Targetted Drug Delivery - An Introduction

TARGETTED
Drug Delivery Systems
Suraj C.
Dept. of Pharmaceutics
Al Ameen College of
Pharmacy.
Bangalore

Introduction
Reasons
M&D
Ideal TDDS
Carriers
Modules/
Levels
Approaches

Introduction
o Definition covers following bullet points:
☼ Selective delivery/targeting
☼ Specific site of action
☼ Eliminates non-targeted organs/systems
1

Introduction
o Aimed at:
☼ Selective + Effective localization
☼ Pre-identified site
☼ ↑ Therapeutic conc.
☼ Restricted to non-specific sites
☼ Minimizing toxic effects
☼ Maximizing Therapeutic index
2

Reasons
o Involves:
1. Overcoming pharmaceutical drug problems
2. Delivery specification:
 The capillary bed of the active sites,
 The specific type of cell (or) even an intracellular region.
Ex- tumour cells but not to normal cells,
 A specific organ (or) tissues by complexing with the
carrier that recognizes the target
3

Free Drug
No access,
No affinity
(Limited Effect)
Access,
Affinity
(Effect: TOXICITY)
Inactivation
Or
↓ T.E.
TARGET
SITE
NON TARGET
SITE
BIO-ENVI
FACTORS
Drug+Carrier
No access,
No affinity
(Limited Effect)Facilitated Transport
(Effect: TARGETING)
Sequestration
↑Therapeutic Avail.
TARGET
SITE
NON TARGET
SITE
BIO-ENVI
FACTORS

Merits
o Simplified Drug administration protocol
o ↓ Dose of drug → Cost of therapy
o ↑ Drug conc. at target than non-target sites
o Rapid Clearance
o Immune reactions (mostly against I.V. route)
o Insufficient localization in tumor cells
o Diffusion & redistribution
5
Demerits

Ideal TDDS*
1) Biochemically inert, non-toxic & non-immunogenic
2) Stability (Physical & Chemical)
3) Restricted delivery to target site/organ
4) Uniform capillary distribution at the site
5) Controlled & predictable rate of delivery
6) Drug release vs Drug action
7) ↑ Therapeutic effect
8) No – Drug leakage
9) Carrier properties
10)Cost of production
6

Terms
 TARGET
 CARRIERS OR MARKERS
 LIGANDS
7

Considerations
o Majorly, considered:
 Specific properties of target cells.
 Nature of markers or transport carriers or vehicles, which
convey drug to specific receptors.
 Ligands and physically modulated components.
8

Introduction
o Required for successful transportation of the loaded drug.
o Delivers the drug within or in the vicinity of target.
o An inherent characteristic or acquired through structural
modification
9

Ideal Criteria
o Able to cross anatomical barriers
o Recognized specifically and selectively by the target cells.
o The linkage and the directing unit (ligand) should be stable in
plasma, interstitial and other bio fluids.
o Non-toxic, non-immunogenic and biodegradable particulate or
macromolecule.
o After recognition/internalization, can release the moiety.
10

Types
o Based on “Nature of Origin”:
1. Endogenous (LDL ,HDL Chylomicrons, Serum albumin,
Erythrocytes)
2. Exogenous (Microparticulates, Soluble polymeric and
Biodegradable polymeric drug carriers.
11

Types
o Based on Pharmaceutical approaches:
1. Colloidal carriers
2. Cellular carriers
3. Supra-molecular delivery systems
4. Polymer based systems
5. Macromolecular carriers
12

Types
 Vesicular systems
Ex: Liposomes, niosomes, pharmacosomes, virosomes,
immunoliposomes.
 Microparticulate systems
Ex: Microparticles, Nanoparticles, Magnetic microspheres,
Albumin microspheres, Nanocapsules.
13
Colloidal Carriers

Types
14
Colloidal Carriers

Types
 It includes cellular or blood components:
Ex: Erythrocytes, Serum albumin, Antibodies, Platelets,
Leucocytes.
15
Cellular Carriers

Types
 Signal sensitive
 Muco-adhesive
 Biodegradable
 Bioerodible
 Soluble synthetic polymeric carriers.
16
Polymer Based

Types
o Proteins, glycoproteins, Neo glycoproteins and artificial viral
envelopes (AVE).
o Glycosylated water soluble polymers (poly-L-lysine).
o Mabs, Immunological fragments, antibody enzyme complex and
bispecific Abs.
o Toxins, immunotoxin .
o Lectins and polysaccharides
17
Macro molecular
forms

Introduction
 Passive targeting
 Inverse targeting
 Active targeting
(a) Ligand mediated targeting
(b) Physical targeting
 Dual targeting
 Double targeting
 Combination targeting
18

Levels
o Systems that target the systemic circulation.
o Devices include-
 drug bearing bilayer vesicular systems
 cellular carriers of micron or submicron size range.
19
Passive Targeting

Levels
o Based on attempts to
- circumvent and - avoid
Passive uptake of colloidal carriers by RES, leading to reversion of bio
distribution trend of the carrier.
20
Inverse Targeting

Levels
o Strategy:
1. Suppression of RES function in host
2. Alternative methods
21
Inverse Targeting

Levels
o 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
 Target specific delivery of drug
22
Active Targeting

Levels
o Orders of Active Targeting:
a. First order targeting (organ compartmentalization)
b. Second order targeting (cellular targeting)
c. Third order targeting (intracellular targeting)
23
Active Targeting

Levels
o First Order:
- Restricted distribution of the drug carrier system to the capillary
bed of the predetermined target site, organ or tissue.
Ex: Compartmental targeting
*Lymphatics *Peritoneal cavity *Plural cavity
*Cerebral ventricles *Lungs, joints, eyes, etc.
24
Active Targeting

Levels
o Second Order:
- Selective delivery of drugs to a specific cell types.
- Such as tumour cells (and not to the normal cells) is referred to
as second order
25
Active Targeting

Levels
o Approaches for Active Targeting
- Ligand Mediated
- Physical (Triggered Release)
26
Active Targeting

Levels
o Using carrier molecules, having intrinsic antiviral effect thus
synergies the antiviral effect of the loaded active drug.
Ex: drug conjugates can be prepared with fortified activity profile
against the viral replication.
Dual Targeting
• The virus replication process can be attacked at multiple points,
excluding the possibilities of resistant viral strain development.
27

Levels
o To achieve a double targeting effect,
 site specificity of the drug,
 by virtue of targeting moiety,
 a high specificity module (mainly a photosensitizer) is
linked to antibodies.
28
Double Targeting

Levels
o Firstly, suggested by Petit and Gombtz.
o Focussed on Site-specific delivery of proteins and peptides.
29
Combination
Targeting

Introduction
 Physical or Mechanical Approach.
 Biological Approach.
 Chemical Approach.
30

Approaches
1. Targeting to the mononuclear phagocytic system (MPS):
 I.V. administered liposomes—localize within MPS.
 MPS consists of connective tissues of mesenchymal origin.
Physical
• Clearance of large variety of harmful substances from plasma.
• Catabolism of macromolecules.
• Participation in immune response.
• Synthesis and secretion of various effector molecules.
• Targeting of AZIDOTHYMIDINE (AZT) to macrophages as
nanoparticle carriers by I.V. & oral routes.
• Liposomal delivery of certain compounds may provide
extended retention.
• Liposomal delivery of drugs systemically enhances drug
concentration of antimicrobials.
31

Approaches
2. Targeting to the Pulmonary region
- Diagnostic purposes
3. Extravascular systems
- anticancer drug camptothecin + nanoparticles = ↑ avg
residence time.
4. Mucosal delivery of antigens
- microspheres of Staphylococcal enterotoxin B toxoid.
32
Physical

Approaches
o Involves delivery of the drug using carrier system with targeting
moiety
 either in-built (by virtue of the structure of the carrier) or
 is chemically coupled.
Biological
• Antibodies directed against specific cell surface antigens,
• Endogenous carbohydrate-binding proteins (lectins).
• Glycoconjugates functioning as specific ligands for receptors
on specific cells that recognize particular sugar residues, and
• Hormones functioning as specific ligands for receptors on
specific targets.
• Ex:
1. Coupling of viral antigens to monoclonal antibodies against
a mouse Class II MHC.
2. Naproxen using lysozyme as carrier (since it is taken up &
catabolized in (PCT) - Showed 70 fold ↑ in retention.
3. Insulin used as enzyme carrier for correcting enzyme
deficiency disease in fibroblasts from patients with
cholesterol storage disease.
33

Approaches
o Incorporates targeting consideration into the drug design
process—for design of safe, localized delivery.
o Targeting to active biological molecules based on predictable
enzymatic activation.
o Allow sustained release of drugs too.
Chemical
• Ex:
1. Drug targeting to lungs
2. Drug targeting to brain
3. Osteotropic DD
34

References
o Drug Targeting Organ-Specific Strategies Edited by Grietje Molema
and Dirk K. F. Meijer, 2007.
o Targeted and Controlled drug delivery (Novel carrier systems), S P
Vyas and R K Khar, CBS publishers, 2002.
o Progress in Controlled and Novel drug delivery systems by N K
Jain, CBS publishers, 2008.
35

Targetted Drug Delivery - An Introduction

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Editor's Notes