TARGETED DELIVERY SYSTEM:- CONCEPTS, EVENTS AND BIOLOGICAL PROCESS INVOLVED IN DRUG TARGETING

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TARGETED DELIVERY SYSTEM:- CONCEPTS, EVENTS AND
BIOLOGICAL PROCESS INVOLVED IN DRUG TARGETING:-

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INTRODUCTION:-
‘Targeted drug delivery system is a special form of drug
delivery system where the 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.’

• It is a method of delivering medication to a patient in a manner
that increases the concentration of the medication in some parts
of the body relative to others.

• Targeted drug delivery seeks to concentrate the medication
in the tissues of interest while reducing the relative concentration
of the medication in the remaining tissues.

• This improves efficacy and reduce side effects.

 

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CONCEPT:-

•The first report published on targeting was by Paul Ehrlich
at 1902 as “Magic Bullet”.

•Later Gregoriadis, 1981, who described a drug targeting by
the name of “older drugs in newer clothes” using novel
drug delivery system.

Drug targeting can, in this respect, serve both as a therapeutic
approach and as a research tool in unravelling the functions of these
processes in normal physiology and under patho-physiological
conditions.

 

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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 complexion with the
carrier that recognizes the target.

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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REASONS FOR DRUG TARGETING:-
•Drug instability
•Low absorption
•Short half-life
•Large volume of distribution
•Low specificity
•Low therapeutic index

 

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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:-

Drug administration protocols may be simplified.
• Toxicity is reduced by delivering a drug to its target site,
there by reducing harmful systemic effects.
• Drug can be administered in a smaller dose to produce the
desire effect.
• Avoidance of hepatic first pass metabolism.
• Enhancement of the absorption of target molecules such as
peptides and particulates.
• Dose is less compared to conventional drug delivery
system.
• No peak and valley plasma concentration.
• Selective targeting to infections cells that compare to
normal cells.

 

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DISADVANTAGES:-
Rapid clearance of targeted systems.
• Immune reactions against intravenous administered carrier
systems.
• Insufficient localization of targeted systems into tumour
cells.
• Diffusion and redistribution of released drugs.
• Requires highly sophisticated technology for the
formulation.
• Requires skill for manufacturing storage, administration.
• Drug deposition at the target site may produce toxicity
symptoms.
•Difficult to maintain stability of dosage form.
E.g.: Resealed erythrocytes have to be stored at 40 C.
• Drug loading is usually law. E.g. As in micelles. Therefore
it is difficult to predict /fix the dosage regimen.

 

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IMPORTANT PROPERTIES INFLUENCING DRUG TARGETING:-

Drug:- Concentration, Particulate location and
Distribution Molecular Weight, Physiochemical properties
Drug Carrier Interaction.

Carrier:- Type, Amount of Excipients, Surface
Characteristics, size, Density.

In Vivo
Environment:-In Vivo Environment

 

TYPES / STRATEGIES OF DRUG TARGETING:-www.DuloMix.com

1) 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.

 

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2) 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

•Thisapproach leads to saturation of RES and
suppression of defence mechanism. This type of targeting
is a effective approach to target drug(s) to non-RES
organs.

 

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3) Active Targeting :
• In this approach carrier system bearing drug reaches to
specific site on the basis of modification made on its surface
rather than natural uptake by RES.

• Surface modification technique include coating of surface with
either a bioadhesive, nonionic surfactant or specific cell or tissue
antibodies (i.e.monoclonal antibodies) or by albumin protein.

3 Types:-
o First order targeting (organ compartmentalization).
o Second order targeting (cellular targeting).
o Third order targeting (intracellular targeting).

 

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FIRST ORDER TARGETING:-

• Restricted distribution of the drug carrier system to the capillary
bed of a pre-determined target site, organ or tissue.

SECOND ORDER TARGETING:-
• The selective drug delivery to a specific cell type such as tumor
cells (& not to the normal cells) .

THIRD ORDER TARGETING
• Drug delivery specifically to the intracellular organelles of the
target cells.

 

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4)Ligand Mediated Targeting : Achieved using specific mechanisms
such as receptor dependent uptake of natural LDL particles and
synthetic lipid microemulsions of partially reconstituted LDL
particles coated with the apoproteins.

5)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.

 

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6) Dual Targeting :
• In this targeting approach carrier molecule itself have their own
therapeutic activity and thus increasethe 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.

7) Double Targeting :
• Temporal and spatial methodologies are combined to target a carrier
system, then targeting may be called double targeting.

• Spatial placement relates to targeting drugs to specific organs,
tissues, cells or even subcellular compartment whereas temporal
delivery refers to controlling the rate of drug delivery to target site.

 

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BIOLOGICAL PROCESS AND EVENTS IN DRUG TARGETING:-

•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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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 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 in varied forms.

Three layer physiology:-
✓ Epithelial
✓ Lamia propria
✓Basal lamina

• Low molar mass drugs cross the above by passive
diffussion carrier mediated systems and by selective and
non-selective endocytosis.

 

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TRANSPORT ACROSS 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 is via transcellular and paracellular
the later being dominant.

 

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TRANSPORT ACROSS EPITHELIAL BARRIER:-

Some examples are:-
• for example:-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 it first
undergo uterine pass effect suggesting that the vaginal route
can be used to target the uterus.

 

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EXTRAVASTATION:-

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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The structure of the blood capillary varies in
different organs tissues.

• It consists of a single layer of endothelial cells joined together by
intercellular junctions.

• 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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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 in liver or present in a discontinuous way in spleen and
bone marrow.

 

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EXTRAVASTATION:-
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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EXTRAVASTATION:-

•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
difference 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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Factors know to influence the clearance of drugs from
interstitial sites are:-

• 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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QUESTIONS:-

 

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