Class II MHC.
 Advantage:
 Preparation of safer vaccines.
 Targeting without use of carriers.
 Targeted antigen required only in 1st injection.
 Upto 1,000 fold increase in efficiency achieved.
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15. Lectins as Targeting Agents
 Endogenous carbohydrate-binding proteins of
tumours are known as lectins.
 Glycoproteins or neoglycoproteins act as carriers 
drug incorporated in glycoproteins  carbohydrate on
glycoprotein cause its uptake by lectin  drug
released intracellularly during proteolysis of carrier.
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16.  Selective lectin-mediated uptake of therapeutically
active glycoproteins by the infected tumour cells.
 E.g. lectin conjugated prodrug of doxorubicin showed
160% increase in cytostatic activity.
 Neoglycoproteins—alternatives to monoclonal
antibodies as carriers.
 Advantage: high drug loading by chemical conjugation
without loss of activity.
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17. Low Molecular Weight Proteins for Renal
Drug Targeting
 E.g.:
 targeting of naproxen using lysozyme as carrier since it
is taken up & catabolized in proximal tubules of
kidney—Showed 70 fold increase in retention in
kidneys compared to free naproxen.
 Captopril conjugated with lysozymes—6 times more
retention in kidneys observed.
 Polysaccharides such as dextran also show high
potential as oral drug carriers.
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18.  Receptor-mediated targeting of cytosine b-D
arabinoside, to liver using glycosylated dextran as
macromolecular carrier.
 Polymeric prodrug of streptomycin coupled via glycine
hydrazide, onto derivatized dextran for intracellular
infections.
 Sugar- and-charge modified albumins provide
opportunities for development of effective therapeutic
strategies.
 Inulin hydrogels as carrier for colonic drug targeting
are also used.
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19. Hormones Functioning as Specific Ligands
for Receptors on the Specific Targets:
 Insulin used as enzyme carrier for correcting enzyme
deficiency disease in fibroblasts from patients with
cholesterol storage disease.
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20. CHEMICAL APPROACH
 Incorporates targeting consideration into the drug
design process—for design of safe, localized delivery.
 Targeting to active biological molecules based on
predictable enzymatic activation. CDS is produced by
chemical reactns with target drug,  covalently
coupled with carrier & protective moieties  convert
to CDS1 CDS2 … CDSn.
 Allow sustained release of drugs also.
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21. The concentration of important precursors & intermediates
will be significantly higher at the site of action than rest of
the body.
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22. Drug Targeting to Lungs
 E.g. ester derivatives of chlorambucil and cromolyn 
hydrolyze in lungs rapidly into active parent drugs 
enhance delivery and retention time to lung tissue.
Drug Targeting to Brain
 Blood-brain barrier (BBB)  obstruct free flow of
blood b/w brain and rest of the body.
 BBB is impermeable to hydrophilic substances 
prevent loss of neurotransmitters to the plasma after
synthesis in brain  hence chemical methods are used.
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23.  Redox chemical delivery system  used to deliver drugs
that are impermeable to BBB.
 Converting a lipophilic drug to hydrophilic form  prevent
its efflux from brain.
 2 types  which do not cross BBB; eg dopamine
 which readily cross BBB
 E.g. dopamine was delivered using the N1-substituted
dihydropyridine-pyridinium salt-type redox system—15
fold increase of dopamine levels in brain.
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24. Osteotropic Drug Delivery
 E.g. bisphosphonic (BP) prodrug for 17 β-estradiol (E2)
 estrogen replacement therapy in patients of post
menopausal oesteoporosis.
In rats showed rapid uptake and enhanced halflife
of estradiol as compared to free estradiol.
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25. CONCLUSION
 Targeted delivery assist the drug molecule to reach
preferably to the desired site.
 Reduction in dose and side effects of the drug.
 Particulate drug carriers get accumulated in the liver cells
due to their smaller size than blood capillaries.
 Among particulate drug carriers, liposomes are potential
mode of delivery for the treatment of intracellular infections
since MPS cells take up liposomes easily.
 Microparticles serve as future mode of delivery for oral route
especially proteins.
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26.  Orally delivered microparticles are taken up by Peyer’s
patches  cause induction of immune response.
 Biological approach is more specific but at the same time
the biology is known for variations and mutations.
 Highly specific monoclonal antibodies may also show
cross-reactivity.
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27. REFERENCE
 Targeted and Controlled drug delivery (Novel carrier
systems), S P Vyas and R K Khar, CBS publishers,
page no: 40-67.
 Drug Targeting Organ-Specific Strategies Edited by
Grietje Molema and Dirk K. F. Meijer, page no:5-20.
 Progress in Controlled and Novel drug delivery
systems by N K Jain, CBS publishers, page no: 365-
369.
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