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➢Introduction
➢Strategies of drug targeting
➢Carrier or markers
➢Liposomes
➢Nanoparticles
➢References
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“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 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 relativeto others.
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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.
OBJECTIVE :
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 enzyme replacement
therapy.
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Passive
Targeting
Combination Inverse
Targeting Targeting
Double Drug Active
Targeting
Targeting Targeting
strategies
Ligand-
Dual mediated
Targeting Targeting
Physical
Targeting
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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.
It is a sort of passive process that utilizes the
natural course of (attributed to inherent characteristics)
bio distribution of the carrier system, through which, it
eventually accumulate in the organ compartment(s) of
body.
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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.
This approach leads to saturation of RES and
suppression of defence mechanism.
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3) Active Targeting :
Conceptually, active targeting exploits modification or
manipulation of drug carriers to redefine its biofate.
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.
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ACTIVE TARGETING
Restricted distribution of the drug
First Order carrier system to the capillary bed
Targeting 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
Drug delivery specifically to the
Targeting
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.
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This approach was found exceptional for tumour
targeting as well as cytosolic delivery of entrapped drug
or genetic material.
6) Dual Targeting :
In this targeting approach carrier molecule itself
have their own therapeutic activity and thus increase the
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.
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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.
where as temporal delivery refers to controlling
the rate of drug delivery to target site.
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8. Combination targeting:
➢These targeting systems are equipped with carriers,
polymers and homing devices of molecular specificity
that could provide a direct approach to target site.
➢Modification of proteins and peptides with natural
polymers, such as polysaccharides, or synthetic
polymers.
➢ It may alter their physical characteristics and favour
targeting the specific compartments.
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Targeted drug delivery can be achieved by using
carrier system.
Carrier isone of the special molecule or system
essentially required for effective transportation of
loaded drug upto the preselected sites.
Pharmaceutical carriers :
➢Polymers
➢Microcapsules
➢Microparticles
➢Lipoproteins
➢Liposomes
➢Micelles
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DEFINITION:
“ Nanoparticles are sub-nanosized colloidal
structures composed of synthetic or semi-synthetic
polymers.”
➢ Size range : 10–1000 nm
➢The drug is dissolved, entrapped, encapsulated or
attached to a nanoparticle matrix.
Based On Method Of Preparation:
➢Nanocapsules:- Nanocapsules are systems in which
the drug is confined to a cavity surrounded by a
unique polymer membrane.
➢Nanospheres:- Nanospheres are matrix systems in
which the drug is physically and uniformly dispersed.
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➢ Solid Lipid Nanoparticles
➢ Polymeric Nanoparticles
➢Ceramic Nanoparticles
➢Hydrogel Nanoparticles
➢Copolymerized Peptide Nanoparticles
➢Nanocrystals and Nanosuspensions
➢Nanotubes and Nanowires
➢ Functionalized Nanocarriers
➢Nanospheres
➢Nanocapsules
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➢ Solid Lipid Nanoparticles:
➢New type of colloidal drug carrier system for i.v.
➢Consists of spherical solid lipid particles in the nm
range, dispersed in water or in aqueous surfactant
solution.
➢Polymeric nanoparticles (PNPs):
➢These are defined as particulate dispersions or solid
particles with size in the range of 10-1000nm.
➢Composed of synthetic or semi-synthetic Polymers.
Biodegradable polymeric nanoparticles Polylactic
acid (PLA), polyglycolic acid (PGA), Polylactic –
glycolic acid (PLGA), and Polymethyl methacrylate
(PMMA) Phospholipids Hydrophobic core
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➢Ceramic Nanoparticles:
➢These are the nanoparticles made up of inorganic
(ceramic) compounds silica, ( Inorganic/metal) titania
and alumina.
➢Exist in size less than 50 nm, which helps them in
evading deeper parts of the body.
➢Hydrogel nanoparticles:
➢Polymeric system involving the self-assembly and
self aggregation of natural polymers like
amphiphiles cholesteroyl pullulan, cholesteroyl
dextran and agarose cholesterol groups provide cross
linking points.
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➢Copolymerized Peptide Nanoparticles:
Drug moiety is covalently bound to the carrier
Instead of being physically entrapped.
➢Nanocrystals and Nanosuspensions: Pure drug coated
with surfactant, aggregation of these particles in
crystalline form .
Drug powder dispersed in aqueous surfactant
solution.
➢Functionalized Nanocarriers
Biological materials like proteins, enzymes, peptides etc.,
are being utilized as a carriers for the drug delivery.
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➢Nano Tubes : They are hollow cylinder made of
carbon, atoms which can be filled and sealed for
potential drug delivery.
➢Application : Cellular scale needle for attaching drug
molecule to cancer cells. As an electrode in thermo
cells.
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➢Nanowires : It is a nanostructure, with the diameter of
the order of a nanometer(10-9 meters)
➢The nanowire pinpoint damage from injury and
stroke, localize the cause of seizures and detect the
presence of tumours and other brain abnormalities.
Fig:1. Nanowires
Application : Technique has potential as a treatment for
Parkinson’s and similar diseases.
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➢Nanoshells : Nanoshells are hollow silica spheres
covered with gold. Scientists can attach antibodies to
their surfaces, enabling the shells to target certain
shells such as cancer cells.
Fig:2 Nanoshells
➢Application : Technique has potential for targeting
cancerous drug.
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➢Quantum dots : Quantum dots are miniscule
semiconductor particles that can serve as sign posts of
certain types of cells or molecules in the body.
Fig: 3.Quantum dots
➢Application : Technique has potential for targeting
cancerous drug.
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➢Nano pores : Engineered into particles, they
are holes that are so tiny that DNA molecules can pass
through them one strand at a time, allowing for highly
precise and efficient DNA sequencing.
Fig: 4.Nanopores
➢Application : Potential in genetic engineering and bio
technology.
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➢Gold Nano : Gold nanoparticles are used to develop
e- ultra sensitive detection system for DNA and
protein markers associated with many forms of cancer,
including breast, prostrate cancer.
Fig:5. Gold Nanoparticles
➢Application : In cancer treatment and Genetic
engineering.
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➢Dendrimers : Dendrimers precisely defined, synthetic
nanoparticles that are approximately 510 nm in diameter.
They are made up of layers of polymer
surrounding a control core. The dendrimers surface
contains many different sites to which drugs may be
attach.
Fig:6. Dendrimers
➢Application : In gene transfection, medical imaging
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➢Liposomes : Liposomes are simple microscopic
vesicles in which and aqueous volume is entirely
composed by membrane of lipid molecule various
amphiphilic molecules have been used to form
liposomes.
The drug molecules can either be encapsulated in
aqueous space or intercalated into the lipid bilayers.
The extent of location of drug will depend upon its
physico-chemical characteristics and composition of
lipids.
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➢Niosomes :Niosomes are nonionic surfactant vesicles
which can entrap both hydrophilic and lipophilic drugs
either in aqueous phase or in vesicular membrane made
up of lipid materials.
It is reported to attain better stability than
liposome’s.
Fig:7. Niosomes
It may prove very useful for targeting the drugs
for treating cancer, parasitic, viral and other microbial
disease more effectively.
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➢Ufasomes :These are bilayer structures formed by
using single chain unsaturated fatty acids.
➢Pharmacosomes:
The term pharmacosome comprises of two
main parts Pharmacon (active principle) and some
carriers postulated that amphipathic drug can self
assemble to form vesicle and these vesicles are termed
as pharmacosomes.
Drug covalently bound to lipid may exist in
a colloidal dispersion as ultrafine, micelles or
hexagonal aggregates which are known as
pharmacosomes.
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➢Virosomes : Virosomes are immuno modulating
liposomes consisting of surface glycoprotein of
influenza virus (immune stimulating reconstituted
influenza virosome) muramyl dipeptide etc.
➢Virosomes must be target oriented and their fusogenic
characteristics could be exploited in genome grafting
and cellular micro injection.
Fig:7.Virosomes
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A. Interaction of the virosomes with cell surface
recepters.
B. Release of the encapsulated drug molecules in the
target cell.
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➢Cubosomes : Cubosomes are liquid crystalline phase
forming small cubic particles suitable for injection.
➢Nanocrystals : Nanocrystal is any nano material with
at least one dimension ≤ 100nm and that is single
crystalline.
Fig:8. Nanocrystals
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➢Nanorobots : Nanorobotics is the technology of
creating machines or robots at or close to the
microscopic scale of a nanometer (10−9meters).
Devices ranging in size from 0.1-10 nm and
constructed of nano scale or molecular components.
Fig: 9 Nanorobots
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➢Transferosomes :
A transferosomes, in functional terms, may be
described as lipid droplets of such deformability that
permits its easy penetration through the pores much
smaller than the droplets size.
Transferosomes is a supramolecular entity that
can pass through a permeability barrier and there by
transport material from the other site.
These are more elastic than standard liposomes.
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➢Nano particle can be administered by parenteral,
oral, nasal, occular routes.
➢By attaching specific ligands on to their surfaces,
nano particles can be used for directing the drugs
to specific target cells.
➢ Improves stability and therapeutics index and
reduce toxic affects.
➢Both active & passive drug targetting can be
achieved by manipulating the particel size and
surface characteristics of nano particles.
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➢ Small size & large surface area can lead to
particle aggregation .
➢ Physical handling of Nano Particles is difficult in
liquid and dry forms.
➢Limited drug loading.
➢Toxic metabolites may form.
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➢Natural hydrophilic polymers
Proteins: – Gelatin, albumin, lectins, legumin.
Polysaccharides:-alginate, dextran, chitosan, agarose.
➢ Synthetic hydrophobic polymers
Pre-polymerized polymers: – Poly e-caprolactone
(PECL),Poly Lactic acid (PLA), Polystyrene
Polymerized in process polymers: – Poly isobutyl
cyanoacrylates (PICA), Poly butyl cyano acrylates
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Polymerization Preformed Super critical
polymer fluid tech.
Dispersion Emulsion
polymerization polymerization
(DP) (EP) Solvent Solvent
evaporation Displacement
method method
Salting out
EP in an organic tech.
continuous
phase
EP in aqueous
Continuous
phase
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(1). EMULSION POLYMERIZATION :-
Monomer
↓Dissolved
Aqueous phase which contains an initiator i.e. a surfactant.
↓
Vigorous agitation
↓
Initiator generates either radicals or ions which
nucleate the Monomeric unit & starts polymerization
process.
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(2). DISPERSION POLYMERIZATION
Acrylate or methyl methacrylate monomer
↓Dissolved
Aqueous Phase
↓Polymerization
By γ-irradiation or chemical initiator (E.g.
ammonia or potassium peroxodisulfide) with heat
to temp above 65°c.
↓
Oligomer formed aggregates & ppt in the form of
nanoparticles.
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(1). SOLVENT EVAPORATION METHOD :-
Drug + Polymer is dissolved in organic solvent.
(Organic solvent used is chloroform)
↓Emulsification
By adding an aqueous phase containing
surfactant to obtain o/w emulsion.
↓Evaporation
Organic Phase
↓
Nanoparticles
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(2). SOLVENT DISPLACEMENT METHOD
Drug dissolved in organic phase (ethanol)
↓ emulsification
By addition of aqueous phase
↓ Displacement of organic phase
Precipitation of polymer
↓
Nanoparticles
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(3). SALTING OUT METHOD :
Organic phase Aqueous Phase
+
Drug + Polymer Mg. Acetate is dissolved in
is dissolved in organic water/PVA.
solvent (acetone).
↓Mixing/ Mechanical stirring
O/w emulsion
↓Distilled water
Dilution
↓
Nanoparticles
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Super critical fluid technology
↙ ↘
Rapid expansion of super critical Super critical anti –solvent.
solution (RESS). (SCA)
↓ ↓
For drugs soluble in SCF For drugs insoluble in SCF
Formation of dry Nanoparticles.
Very low traces of organic solvent is
found.
Rapid precipitation process.
47Suwpwew.rD uclorMiitxi.ccomal carbon dioxide is used.
1. BY ULTRACENTRIFUGATION :-
➢ Most common way to remove large quantities of impurities
& raw nanoparticulate suspensions.
➢ It causes aggregation of nanoparticles with difficulty in re-
dispersion.
➢ Cause loss of finer nanoparticles in the supernatant liquid
resulting in a low yield.
➢ It can remove excess reagents from small batches of
nanoparticles.
➢ It is a time consuming process & only suitable for
laboratory scale batches.
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2. BY CROSS-FLOW FILTRATION
➢ Crossflow filtration is usually to concentrate,separate
and clarify nanoparticles.
➢ The feed is pumped tangentially along the membrane
& large particles are swept along.
➢ During filtration, the starting solution is divided into
two solution:-concentrate and filtrate.
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3. BY GEL FILTRATION :- It used for the
purification of polymeric colloidal carriers mainly for
poly(cyanoacrylate) & polyster nanoparticles.
For Ex.Fractogel*HW55 is used.
4. BY DIALYSIS :-The dialysis tubing cellulose
membrane is used.
➢The dialysis is done in three days. The water is
changed every 24 hour.
➢The buffers used must be maintained under strict pH
control to stabilize their molecular properties.
➢The typical pH range of dialysis buffer is 6 to 8.
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1. Particle size
2. Density
3. Molecular weight
4. Structure and crystallinity
5. Surface charge & electronic mobility
6. Surface hydrophobicity
7. Invitro release
8. Nanoparticle yield
9. Drug entrapment efficiency
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1. PARTICLE SIZE:
➢ Photon correlation spectroscopy (PCS) : For smaller
particle.
➢ Laser diffractrometry : For larger particle.
➢ Electron microscopy (EM) : Required coating of
conductive material such as gold & limited to dry
sample.
➢ Transmission electron microscopy (TEM) : Easier
method & Permits differntiation among nanocapsule &
nanoparticle.
➢ Atomic force microscope
High resolution
➢ Laser force microscope
microscope
➢ Scanning electron microscope
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2.DENSITY :
➢ Helium or air using a gas pycnometer
➢ Density gradiant centrifugation
3. MOLECULAR WEIGHT :
➢ Gel permeation chromatography using refractive
index detector.
4. STRUCTURE & CRYSTALLINITY :
➢ X-ray diffraction
➢ Thermoanalytical method such as,
1) Differential scanning calorimetry
2) Differential thermal analysis
3) Thermogravimetry
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5. SURFACE CHARGE & ELECTRONIC MOBILITY
➢ Surface charge of particle – measuring particle velocity
in electrical field.
➢Laser Doppler Anemometry tech. for determination of
Nanoparticles velocities.
➢ Surface charge is also measured as electrical mobility.
➢Charged composition critically decides bio-distribution
of nanoparticle .
➢Zeta potential can also be obtain by measuring the
electronic mobility
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6. SURFACE HYDROPHOBICITY :
➢ Several methods have been used,
1.Hydrophobic interaction chromatography.
2.Two phase partition.
3.contact angle measurement.
7. INVITRO RELEASE :
➢Diffusion cell
➢Recently introduce modified Ultra-filtration tech.
➢Media used : phosphate buffer
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8. NANOPARTICLE YIELD :
% yield = Actual weight of product / Total weight of
excipient & Drug×100
9. DRUG ENTRAPMENT EFFICIENCY :
Drug entrapment % = Mass of drug in Nanoparticles /
Mass of drug used in formulation×100
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DEFINITION :Liposomes are concentric bilayered vesicles
in which an aqueous volume is entirely enclosed by a
membranous lipid bilayer mainly composed of natural or
synthetic phospholipids.
➢Liposome were first produced in England in 1961 by
AlecD.Bangham
➢The size of a liposome ranges from 20 nm up to several
micrometers.
Phospholipid bilayer
Aqueous phase
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Fig: 10.Structure of liposomes
COMPOSITION OF LIPOSOMES
• The main components of liposomes are :-
1. Phospholipids
2. Cholesterol
Phospholipids
Phospholipids are the major structural components
of biological membranes such as the cell membrane.
Two Types:(along with thier hydrolysis product)
➢ Phosphoglycerides
➢ Sphingolipids
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Fig:11. Structure of phospholipids
➢Each phospholipid molecule has 3 major parts,1 head
& 2 tails.
➢Head is made from 3 molecular components: choline,
phosphate & glycerol which is hydrophilic.
➢Each tail with a long chain which are hydrophobic.
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COMMONLY USED PHOSPOLIPIDS
PHOSPHATIDYL
CHOLINE
PHOSPHATIDYL
NATURAL
ETHANOLAMINE
PHOSPHATIDYL
COMMONLY SERINE
USED
PHOSPHOLIPIDS DIOLEOYL
PHOSPHATIDYL
CHOLINE
DISTEAROYL
SYNTHETIC PHOSPHOTIDYL
CHOLINE
DIOLEOYL
PHOSPHATIDYL
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➢Cholesterol stabilizes the membrane.
➢ It plays important role in bilayer formation.
➢Cholesterol by itself does not form bilayer structure.
➢Cholesterol act as fluidity buffer.
➢Enhances the stability of the membrane.
➢Enhances the rigidity of the phospholipid bilayer.
➢Reduces the permeability of water soluble substance
through the membrane.
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➢Non-toxic.
➢Biodegradable.
➢Increased stability of encapsulated drugs.
➢Lowers systemic toxicity.
➢Site avoidance effect (avoids non-target tissues).
➢Protection of sensitive drug molecules.
➢Improved pharmacokinetic effects.
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➢Leakage of encapsulated drug during storage.
➢ Shorthalf-life.
➢Batch to batch variation.
➢Difficult in large scale manufacturing and sterilization.
➢ Production cost is high.
➢Once administered, liposomes can not be removed.
➢ Sometimes phospholipidsundergoes hydrolysis and
oxidation reactions.
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VESICLE TYPE ABBREVIAT DIAMETER NO. OF
ION SIZE LIPID BI –
LAYER
Unilamellar vesicle UV All size range ONE
Small unilamellar SUV 20-100 nm ONE
vesicle
Medium unilamellar MUV >100µm ONE
vesicle
Large unilamellar LUV >1000µm ONE
vesicle
Giant unilamellar GUV >1µm ONE
vesicle
Oligolamellar vesicle OLV 0.1-1µm 5
Multilamellar vesicle MLV >0.5µm 5-25
Multivesicular vesicle MV >1µm Multicompartmental
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Passive loading Active loading
( Remote loading )
Mechanical dispersion method
Solvent dispersion method
Detergent removal method
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ACTIVE LOADING TECHNIQUE
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2
ADVANTAGES OF ACTIVE LOADING METHOD
➢A high encapsulating efficiency and capacity.
➢A reduced leakage of the encapsulated compounds.
➢ Flexibility for the use of constitutive lipids, as drug is
loaded after the formation of carrier units.
➢Avoidance of biological compound during preparation
steps in the dispersion thus reducing safety hazards.
➢ For amphipathic weak bases by active loading
procedures such as using a proton gradient or an
ammonium sulphate gradient or calcium acetate
gradient.
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(A)Physical dispersion
a)Hand-shaken multilamellar vesicles
b)Non-shaking vesicles
c)Pro-liposomes
d)Freeze drying
(B)Processing of lipids hydrated by physical means
a)Micro emulsification liposomes (MEL)
b)Sonicated unilamellar vesicles (SUVs)
c)French pressure cell liposomes
d)Membrane extrusion liposomes
e)Dried-reconstituted vesicles (DRVs)
f)Freeze thaw sonication (FTS)
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(C) Solvent dispersion methods
i. Ethanol Injection
ii. Ether injection
iii. Water in organic phase
iv. Reverse phase evaporation vesicles
v. Stable plurilamellar vesicles (SPVs)
vi. Double emulsion vesicles
(D) Detergent solubilization
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All the methods of preparing liposomes involve three
or four basic stages:
➢Drying down lipids from organic solvent
➢Dispersion of lipids in aqueous media
➢Purification of resultant liposomes
➢Analysis of final product.
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Physical dispersion: There are four basic method of
physical dispersion. i.e. hand shaking, non-shaking, freeze
dry and proliposomes.
Hand-shaken multilamellar vesicles (MLVs)
Fig:12.Hand shaking method
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Sonicated Unilamellar Vesicles (SUVs) :
Two Types : Bath Sonicator and Probe Sonicator
Bath- more suitable for large volumes of dilute lipids
Probe- for dispersion, which require high energy in a small
volume
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French pressure cell liposomes:
➢ Type of liposomes : ULV or OLV
➢Pressure :20000 or 40000
➢Sample volume : maximum 40ml
Minimum 4ml
➢Out flow : 0.5-1 ml /min.
➢This is suitable for drugs which are
sensitive to ultrasonic vibrations.
➢These liposomes are more stable than
sonicated liposomes
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Membrane extrusion liposomes :
➢Type of liposomes : MLV or
LUV
➢Pressure : 100 psi
➢Type membranes : Tortuous path,
Nucleation track (polycarbonate )
➢Batch to batch reproducibility is
high, freedom from solvent or
surfactant contamination.
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Solvent dispersion methods:
In this methods, lipids are first dissolved in an
organic solution, which is then brought into contact with
the aqueous phase containing material to be entrapped
within the liposomes.
Methods employing solvent dispersion fall into one
of three categories.
➢The organic solvent is miscible with the aqueous phase.
➢The organic solvent is miscible with the aqueous phase,
the latter being in a large excess.
➢Organic solvent is in large excess, and is again
immiscible.
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Ether injection & Ethanol injection
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DETERGENT SOLUBILIZATION :
In this method, the phospholipids are brought into
intimate contact with the aqueous phase via the
intermediary of detergents, which associate with
phospholipid molecules and serve to screen the
hydrophobic portions of the molecule from water.
The structures formed as a result of this association
are known as micelles, and can be composed of several
hundred component molecules.
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➢Liposomes as drug or protein delivery vehicles.
➢Liposome in antimicrobial, antifungal(lung therapeutics)
and antiviral (anti HIV) therapy.
➢ In tumor therapy.
➢ In gene therapy.
➢ In immunology.
➢Liposomes as artificial blood surrogates.
➢Liposomes as radio pharmaceutical and radio diagnostic
carriers.
➢Liposomes in cosmetics and dermatology.
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1. Donald L.Wise., Handbook of pharmaceutical controlled
release technology., Marcel dekker Inc, Indian edition -2
(reprint 2008) Page No. 86-107.
2. Jain N. K., Controlled and novel Drug Delivery, 1st edition
2001, CBS Publication; Page No.304 – 344.
3. Sultana.Y., Liposomal Drug Delivery Systems: An Update
Review., Current Drug Delivery 2007, 4, 297-305.
4. Sharma Shailesh, Sharma Neelam, Kumar Sandeep, Gupta
GD., Liposomes: A review., Journal of Pharmacy Research
2009, 2(7),1163-1167.
5. Vyas S.P. , Khar R.K. Targeted & Controlled Drug Delivery,
Novel Carrier Systems, CBS Publication ,2002 ,Page No.3-
360
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