Introduction Advantages and disadvantages Basic biological process and events in Targeted delivery

1. Targeted Drug Delivery
Systems

2. ONTARGET
TARGETED DRUG DELIVERY SYSTEMS
Vishnu Datta M
Dept. of pharmaceutics
JSSCP, MYSORE
JSS University

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 Biological processes and events involved
in drug targeting2
Agenda
 Concept. Introduction
 Advantages and Disadvantages
Targeted Drug delivery

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Introduction
• It 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 or
absorption and not to the non-target organs
or tissues or cells.
• The drug may be delivered:
 To the capillary bed of the active sites,
 To the specific type of cell (or) even an
intracellular region. Ex- tumour cells but not
to normal cells,
 To a specific organ (or) tissues by complexing
with the carrier that recognizes the target

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SMART DRUG THERAPY???
INDEED1..

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Reasons for Site specific delivery of
drugs2
Pharmaceutical
• Drug instability in conventional dosage form
• Solubility
Biopharmaceutical
• Low absorption
• High-membrane bounding
• Biological instability
Pharmacokinetic / Pharmacodynamic
• Short half-life
• Large volume of distribution
• Low specificity
Clinical
• Low therapeutic index.

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OBJECTIVES
• 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.
• Ex- in cancer chemotherapy and in enzyme
replacement therapy.

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IDEAL CHARACTERISTICS
Targeted drug delivery system should be-
HOW??
• Biochemically inert (non-toxic)
• Non-immunogenic.
• Both physically and chemically stable in vivo
and in vitro.
• Restrict drug distribution to target cells or
tissues or organs
• Should have uniform capillary distribution.
• Controllable and predicate rate of drug
release.

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IDEAL CHARACTERISTICS
• 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.

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ADVANTAGES
Control of drug delivery on
to a particular site or
vicinity with predetermined
or expected release
kinetics
DISADVANTAGES
• Expensive
• Technical skill required
• Stability issues both
Chemical and physical biological as
well
• Yield comparatively very less
Advantages and Disadvantages
Targeted drug delivery systems

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Biological processes and events
involved in drug targeting2
• Cellular Uptake and Processing
• Transport across the epithelial
barrier
• Extravasation
• Lymphatic Uptake

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Cellular Uptake and Processing
• Following administration low molar mass
drugs can enter into or pass through various
cells by simple diffusion process.
• Targeted drug delivery usually have macro
molecular assemblies hence cannot enter by
such simple process. Hence take up by a
process called ENDOCYTOSIS
• Steps involved :
 Internalization of the plasma membrane
 Concomitant with engulfment of
extracellular material

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Cellular Uptake and Processing
• Phagocytes^^^^ rest of the cells
• opsosins immunoglobulin G complement C3b fibronectin
• dysopsonins IgA & sIgA impart degree of hydrophilicity>>>decrease the uptake

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Cellular Uptake and Processing
• Compared with phagocytosis pinocytosis is a
universal phenomenon in all the cells
pinocytosis does not require any external
stimulus
• Pinocytosis is divided into two types:
 Fluid phases pinocytosis
 Adsorptive pinocytosis
• Compared with phagocytosis fluid phase
pinocytic capture of molecules is relatively
slower being directly proportional to the
concentration and size dependant

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Transport across the epithelial
barrier
• The oral buccal nasal vaginal and rectal
cavities are internally lined with one or
more layers of epithelial cells
• Depending on the position and function in
the body epithelial cells can be varied forms
Three layer physiology:
 Epithelial
 Lamia propria
 Basal lamina
• Low molar mass drugs cross the above by
passive difussion carrier mediated systems
ans selective and non-selective endocytosis

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Transport across the epithelial
barrier
• The polar materials diffuse through tight
junctions of epithelial cells
• Passive transport is usually higher in
damaged mucosa where as active transport
depends on structural integrity of epithelial
cells
• Positively charged particles showed
increased uptake than negatively charged
counterparts.
• Absoption of drugs from buccal via
transcellular and paracellular later being
dominant

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Transport across the epithelial
barrier
• Some proposals
• Ex-vaginal cavity could be an effective
delivery site for certain pharmaceuticals
• Such as calcitonin for the treatment of
postmenopausal osteoporosis
• It was demonstrated that when delivered
vaginally first undergo uterine pass effect
suggesting that the vaginal route can be
useed to target to the uterus

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Extravasation
• Many diseases result from the dysfunction of
cells located outside the cardiovascular
system thus for a drug to exert its
therapeutic effects it must exit from the
central circulation this process of trans
vascular exchange is called Extravasation
which is governed by blood capillary walls
• Factors that control permeability of
capillaries
• Structure of the capillary wall
• Pathological condition
• Rate of blood and lymph supply
• Physicochemical factors of drug

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Extravasation
• The structure of the blood capillary varies in
different organs tissues.
• It consists of a single layer of endothelial
cells joined together by intercellular
juctions
• Depending on the morphology and continuity
of the endothelial layer and the basement
membrane blood capillaries are divided into
• Continuous
• Fenestraded
• Sinusoidal

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Extravasation

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Extravasation
• Continuous capillaries are common and
widely distributed in the body exhibit tight
inter endothelial junctions and an
uninterrupted basement membrane
• Fenestrated capillaries shows inter-
endothelial gaps of 20-80nm
• Sinusoidal capillaries show inter endothelial
gaps of 150nm
• Depending on the tissue or organ the basal
membrane is either absent ex-liver or
present in discontinuous ex-spleen and bone
marrow

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Extravasation
• Macromolecules can transverse the normal
endothelium by passive process such as
nonspecific fluid phase trans capillary
pinocytosis and passage through inter
endothelial junctions gaps or fenestrate or
by receptor-mediated transport systems
• Organs such as the lung with very large
surface areas have a proportionately large
total permeability and consequently a high
extravasation
• Depends on charge shape, size, HLB,
characteristics of macromolecules

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Extravasation
• The endothelium of brain is the strongest of
all endothelia formed by continous
nonfenestrated endothelial cells which show
no pinocytic activity
• Soluble macromolecules permeate the
endothelial barrier more readily than
particulate macromolecules the rate of
movement of fluid across the endothelium
appears to be directly related to the diff
between the hydrostatic and osmotic forces

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Lymphatic Uptake
• Following extravasation drug molecules can
either reabsorb into the blood stream
directly or enter into the lymphatic system
and return with the lymph to the blood
circulation
• Also drugs administered by subcutaneous
intracellular transdermal peritoneal routes
can reach the systemic circulation by
lymphatic system

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Lymphatic Uptake

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Lymphatic Uptake
• Factors know to influence the clearance of
drugs from interstitial sites
 Route of administration
 Size and surface characteristics of particles
 Formulation medium
 The composition and
 pH of the interstitial fluid and
 Disease within the interstitium
• The direct delivery of drugs into lymphatics
has been proposed as a potential approach
to kill malignant lymphoid cells located in
lymph nodes

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References:
1. Muller, R; Keck, C (2004). "Challenges and solutions
for the delivery of biotech drugs – a review of drug
nanocrystal technology and lipid
nanoparticles". Journal of Biotechnology 113 (1–3):
151–170. doi:10.1016/j.jbiotec.2004.06.007
2. Target-Oriented Drug Delivery Systems(9) by Vijay
kumar Modern Pharmaceutics Volume 2
Applications and Advances; Fifth edition edited by
Alexander T. Florence Pg.no 329-342.
3. Encyclopaedia of controlled delivery by Edith
Mathiowitz
4. S.P Yyas and R.K Khar Controlled drug Delivery
concepts and advances Vallabh prakashan first
edition

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~~~Thank you~~~