targeted drug

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Targeted drug delivery:

Presented by: Maria Rose Kuriakose 1 st year M. pharm APSC, Pariyaram T argeted drug delivery 1


overview Introduction Concept and components of TDDS Type of targeting Applications of TDDS Reference 2


INTRODUCTION: TARGETED DRUG DELIVERY is a special form of drug delivery system where the pharmacologically active agent or medicament is selectively targeted or delivered only to its site of action and not to the non-target organs, tissues or cells. The drug may be delivered : To the capillary bed of the active sites To the specific type of cell / even an intracellular region . To a specific organ / tissues by complexing with the carrier that recognizes the target . Eg - tumour cells but not to normal cells, 3

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Paul Ehrlich's “magic bullet” concept has been translated to describe “drugs that go straight to their intended cell-structural targets,” interacting only with the specific target molecule. In reality, drugs never go straight to their intended targets. Drugs reach their targets as a result of properties that affect their stability in the systemic circulation, extravasations and intratumoral distribution, etc. Therefore, a more realistic interpretation of the “magic bullet” concept is for a compound that interacts with its target in an exclusive, highly specific fashion. In drug delivery, the “magic bullet” should refer to a system that delivers the majority, if not all, of a drug payload to the intended target without resulting in significant effects on non-target tissues. 4

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Objective To achieve a desired pharmacological response at a selected sites without undesirable interaction at other sites, there by the drug have a specific action with minimum side effects & better therapeutic index. E.g.- In cancer chemotherapy and enzyme replacement therapy. CHOICE OF DRUGS FOR TARGETING Pharmaceutically instable drugs (poor solubility) low absorption / bio- avilable drugs high-membrane bounding drugs pharmacokinetic / pharmacodynamic short half life large volume of distribution low specificity low therapeutic index drugs. 5


IDEAL CHARACTERISTICS Targeted drug delivery system should be- biochemically inert (non-toxic), non-immunogenic. both physically and chemically stable in vivo and in vitro. restrict drug distribution to target cells ,tissues or organs and should have uniform capillary distribution. controllable rate of drug release. drug release does not effect the drug action. therapeutic amount of drug release. minimal drug leakage during transit. carriers used must be bio-degradable or readily eliminated from the body without any problem and no carrier induced modulation of diseased state. the preparation of the delivery system should be easy or reasonably simple, reproductive and cost effective. 6


ADVANTAGES OF DRUG TARGETING OVER CONVENTIONAL DRUG DELIVERY Specific, high affinity or irreversible binding Administering the drugs at the lowest concentration needed to saturate “drug accessible” receptors Decreasing nonspecific binding Increasing the quantity of drug receptors Prolonging treatment time Chemical stability Lack of antigenicity Cell amplification 7


CONCEPT AND COMPONENTS OF TDDS Targeting of drugs to special cells and tissues of the body, without their becoming a part of systemic circulation is a very novel idea. If a drug can be administered in a form such that it reaches the receptor sites in sufficient concentration without disturbing in extraneous tissue cells . Such products are prepared by considering- 1.specific properties of target cells. 2.nature of markers or transport carriers or vehicles, which convey drug to specific receptors. 3.ligands and physically modulated components. 8

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TARGET: Target may be defined as a cell or group of cells in minority, identified to be in the need of treatment. CARRIERS OR MARKERS: Carrier is one of the important entity essentially required for effective transportation of loaded drugs. They are vectors, which sequester, retain drug and transport or deliver it into the vicinity of the target cells .. 9

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10 An ideal drug carrier should have the following features : It must be able to cross anatomical barriers It must be recognized specifically and selectively by the target cells and must maintain the avidity and specificity of the surface ligands . The linkage of the drug and the directing unit ( ligand ) should be stable in plasma , interstitial and other biofluids . Carrier should be non-toxic , non-immunogenic and biodegradable particulate or macromolecule and after recognition , and internalizaton , the carrier system should release the drug moiety inside the target organs , tissues or cells. The biomodules used for carrier navigation and site recognition should not be ubiquitous otherwise it may cross over the sites, defeating the concept of targeting

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11 Based on the nature of their origin carriers are categorized as: Endogenous ( low density lipoprotein, high density lipoprotein, chylomicrons , serum albumin, erythrocytes). Exogenous ( microparticulates , soluble polymeric and biodegradable polymeric drug carriers ).

Targeting Ligands:

Targeting Ligands Ligand Receptor Complex Ligands are chemical groups that bind together like a lock and key to target receptors. LIGANDS: The ligands confer recognition and specificity upon carrier/vector and lend them to approach the respective target and deliver the drug. Ex-antibodies, polypeptides, endogenous hormones etc 12

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Types of Targeting 13

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Passive targeting : Normal distribution pattern Composed of phospholipids/ PLP, sterols Particle possesses inadequate size less than 5µm are undergo phagocytosis- taken up by MPS.(, lymph, bone marrow, spleen) Active targeting Normal distribution pattern are modified through changes in the structure & composition. Charged lipids, ligands, carriers 14

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15 first order targeting : It refers to restricted distribution of the drug carrier system to the capillary bed of a predetermined target site, organ or tissue. Compartmental targeting in lymphatics , peritoneal cavity , plural cavity ,cerebral ventricles , lungs , joints, eyes,etc . Represents first order targeting. The ability of liposomes to extravasate and penetrate into diseased states other than MPS is directly related to their size. Large liposomes (10 µ or above ) are rapidly removed via mechanical filtration of lungs and from this size range down upto 150 nm are removed by tissue macrophages originated in the liver and spleen , which are the natural target for these vesicles

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Particles administered into the body intravenously will distribute itself in different organs depending on the size of the particles. Particles <7µm enter into the systemic circulation. Bigger particles may cause toxicity, particles of size 10-15µm can be used for lung targeting. Particles of 60-150nm size coated with the polymer and are taken up by the bone marrow. 17


applications Transdermal approach Folate targeting Targeting to the Brain Targeting to the Pulmonary Renal targeting Osteoporotic targeting Cytotoxic drug targeting Magnetic drug targeting Ag&Ab targeting Liposomal drug delivery 18

Transdermal approach:

Transdermal approach 19

Folate delivery :

Folate delivery It involves the attachment of the vitamin, folate (folic acid), to a molecule/drug to form a "FOLATE CONJUGATE". Based on the natural high affinity of folate for the folate receptor protein (FR), which is commonly expressed on the surface of many human cancers, folate-drug conjugates also bind tightly to the FR and trigger cellular uptake via endocytosis. 20

Delivery to brain:

Delivery to brain 21

As Liposomes :

As Liposomes Enhanced safety and efficacy have been achieved for a wide range of drug classes: including antitumor agents, antiviral, antimicrobials, vaccines, gene therapeutics etc. . using liposomes is to reduce toxicity and side effect of drugs. problems like poor solubility, short half life, poor bioavailability & strong side effect of various drugs can be overcome by employing the concept of liposomes especially in various diseases like cancer…. 22

Concept of drug targeting by monoclonal antibody:

Concept of drug targeting by monoclonal antibody Targeting with Ab depends on: the presence of new Ag from the tumor cells of Ab the ability to obtain specific Ab against them in normal cell - the antigen are absent. The antigen associated with tumor cells are called as the” TUMOR MAKER”. Antibodies produced as the results of the specific markers monoclonally can be conjugated with drug molecule which in turn can be targeted to the specific cells or tumor tissues. 23

As nanoparticles :

As nanoparticles The major goals in designing nanoparticles as a delivery system are: to control particle size, surface properties and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutically optimal rate and dose regimen. overall pharmacological response per unit dose is enhanced . They are reproducible , can be freeze dried, so obtain in a dried powder form. Non toxic and biodegradable Relatively cheaper and stable 24


MAGNETIC MICROSPHERES M icrospheres containing substance (ferric sub.) which can be easily targeted by applying external magnetic field. Magnetic microspheres were developed : minimize renal clearance To increase target site specificity To entrap a wide variety of drugs In the entrapment of localised tumours in the religions of well defined blood supply For controlled release of peptide protein drugs such as LHRH, which have the short half life. To minimize reticulo endothelial clearance at target site High specificity. 25

Cytotoxic delivery:

Cytotoxic delivery Chemotherapeutic agents do not specifically target tumor cells, but rather interfere with cell division or inhibit enzymes involved DNA replication or metabolism. These drugs therefore also damage the normal dividing cells of rapidly regenerating tissues, such as those of the bone marrow, gut mucosa and hair follicles. Cancer chemotherapy is limited by a lack of specificity, resulting in damage to not only cancer cells but also normal cells. 26

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drug Current status Gefitinib / Iressa  FDA approved Lapatinib / Tykerb  FDA approved Erlotinib / Tarceva  FDA approved Canertinib phase11 VEGFR Vatalanib phase111 Imatinib FDA approved pazopanib FDA approved drug Current status Bevacizumab FDA approved IMC-1C11 phase1 mF4-31C1 Pre-clinical trail Vitaxin phase1 MARKETED DRUG PRODUCTS 27

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Name of drug Type of cancer used to treat Alemtuzumab (Campath) Chronic lymphocytic leukemia. Bevacizumab ( Avastin ) Breast cancer. Colon cancer. Lung cancer. Glioblastoma multiforme . Cetuximab ( Erbitux ) Colon cancer. Head and neck cancers. Gemtuzumab (Mylotarg) Acute myelogenous leukemia. Ibritumomab (Zevalin) Non-Hodgkin’s lymphoma. Chronic lymphocytic leukemia. Panitumumab (Vectibix Colon cancer. Rituximab (Rituxan) Non-Hodgkin’s lymphoma. Tositumomab (Bexxar) Non-Hodgkin’s lymphoma Trastuzumab (Herceptin Breast cancer FDA-approved monoclonal antibodies for cancer treatment 29


References Advances in controlled and novel drug delivery by n.k jain pag n:452-464 Targeted and contolled drug delivery by: vays and khar . Targeted drug delivery system: A Review Gupta Manish and Sharma Vimukta, BM College of Pharmaceutical Education and Research, Indore, INDIA Available online at: 30

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TARGETED DRUG DELIVERY SYSTEM Department of pharmaceutics BLDEA’S College of pharmacy, Bijapur Prepared by: Geetha B. Singri Submitted to: Dr.R.V . KULKARNI An article of Liposomes As Drug Delivery Systems for the Treatment of TB: Passive & Active Targeting of Liposomes as Drug Delivery Systems for the Treatment of TB Overview on monoclonal antibody therapy: images and videos, Pharmacology education for healthcare professionals Journal of Controlled Release journal homepage: locate/ jconrel Targeted drug delivery to tumors: Myths, reality and possibility You Han Bae a, Kinam Park 31

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Thank you… 32

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