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Introduction:-
• Novel drug delivery systems are designed
for targeting the biologically active
molecules to its site of action.
• They also control the delivery of drug over
an extended period of time.
• Vascular targeting of drugs provide more
concentration of drug to the target site.
What is vascular targeting?
• The targeting of the drug to a specific target site
through the endothelium of blood vessels is
called as vascular targeting.
• The drug reaches the target site through blood.
• The drug is introduced into blood stream by
using various catheters.
Approaches to drug targeting:-
PASSIVE TARGETING
1.Pathophysiological factors:
.Inflammation
.EPR effect
ACTIVE TARGETING
1.Biochemical targets:
.organs .cellular
.organelles .intracellular
2.Physicochemical factors:
.Size
.Molecular weight
2.External stimuli:
.ultra sound
.magnetic field
3.Anatomical opportunities:
.Catherization
.Direct injection
3.Sandwich targeting
4.Chemical approaches:
.Prodrugs
.Chemical delivery
systems
4.Transcriptional targeting
Reference:Nanosystems in Drug Targeting: Opportunities and Challenges
• 1.Receptors:
Folic acid
LDL
Peptide
• 2.Lipid components of cell
membranes
• 3.Surface antigens or proteins
Reference:Nanosystems in Drug Targeting: Opportunities and Challenges
Targeting Ligands for vascular
endothelium:-
• Folic acid
• Sugars
• Lectins
• Modified Albumins
• Peptides
• Antibodies
Reference:Nanosystems in Drug Targeting: Opportunities and Challenges
Advantages of Vascular
targeting:1.Increased regional drug concentration.
2.Decreased systemic toxicity.
3.Enhanced activity of some drugs.
Reference:Advances in controlled & novel drug delivery system by N.K.Jain,
page no.167
Applications of Vascular targeting:
1.Regional therapy via capillary filtration.
2.Acts as a circulating depot of drug.
3.Diagnostic imaging.
4.Prevention of Restenosis.
Reference:Advances in controlled & novel drug delivery system by N.K.Jain,
Page no.168
Criteria that define a good target:
• 1.It must be expressed on endothelial cells.
• 2.Surface density of the target must be sufficient
to promote the binding of drugs.
• 3.Binding site must be accessible to blood.
• 4.Consequences of DDS binding to a target
determinant must meet therapeutic goals.
Advanced Drug Delivery Systems That Target The Vascular Endothelium
Affinity Moiety Selection:
• Affinity ligands for endothelial cell targeting
are
1)Natural ligands-
Transferrin and
Vascular endothelial growth factor
2)Immunoglobulin G
>These are well suited for conjugation with
drugs and drug carriers.
Advanced Drug Delivery Systems That Target The Vascular Endothelium
Drug delivery vehicles for vascular
targeting:-
• Polymeric Nanoparticles
• Liposomes
• Micelles
• Microcapsules
• Microspheres
• Microemulsions
Davies, P.F. Mechanisms involved in endothelial responses to hemody-namic forces.
Liposome Ingredients
45% DPPC dipalmitoylphosphatidylcholine
45% Cholesterol
5% DPPG dipalmitoylphosphatidylglycerol
5% DPPE dipalmitolyphosphatidylanolamine
• Niosomes are non-ionic surfactant vesicles. The
success achieved with Liposomal systems
stimulated the search for other vesicles forming
amphiphiles.
• Non-ionic surfactants were among the first
alternative materials studied. A large number of
surfactants have been found to self assemble into
bilayer vehicles which can be used as drug delivery.
Liposome Preparation
http://www.avantilipids.com
Lipid Hydration method
Most widly used method for the preparation
of MLV
Involves: drying a solution of lipids – thin film
at the bottom of rbf
Hydrating the film by adding aqueous buffer
and vortexing the dispersion for some
time.
Hydration above the Tc of lipids.
Lipid Hydration method
The compond to be encapsulated is either
added in the lipid solution or aqueous
buffer.
Disad.:low internal vol
low encalsulation efficiency
heterogeneous size distribution
Hydration
MLV with high encapsulation – prepared by
hydrating the lipids in presence of an
immiscible organic solvent (petroleum
ether).
Content emulsified by sonication or vortexing.
Organic liquid is removed by passing stream
of nitrogen over mixture.
Disad.:exposure to organic solvent and
sonication
Solvent spherule method
Dispersing in aqueous solution the small
spherule of volatile hydrophobic solvent in
which lipid has been dissolved.
Then controlled evaporation of organic
solvent in a water bath
Small unilamellar liposomes
MLV are sonicated either with bath type or
probe sonicator under an inert
atmosphere.
Disadv.:low encapsulation, low internal vol.
degradation of phospolipids and
drug
Metal contamination from tip of probe and
Presence of MLV .
SUV by french pressure cell
methodInvolves the extrusion of MLV at 20,000 psi
at 40C through a small orifice.
Adv.:simple, rapid, reproducible
Disadv.:Temp. Difficult to achieve, working
vol. Is small(50 ml max.)
LUV( large unilamellar
liposomes)They have high encapsulation efficiency.
Solvent injection method:
- Ether infusion method
- Ethanol injection method
Ether infusion :A solution of lipid dissolved in
diethyl ether or ether/methanol mix. Is
slowly injected to an aqueous solution of
the drugat 55-65oC or under reduced
pressure.Subsiquent removal of
ether(vacuum)
Ethanol injection
Lipid solution of ethanol is rapidly injected to
a vast excess of buffer.
Disad:- size 30-110 nm
- liposomes are dilute
-removal of all ethanol difficult(azeotrope)
drug degradation in ethanol
LUV, detergent removal method
The detergents at their CMC are used to
solubilize lipids.As the detergent is
removed,the micelle becomes richer in
phospholipid and finely combined to form
LUV.
Detergent removed by dialysis.
Adv.- reproducible, uniform size.
Disadv: presence of trace detergent.
LUV, reserves phase
evaporationFirst w/o emulsion is formed by brief
sonication of two phases;phospholipid in
organic solvent (diethyl ether or isopropyle
ether or mix. Of isopropyl ether and
chloroform) and aqueous buffer.
The organic solvent is removed under
reduced pressure.
Disadv.-exposure to organic solvent
-sonication
LUV, Calcium-induced fusion
method Used to prepare luv from acidic
phospholipid.
When calcium is added to suv it induces
fusion of suv and results in formation of
multilamellar structure in spiral
configuration.
Addition of EDTA to this results in formation
of luv.
Adv:-gentle condition
Disad; only from acidic phospholipid
Liposome encapsulation
• Reverse-phase evaporation method
Lipid in organic solvent solution
Add nanoparticles in buffer under
sonicationEvaporation
Extrusion
Liposomes and unencapsulated nanoparticles
Size exclusion
chromatographyPurified liposomes