2. Objective
⚫ To achieve a desired pharmacological response at a
selected site without undesirable interaction at other
sites, there by the drug have a specific action with
minimum side effects & better therapeutic index.
⚫ Site-specific drug delivery is desirable , in order to
improve:
- drug safety 🡪 reduce side effects
- drug efficacy 🡪 improved effect with lower dose
- patient compliance.
2
3. ⚫ Drug targeting systems are used to achieve
site- specific drug delivery
Targeted drug delivery
Tumou
r
Tumou
r
Conventional formulation Targeted drug delivery
4. IDEAL
CHARACTERISTICS
⚫ Non toxic
⚫ Restrict drug distribution to target cells or tissues or organs
⚫ Drug release does not effect the drug action.
⚫ Therapeutic amount of drug release.
⚫ Able to protect the drug and does not release the drug before
reaching the target site.
⚫ Carriers used must be bio-degradable or readily eliminated from the
body
⚫ Capable of pharmaceutical production.
4
5. ⚫ If a drug can be administered in a form such that it reaches the
receptor sites in sufficient concentration without disturbing other
tissue cells - a very novel idea
Such products are prepared by considering-
❖Specific properties of target cells.
❖carriers or vehicles, which convey drug to specific receptors.
❖Ligand components.
5
6. Rationale of drug
targeting
⚫ No access,
no effect
⚫ (limited
effect)
⚫ Access,
affinity
⚫ (effect:
toxicity)
⚫ Non target
site
⚫ Free drug
⚫ Bio-
environmental
factors
⚫ Inactivation/less
⚫ Therapeutic effect
⚫ Target site
⚫Principle and rationale of drug
targeting 6
7. ⚫ Drug in carrier
⚫ Bio-
environmen
tal factors
⚫ Sequestration and
improved
therapeutic
availability
⚫ Facilitated
transport
⚫ (effect: targeting)
⚫ Non target site
⚫ No
access,no
affinity
⚫ (limited
effect)
⚫ Principle and rationale of drug targeting
⚫ Target site
7
8. Levels
⚫ First level
◦ to the organ, e.g. liver.
⚫ Second level
◦ to the particular type of tissue
within the organ
⚫ Third level
◦ selective uptake by the
diseased cell, e.g. specific
tumour cells.
1st level - Liver
2nd level-
tissue
3rd level – uptake by the
diseased cell
The higher the level the
more efficacious, however it
is more complicated to
achieve.
8
11. Schematic diagram of phagocytosis of particulate carriers by macrophages.
Macrophages take up the carriers by the process of endocytosis. Drugs are
released from the carriers following intralysosomal degradation of the carriers
11
13. ⚫ Opsonin binding to liposomes
⚫ (a) Conventional liposomes are opsonized by plasma proteins and trapped
by RES. Fluid liposomes are also attacked by lipoproteins.
⚫ (b) Opsonins and lipoproteins hardly attack the rigid liposomes.
⚫ (c) PEG-coating protects liposomes against opsonization and attack of
lipoproteins by surface water layer.
⚫ (d) Unknown mechanisms that protect liposomes being recognized as
foreign. One possibility is that some molecules which are recognized as self
are bound on the surface of liposomes and protect them.
13
14. Opsonization is a term that refers to an immune process where particles such
as bacteria are targeted for destruction by an immune cell known as a phagocyte
14
20. Components and their purpose
Components Purpose
Active moiety Achieves the therapeutic effect
Carrier system Protect the drug from metabolism
Aids in distribution of drug
Protect the drug from early
clearance
Homing device Specifically targets the drug to the
target(cells/tissue)
20
21. ⚫ carri
er
⚫ Drug
⚫ 1. Incorporating or
binding
⚫ 3.
Immunogenicity
⚫ 5. Delivery to liver,
spleen and bone
marrow (passive
delivery)
⚫ 7. Targeted
delivery to
discontinuous
capillary
⚫ 2. Maximization of
therapeutic index
and minimization of
side and toxic
effects
⚫ 4. Non toxic to host cell
and biocompatible
⚫ 6. Selective delivery
to target or in the
vicinity of target
cells(Active
delivery)
⚫ Schematic illustration of requirement of drug carriers 21
22. Carrier systems used for targeted drug delivery
Collodial carriers:
1. Vesicular systems
liposmes,niosomes
2.Microparticulate systems:
nanoparticles,microspheres
Cellular carriers:
Resealed erythrocytes,serum
albumins,antibodies,platelets
Supramolecular delivery
systems
Micelles,lipoproteins,
Polymer based systems:
Mucoadhesive,biodegradable,
nonbiodegradable ,soluble
synthetic polymeric carriers
Macromolecular carriers:
1.proteins,glycoproteins
2.Monoclonal antibodies
3.polysaccharides
22
23. Levels of drug targeting
•Passive targeting
•Inverse targeting
•Active targeting
•Dual targeting
•Double targeting
•Combination targeting
23
25. ⚫ Devices include-
⮚ drug bearing bilayer vesicular systems
⮚ cellular carriers of micron or submicron size range.
⚫ Drug + carrier (modified by physical property)→ TDDS
⚫ Target the drug to systemic circulation or to the reticuloendothelial
system (RES).
⚫ The physicochemical properties of the drug carrier are modified, so
as to make it suitable to the target site.
⚫ Molecular size and molecular weight, surface hydrophobicity,
surface charge, and sensitivity to triggering are critical to
distribution. 25
26. Enhanced permeability and
retention effect (EPR Effect )
⚫Increased vascular permeability +
impaired lymphatic drainage
⚫Drug stays along with the carrier until the
accumulation of drug is attained
26
27. Drug carriers that can disintegrate at lower pH
values or higher temperature.
27
30. Inverse targeting
⚫
It is based on successful attempts to avoid passive
uptake of colloidal carrier by reticuloendothelial
system. leading to reversion of bio distribution
trend of the carrier
⚫ Phospholipid microsphere emulsified with
poloxamer 338 showed the lowest RES uptake in
mouse.
30
31. � Molecular weight -more than 30 KDa to escape elimination by the kidneys.
� Size of the drug-carrier complex in between 100nm-200nm.
� Surface nature must be hydrophilic to escape opsonisation in blood.
� Surface charge should be neutral to facilitate long circulation time.
31
32. INVERSE TARGETING
1. RES blocked by dummy injection.
2. TDDS injection given
3. Block the reticuloendothelial system (RES),
4.By administering a dummy (ex: dextran) injection
5.Then administer the real TDDS injection.
32
33. ⚫ As the RES is filled with the dummy drug, the actual drug
given through the TDDS injection will be free to circulate in
the blood stream, to be taken up by the targeted site.
33
34. ⚫ Suppose there is a target in the blood and not in
the liver.
⚫ We want the drug carrier complex to go on
circulating in the blood and slowly release the drug.
Now this is the strategy.
⚫ First we give a good volume of placebo injection
like dextran IV injection.
34
36. Active targeting
⚫ The facilitation of the binding of the drug carrier to target cells
by the use of ligands to increase receptor mediated
localization of the drug and target specific delivery of drug is
referred to as active targeting.
� Drug + carrier-(modified by physical property)+ ligand as
homing device= TDDS
� Make a drug- carrier complex more target specific, by
attaching a homing device or a ligand to it.
� This attachment will help the TDDS in circulating in the
bloodstream for a prolonged time and in accumulating at the
target site. 36
37. ⚫ Ligand - receptor recognition to make a drug
accumulate in the target cells. We call ligands as
homing devices and some homing devices are
antibodies, peptides, sugars and vitamins.
⚫ An active targeted carrier arrives when a ligand is
attached to a passive targeted device.
⚫ Two qualities are important.
❖ the specificity with which the ligand homes onto the
receptors and
❖ the capacity to deliver the required dose of drug for the
required period of time.
37
40. FIRST ORDER TARGETING
⚫ When a TDDS is targeted to an organ, it is
first order targeting.
⚫ Compartmental targeting to lymphatics,
peritoneal cavity, plural cavity, lungs, joints
or to eyes, represents first order targeting
40
41. SECOND ORDER TARGETING
⚫ When a TDDS is targeted to a particular type of
cells, it is called second order targeting.
⚫ The selective delivery of drugs to a specific cell
type such as tumour cells is an example and the
selective drug delivery to the Kupffer cells in the
liver is another example.
41
42. THIRD ORDER TARGETING
⚫ When a TDDS is targeted to within the intracellular sites of a
particular type of cells, it is third order targeting.
⚫ Ex: the receptor based ligand-mediated entry of a drug
complex into a cell by endocytosis, lysosomal degradation of
carrier followed by release of drug within the cell.
42
43. ❖ 1. Passive or physical targeting involves preparing the
delivery system of a definite molecular weight(>30Kda),
molecular size(100-200nm)
❖ 2. The physiological conditions in the tumor are
considered. The physical properties of the target are
studied.
❖ 3. We can do targeting by adjusting the delivery system
to be sensitive to pH or temperature or charge or an
enzyme.
❖ 4. The triggering mechanism may be supplied from
outside the body also.
5. Targeting to the reticuloendothelial system or the
circulatory system may be done by passive targeting.
43
44. DUAL TARGETING
⚫ Drug targeting using carrier molecules, having intrinsic
antiviral effect thus synergies the antiviral effect of the loaded
active drug.
⚫ Based on this approach, drug conjugates can be prepared
against the viral replication.
⚫ ADV: The virus replication process can be attacked at
multiple points, excluding the possibilities of resistant viral
strain development
44
47. Problems associated
⮚ Rapid clearance of targeted systems specially antibody targeted
carriers.
⮚ Immune reactions against intravenous administered carrier systems.
⮚ Target tissue heterogeneity.
⮚ Problems of insufficient localization of targeted systems into tumor
cells.
47
48. CONCLUSION
⚫ There is immense scope for targeted drug
delivery systems for many diseases
⚫ As our understanding of the drug action and
pathogenesis becomes clearer, more
rational approaches will emerge
⚫ The challenge to the pharmacy researcher
is to produce them so that they are
economic.
48
49. References
• Modern pharmaceutics, fourth edition, edited by Gilbert S. Banker, Christopher T.
Rhodes,chapter 16
• Khar R. k., Diwan Manish, ‘Targeted Delivery of Drugs’, In: Jain N.K.,editor , ‘Advances
in Controlled & Novel Drug Delivery’, first edition 2001,CBS publishers & Distributors,
New Delhi, pg. 452-464.
• Vyas S.P., Khar R.K., ‘Targeted and Controlled Drug Delivery: Novel Carrier System’,
first edition 2004, CBS Publishers & Distributors, New Delhi, pg 487-511.
• Design of Controlled Release Drug Delivery Systems by Xiaoling Li and Bhaskara R.
Jasti ; Mc Graw – Hill publications. Pg339-346
• Textbook of industrial pharmacy drug delivery systems and cosmetic& herbal drug
technology-shobarani R Hiremath,chapter 8
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