Targeted Drug Delivery Systems

Prepared by
Guided By Parth S. Abhangi
Dr Sunny R. Shah 2nd Sem M.Pharm
Assistant Professor Enroll no. -202120820006

Department of Pharmaceutics
B. K. Mody Government Pharmacy College, Rajkot
 LIST OF CONTENTS

 Introduction
 Characteristics and applications of targeted drug delivery system
 Generation of drug delivery system
 Need of targeted drug delivery system
 Advantages and disadvantages of targeted drug delivery system
 Types of targeted drug delivery system
 Drug delivery vehicles
 Questions included in past GTU examination
 Reference
 INTRODUCTION

 Targeted drug delivery is a kind of smart drug delivery system which

is miraculous in delivering the drug to a patient.
 The conventional drug delivery system is done by the absorption of
the drug across a biological membrane, whereas in targeted release
system drug is released in a dosage form.
 The drug delivery system is highly integrated and requires various
disciplines, such as chemists, biologist and engineers, to join forces to
optimize this system.
 INTRODUCTION

 When implementing a targeted release system, the following design

criteria for the system need to take into account: -
 The drug properties,
 Side effects of the drugs,
 The route taken for the delivery of the drug,
 The targeted site and
 The disease.
Why Targeted drug delivery system is preferred over
Conventional drug delivery systems?

Pharmaceutical Pharmacokinetic Pharmacodynamic

Reason Reason Reason

• Poor Absorption
• Low Specificity
• Drug Instability • Short Half Life
• Low Therapeutic
• Low Solubility • Large Volume of
Index
Distribution
 Free Drug V/S Drug in carrier
target site
Non target target site
Non target site
site

Facilitated transport
Access, affinity No access No access (effect: targeting)
(effect : toxicity) No affinity No affinity
(limited effect) (limited effect)
Drug in carrier
FREE DRUG

Inactivation/less Sequestration and improved

therapeutic effect therapeutic availability

Bio-environmental Bio-environmental
factors factors
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 Characteristics of Targeted Drug Delivery System

 Should be biochemically inert.

 Should be non-immunogenic.
 Should be physically and chemically stable in in-vivo and
in-vitro conditions.
 Should have therapeutic amount of drug release.
 Should have minimal drug leakage during transit.
 Carriers used should be biodegradable or readily eliminated
from the body.
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 Applications of Targeted Drug Delivery System

 Targeted drug delivery can be used to treat many diseases, such as

cardiovascular diseases and diabetes. However, the most important
application of targeted drug delivery is to treat cancerous tumour.
 Liposomes can be used as drug delivery for the treatment of
tuberculosis. The traditional treatment of TB is skin chemotherapy
which is not overly effective, which may be due to the failure of
chemotherapy to make a high enough concentration at the infection
site. The liposome delivery system allows for better microphage
penetration and better builds a concentration at the infection site.
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 Generation of drug delivery system

First Generation Second Third Generation Fourth Generation

DDS: Generation DDS: DDS: DDS: Fifth Generation
Tablet Repeat action Osmotically controlled Targeted drug DDS:
Capsule tablet system delivery system Gene therapy
Ointment Prolong action Swelling controlled Modulated drug under various
Suspension tablet system delivery system phase of
Emulsion Enteric coated Diffusion controlled Self regulated Drug development
Suppositories tablet system delivery system
 Need of targeted drug delivery

 Targeted drug delivery system means specific organ or a cell or group

of cells, which is in chronic or acute condition need treatment.
 The need of this system is to deliver the certain amount of drug to the
targeted diseased area within the body.
 This will help to maintain the required plasma level and tissue drug
level in the body therefore avoiding any damage to the healthy tissue
via drug.
 Various reason for need of Targeted drug delivery system can be
understood from following flowchart: -
 Pharmaceutical Reasons  Biopharmaceutical Reasons
Drug instability in conventional Poor absorption
dosage form High-membrane bounding
Low Solubility Biological instability

Need of targeted drug

delivery system

 Pharmacokinetic /
Pharmacodynamic Reasons
 Clinical Reasons
Short half-life
Low therapeutic index
Large volume of distribution
Low specificity 11
 NEED OF TDDS

 Targeted drug delivery system means specific organ or a cell or group

of cells, which is chronic or acute condition need treatment. Drug
carrier is one of the special molecules required for effective
transportation of loaded drug to pre selective site.
 The drug carrier should be bio degradable or readily eliminated from
the body without any problem. The need of this system is to deliver
the certain amount of drug to the targeted diseased area within the
body. This will help to maintain the required plasma level and tissue
drug level in the body therefore avoiding any damage to the healthy
tissue via drug.
 Advantages

 Target drug delivery system reduces the side effects and toxicity.
 The Dose of the drug reduces by targeting organ.
 It avoids the degradation of drug (first pass metabolism).
 Drug bioavailability increases and fluctuation in concentration
decreases.
 It also has positive effect on permeability of proteins and peptide.
 No peak and valley plasma concentration.
 These all factors in combination cause in reduction in dosage
frequency and hence reduce the cost of expensive drug.
 disadvantages

 Advanced techniques and skilled persons are required.

 Rapid clearance of targeted system.
 Immune reactions against i.v administered carrier system.
 Diffusion and redistribution of released drug.
 Drug deposition at the target site may produce toxicity symptoms.
 Difficult to maintain stability of dosage form.
 Types of Targeted Drug Delivery Systems

Double Targeting Active Targeting

Drug
Dual Targeting Passive Targeting
Targeting

Combination Targeting Inverse Targeting

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 Active Targeting

 Active targeting means a specific ligand – receptor type interaction for

intracellular localization which occurs only after blood circulation and
extravasations.
 This active targeting approach can be further classified into three
different levels of targeting which are: -
 First order (organ compartmentalization),
 Second order (cellular targeting) and
 Third order (intracellular targeting).
 Active Targeting

1) First order targeting refers to restricted distribution of the drug

carrier systems to the capillary bed of a predetermined target site,
organ or tissue e.g., compartmental targeting in lymphatics,
peritoneal cavity, plural cavity, cerebral ventricles and eyes, joints.
2) Second order targeting refers to selective delivery of drugs to
specific cell types such as tumour cells and not to the normal cells
e.g., selective drug delivery to kupffer cells in the liver.
 Active Targeting

3) Third order targeting refers to drug delivery specifically to the

intracellular site of targeted cells e.g., receptor-based ligand
mediated entry of a drug complex into a cell by endocytosis.
 The Active Targeting can be done in two ways which can be enlisted
as under: -
1) Physical Targeting
2) Ligand mediated active targeting
 Physical Targeting

 In this type of targeting some characteristics of environment changes

like pH, temperature, light intensity, electric field, ionic strength,
small and even specific stimuli like glucose concentration are used to
localize the drug carrier to predetermined site.
 This approach was found exceptional for tumour targeting as well as
cytosolic delivery of entrapped drug or genetic material.
 Ex.- Temperature sensitive liposomes and acid swelling chitosan
nanoparticles.
 Ligand mediated active targeting

 A ligand is some molecule which we attach to the drug delivery

system and takes it to the target site. A ligand and its receptor form a
complex because structurally they are complimentary to each other.
 A variety of molecules are represented as ligands including
antibodies, hormones, low density lipoproteins etc.
 Example- Biotin avidin conjugates
 Biotin avidin conjugates

Drug loaded
carrier conjugated
with avidin

Targeting Moiety Receptor

Biotin molecule
Drug molecule

Avidin molecule
 Passive Targeting

 Drug delivery systems which are targeted to systemic circulation are

characterized as Passive delivery systems. In this technique drug
targeting occurs because of the body’s natural response to
physicochemical characteristics of the drug or drug carrier system.
 In passive targeting, the drug's success is directly related to circulation
time. This is achieved by cloaking the nanoparticle with some sort of
coating and example of it is polyethylene glycol (PEG).
 Passive Targeting

 By adding PEG to the surface of the nanoparticle, it is rendered

hydrophilic, thus allowing water molecules to bind to the oxygen
molecules on PEG via hydrogen bonding. The result of this bond is a
film of hydration around the nanoparticle which makes the substance
antiphagocytic.
 The particles obtain this property due to the hydrophobic interactions
that are natural to the RES, thus the drug-loaded nanoparticle is able
to stay in circulation for a longer period of time.
 Example of Passive Targeting

 The ability of some colloid to be taken up by the Reticulo Endothelial

Systems (RES) especially in liver and spleen made them ideal
substrate for passive hepatic targeting of drugs.
 In case of cancer treatment, the drug carrier complex can be targeted
to the tumour site by employing the Enhanced permeability retention
(EPR) effect.
 Passive targeting may also be directed to lymphoid organs, as these
organs are finely structured and nanoparticles may easily penetrate
into lymphatic vessels.
 Inverse Targeting

 In this type of targeting attempts are made to avoid passive

uptake of colloidal carrier by RES (Reticulo Endothelial
Systems) and hence the process is referred to as inverse
targeting.
 To achieve inverse targeting, RES normal function is
suppressed by pre injecting large amount of blank colloidal
carriers or macromolecules like dextran sulphate.

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 Inverse Targeting

 This approach leads to saturation of RES and suppression of

defence mechanism. This type of targeting is a effective
approach to target drugs to non-RES organs.
 Alternative strategies include modification of size, surface
charges, composition, surface rigidity & hydrophilicity
characteristics of carriers for desirable biofate.

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 Dual targeting

 In this targeting approach carrier molecule itself have

therapeutic activity and thus increase the therapeutic effect
of drug.
 For example, a carrier molecule having its own antiviral
activity can be loaded with antiviral drug and the net
synergistic effect of drug conjugate was observed.

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 Double targeting

Targeting drugs to specific

organs, tissues, cells or
even sub cellular Spatial
compartment control

Double
Targeting

Controlling the rate of

drug delivery to target Temporal
site. control
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 Combination Targeting

 The idea of combination targeting was proposed in 1998. It

can be given as site specific targeting for delivery of protein
and peptides.
 These targeting systems are equipped with carriers,
polymers and homing devices of molecular specificity that
could provide a direct approach to target site.

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 Components of drug targeting

Specific organ or a cell or a group of cells, which in

TARGET chronic or acute condition need treatment

Special molecules or system essentially required for

CARRIER effective transportation of loaded drug to the pre-
selected sites.
 Drug delivery vehicles

 Drug delivery vehicles are at the most important entity required for
successful transportation of the loaded drug at the specific site.
 Characteristics of an ideal drug vehicle
 An ideal drug vehicle should be able to cross blood brain barriers.
 It must be recognized by the target cells specifically and selectively
the drug vehicle used should be non-toxic, nonimmunogenic and
biodegradable.
 After recognition, the carrier system should release the drug moiety
inside the target organs, tissues or cells.
 Different types of carriers

1) Liposomes
2) Monoclonal antibodies and fragments
3) Modified (plasma) proteins
4) Quantum dots
5) Microspheres and Nanoparticles
6) Lipoproteins
 Liposomes

 Delivery of larger fraction of drug to the desired (diseased) site, by

reducing the drug’s exposure to normal tissues can be achieved by
site specific targeting.
 Encapsulating the drug in liposomes can be used for both active and
passive targeting of drugs in order to achieve a safer and Efficacious
therapy.
 On systemic administration, long circulating immunoliposomes are
able to recognize and bind to target cells with greater specificity.
 Liposomes

 In patients with Recurrent osteosarcoma, there

was an enhanced tumoricidal activity of
monocytes, when muramyl Peptide derivatives
were formulated as liposomes and
administered systemically.
 Marketed Formulation – EvacetTM
containing doxorubicin drug used for
Metastatic Breast cancer.
 Monoclonal antibodies and fragments

 The use of monoclonal antibodies (mAbs) as therapeutic agent is

gaining importance in the treatment of various conditions such as
cancer, cardiovascular diseases and viral infections.
 In concert with their clinical acceptance, mAbs have become
commercially viable drug. In addition, mAbs that target tumours have
been conjugated to radioisotopes, chemotherapeutic agent, bacterial
toxins, cytokines and enzymes in order to potentiate their cytotoxic
effects.
mAbs Preparation

36
 Monoclonal antibodies and fragments

 In 2002, human mAbs are developed as antitumor agent. Adalimumab

(HUMIRA) is the first human mAb approved for human use.
 Marketed Formulation - BLINCYTO® containing blinatumomab
drug and it is different from chemotherapy, it works with your
immune system to find and destroy cancer cells.
 Modified plasma proteins

 Modified plasma proteins can be good drug vehicle for drug

transportation due to their solubility and having relatively small
molecular weight.
 They can be easily modified by the attachment of different molecules
like peptides, sugar and other ligands to transport the drug of interest
makes them a suitable mode of drug delivery.
 In the case of liver cell targeting, extensive modification of protein
backbones such as albumin have been carried out effective for
delivery of the drug.
 Quantum dots

 Optical characterization of quantum dots is usually done by UV-VIS and

photoluminescence spectroscopy, which offer fast, non-destructive and
contactless option.
 The optical properties (fluorescence emission) of Quantum dots can be
fine-tuned by the Quantum dots size and is calculated using
conventional techniques like scanning electron microscopy (SEM),
transmission electron microscopy (TEM), atomic force microscopy
(AFM) or more preferably scanning tunnelling microscopy (STM) and
dynamic light scattering (DLS) studies.
 Quantum dots

 Besides these techniques, field flow

fractionation was also successfully
employed an excellent complement
to characterization of water-soluble
quantum dots by the conventional
tools.
 Action of quantum dots

 After administration of colloidal solution of quantum dots by S.C. or

I. V. injection, they identify and bound to target.
 Once bound to target, each quantum dot particle emits light and
depending on their size, they can fluorescence in a variety of colours
which can be identified or detected by different techniques.
 Lipoproteins

 Lipid particles such as LDL and HDL containing a lipid and an

apoprotein moiety is termed as natural targeted liposomes and its core
can be used to incorporate lipophilic drugs and it does not require
covalent bonding with the drug.
 Modification at the level of glycolipid incorporation can be used to
introduce new targeting moieties.
 Lipoproteins

 The majority of the

research on the use of LDL
and HDL particles has been
done and improved at the
level of targeting the drugs
to the liver.
 Microspheres and nanotechnology

 Microspheres are characteristically free flowing powders consisting of

proteins or synthetic polymers, which are biodegradable in nature and
ideally having a particle size less than 200µm.
 This is the important approach in delivering therapeutic substance to
the target site in sustained and controlled release fashion.
 Marketed formulation – RESPERIDAL® CONSTA ®
containing
Risperidone drug
Construction and structure of microspheres
(a) mononuclear/single core,
(b) multi-wall,
(c) polynuclear/multiple cores,
(d) matrix,
(e) coated polynuclear core,
(f) coated matrix particle,
(g) patchy microparticle,
(h) dual-compartment microcapsule,
(i) colloidosome,
(j) giant liposome,
(k) irregular-shaped,
(l) torus-shaped,
(m) bullet-shaped,
(n) micro tablet and 45
(o) cubic-shaped microparticle.
 Questions included in past GTU examination

Summer 2018 (14/05/2018)

Q6(C) Write a note on passive targeting
Winter 2018 (15/11/2018)
Q11(A) Define targeted drug delivery systems and explain different types of
drug targeting
Summer 2019 (27/05/2019)
No question was asked from this topic
Winter 2019 (02/12/2019)
No question was asked from this topic 46
 REFERENCE
Progress in Controlled and Novel drug delivery systems by N K Jain,
CBS publishers, page no: 362- 366.
Drug Targeting Organ-Specific Strategies Edited by Grietje Molema and
Dirk K. F. Meijer, page no:1-16
International Journal of Pharmaceutical and Medicinal Research Res.
2017; 5(2):448-454
Targeted and Controlled drug delivery (Novel carrier systems), S P Vyas
and R K Khar, CBS publishers, page no: 38-61.
Chien Y.W., Novel drug delivery systems, Drugs and the Pharmaceutical
Sciences, 50, New York, 797, 992 (2008) 47
48