Approaches to Targeted Delivery of Drugs

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

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Approaches to Targeted Delivery of Drugs

  1. 1. DIFFERENT APPROACHESPresented by:Muhammed Fahad
  2. 2.  Delivery of drugs to specific part of the body. Significantly reduce overall drug toxicity whilemaintaining therapeutic benefits. Improve therapeutic index of drugs.  eg. peptide drugs High dosing required due to transport factorsincluding widespread disposition, rapid metabolismand excretion.2
  3. 3. Approaches to Drug Targeting 3 different approaches:1. Physical or Mechanical Approach2. Biological Approach3. Chemical Approach3
  4. 4. PHYSICAL OR MECHANICAL APPROACH Involves formulation of drug using particulate deliverydevice  physical localization  differential releaseof drug. Site specificity is due to higher drug concns at the site. Also called ‘passive targeting’  exploit natural fate ofparticles. Carrier systems may be microspheres, nanoparticles orliposomes. Crucial factors—size & surface of particles.4
  5. 5. Localization of particulate carriers Liver—main site for clearance; hence majority of drugsconcentrate in liver. Oral microspheres—taken up from GI by Peyer’spatches.5
  6. 6. Targeting to the mononuclearphagocytic system (MPS) iv administered liposomes—localize within MPS. MPS consists of connective tissues of mesenchymalorigin. Functions of MPS: Clearance of large variety of harmful substances fromplasma. Catabolism of macromolecules. Participation in immune response. Synthesis and secretion of various effector molecules.6
  7. 7.  Egs: Targeting of azidothymidine (AZT) to macrophages asnanoparticle carriers by iv & oral routes—18 fold increasein reticuloendothelial system. Liposomal delivery of certain compounds may provideextended retention. Liposomal delivery of drugs systemically enhances drugconcn of antimicrobials.7
  8. 8.  Infections caused by bacteria, fungi, viruses & protozoa difficult to manage with conventional chemotherapydue to limited permeation of drugs into cells. Administration of antimicrobial drugs in liposomessolves this. Drug-loaded liposomes are readily taken up byphagocytic cells  help drug delivery directly to site ofaction. Used in the treatment of systemic fungal infections suchas candidosis.8
  9. 9. Targeting to the pulmonary region Liposomes 50 nm in size—retained for many hrs. iv administered microspheres of certain drugs tend tolocalize in lungs—diagnostic purposes.Extravascular delivery Extravasation—ability of particles to leave blood pool. Solid lipid nanoparticles on iv administration accumulatein the brain. E.g.: anticancer drug camptothecin loaded innanoparticles  increase avg residence time.9
  10. 10.  pH sensitive nanoparticle suspension used fortargeting in the eye to prevent early drug wash out. intraarticular administration of liposomes ofcortisol—showed increased retention in joints. E.g. treatment of knee arthritis with such carrier drugsrequired lower dose of drug than conventional therapy.10
  11. 11. Mucosal Delivery of Antigens Mucosal surface—main site for pathogenic entry. Production of IgA provide immunity for mucosal surfaceagainst many pathogens. Orally administered microspheres are taken up byPeyer’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 othermucosal surfaces like respiratory & genitourinary tracts. E.g. microspheres of Staphylococcal enterotoxin B toxoid11
  12. 12.  Size of microspheres also determine the type ofimmunity offered—systemic or mucosal. Experiments show that microspheres smaller than 5μm passed onto systemic circulation; those greaterthan 5 μm ramained in Peyer’s patch for upto 35 days.Magnetic Drug Targeting Ferrofluids—magnetic fluids Anticancer drugs bound to ferrofluids are targeted totumours by magnetic fields placed outside pateintsbody. E.g. Epidoxorubicin12
  13. 13. BIOLOGICAL APPROACH Involves delivery of the drug using carrier system withtargeting moiety either in-built (by virtue of thestructure of the carrier) or is chemically coupled. 4 approaches:1. Antibodies directed against specific cell surfaceantigens,2. Endogenous carbohydrate-binding proteins (lectins),3. Glycoconjugates functioning as specific ligands forreceptors on specific cells that recognize particularsugar residues, and4. Hormones functioning as specific ligands for receptorson specific targets.13
  14. 14. Antibodies for Antigen Targeting higher immune response—when antigens are directedto antigen presenting cells (APCs) & lymphocytes. Done by coupling antigen with a ligand of strongbinding affinity for molecules of MHC. E.g. coupling of viral antigens to monoclonalantibodies 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.14
  15. 15. Lectins as Targeting Agents Endogenous carbohydrate-binding proteins oftumours are known as lectins. Glycoproteins or neoglycoproteins act as carriers drug incorporated in glycoproteins  carbohydrate onglycoprotein cause its uptake by lectin  drugreleased intracellularly during proteolysis of carrier.15
  16. 16.  Selective lectin-mediated uptake of therapeuticallyactive glycoproteins by the infected tumour cells. E.g. lectin conjugated prodrug of doxorubicin showed160% increase in cytostatic activity. Neoglycoproteins—alternatives to monoclonalantibodies as carriers. Advantage: high drug loading by chemical conjugationwithout loss of activity.16
  17. 17. Low Molecular Weight Proteins for RenalDrug Targeting E.g.: targeting of naproxen using lysozyme as carrier since itis taken up & catabolized in proximal tubules ofkidney—Showed 70 fold increase in retention inkidneys compared to free naproxen. Captopril conjugated with lysozymes—6 times moreretention in kidneys observed. Polysaccharides such as dextran also show highpotential as oral drug carriers.17
  18. 18.  Receptor-mediated targeting of cytosine b-Darabinoside, to liver using glycosylated dextran asmacromolecular carrier. Polymeric prodrug of streptomycin coupled via glycinehydrazide, onto derivatized dextran for intracellularinfections. Sugar- and-charge modified albumins provideopportunities for development of effective therapeuticstrategies. Inulin hydrogels as carrier for colonic drug targetingare also used.18
  19. 19. Hormones Functioning as Specific Ligandsfor Receptors on the Specific Targets: Insulin used as enzyme carrier for correcting enzymedeficiency disease in fibroblasts from patients withcholesterol storage disease.19
  20. 20. CHEMICAL APPROACH Incorporates targeting consideration into the drugdesign process—for design of safe, localized delivery. Targeting to active biological molecules based onpredictable enzymatic activation. CDS is produced bychemical reactns with target drug,  covalentlycoupled with carrier & protective moieties  convertto CDS1 CDS2 … CDSn. Allow sustained release of drugs also.20
  21. 21. The concentration of important precursors & intermediateswill be significantly higher at the site of action than rest ofthe body.21
  22. 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 ofblood b/w brain and rest of the body. BBB is impermeable to hydrophilic substances prevent loss of neurotransmitters to the plasma aftersynthesis in brain  hence chemical methods are used.22
  23. 23.  Redox chemical delivery system  used to deliver drugsthat are impermeable to BBB. Converting a lipophilic drug to hydrophilic form  preventits efflux from brain. 2 types  which do not cross BBB; eg dopamine which readily cross BBB E.g. dopamine was delivered using the N1-substituteddihydropyridine-pyridinium salt-type redox system—15fold increase of dopamine levels in brain.23
  24. 24. Osteotropic Drug Delivery E.g. bisphosphonic (BP) prodrug for 17 β-estradiol (E2) estrogen replacement therapy in patients of postmenopausal oesteoporosis.In rats showed rapid uptake and enhanced halflifeof estradiol as compared to free estradiol.24
  25. 25. CONCLUSION Targeted delivery assist the drug molecule to reachpreferably to the desired site. Reduction in dose and side effects of the drug. Particulate drug carriers get accumulated in the liver cellsdue to their smaller size than blood capillaries. Among particulate drug carriers, liposomes are potentialmode of delivery for the treatment of intracellular infectionssince MPS cells take up liposomes easily. Microparticles serve as future mode of delivery for oral routeespecially proteins.25
  26. 26.  Orally delivered microparticles are taken up by Peyer’spatches  cause induction of immune response. Biological approach is more specific but at the same timethe biology is known for variations and mutations. Highly specific monoclonal antibodies may also showcross-reactivity.26
  27. 27. REFERENCE Targeted and Controlled drug delivery (Novel carriersystems), S P Vyas and R K Khar, CBS publishers,page no: 40-67. Drug Targeting Organ-Specific Strategies Edited byGrietje Molema and Dirk K. F. Meijer, page no:5-20. Progress in Controlled and Novel drug deliverysystems by N K Jain, CBS publishers, page no: 365-369.27
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