3. INTRODUCTION
DEFINITION:
Nanoparticles are subnanosized colloidal drug delivery systems
it’s particle size ranges from 10-1000 nm in diameter.
They are composed of synthetic or semi synthetic polymers
carrying drugs or proteinaceous substances, i.e. antigen(s).
Drugs are entrapped in the polymer matrix particulates or solid
solutions or may be bound to particle surface by physical
adsorption or in chemical form.
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4. 4
Selective and Effective Localization of pharmacologically
active moiety at preselected target(s) in therapeutic
concentration,,
Provided restriction of it’s access to non-target normal tissues and
cells.
Nanoparticles are mainly taken by :
ReticuloEndothelial System (RES), after theadministration.
5. By modifying the surface characteristics of the nanoparticles it
is possible to enhance the delivery of drugs to spleen relative to
the liver.
Distribution of the nanoparticles in the body may be achieved
possibly by :
Coating of nanoparticles with certain Serum components,
Attachment of antibodies or sulfoxide groups and the use of
Magnetic nanoparticles.
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Hence are useful to carry drugs to the liver and to cells that are
phagocytically active.
6. 6
ADVANTAGES:
Reduction in the frequency of the dosages taken by the patient
More uniform effect of the drug
Reduction of drug Side Effects
Reduced fluctuation in circulating drug levels
Avoids hepatic first pass metabolism
7.
8. High cost
Productivity more difficult
Reduced ability to adjust the dose
Highly sophisticated technology
Requires skills to manufacture
Difficult to maintain stability of dosage form.
E.g.: Resealed erythrocytes stored at 40C.
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DISADVANTAGES
9. It should be biochemical inert , non toxic and non-
immunogenic.
It should be stable both physically and chemically in Invivo &
invitro conditions.
Restrict drug distribution to non-target cells or tissues or organs &
should have uniform distribution.
Controllable & Predicate rate of drug release
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IDEAL CHARACTERISTICS
10. Drug release should not effect drug action
Specific Therapeutic amount of drug release must be possessed
Carriers used must be biodegradable or readily eliminated from
the body without any problem and no carrier induced
modulation in disease state.
The preparation of the delivery system should be easy or
reasonable
simple, reproducible & cost effective.
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11. METHOD OF PREPARATION
A) CROSS LINKING METHODS
By Cross-linking of Amphiphilic Macromolecules
By Crosslinking in W/O Emulsion
By Emulsion chemical dehydration
By Phase Separation
B : Polymerization Methods
Emulsion polymerization
Dispersion polymerization
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12. 1) BY CROSS-LINKING OF AMPHIPHILIC
MACROMOLECULES
Nanoparticles can be prepared from Amphiphilic
macromolecules, proteins and polysaccharides (which have
affinity for aqueous and lipid solvents).
The method involves Aggregation of Amphiphiles followed by
stabilization either by heat denaturation or chemical cross-linking
2) By Cross linking in W/O Emulsion
Emulsification of bovine serum albumin (BSA) OR human
serum albumin (HSA) or protein aqueous solution in oil using
high-pressure homogenization or high frequency sonication.
13.
14. 3) EMULSION CHEMICAL DEHYDRATION
Stabilization can also be achieved by emulsion chemical
dehydration.
Hydroxypropyl cellulose solution in chloroform is used as a
continuous phase
while a chemical dehydrating agent,
2,2, di-methyl propane is used to disperse into the internal
aqueous phase to form an Emulsion.
ADV: The method avoid coalescence of droplets and could
produce nanoparticles of smaller size (300nm).
15. 4) PHASE SEPERATION
The protein or polysaccharide from an aqueous phase can be
Desolvated by:
A) pH change
B) Change in temperature
C) Addition of appropriate counter ions e.g.alginate
16.
17. POLYMERISATION METHODS
1) EMULSION POLYMERIZATION:
Emulsion Polymerization is a method in which the monomer to
be polymerized is emulsified in a non-solvent phase.
The process can be conventional or inverse, depending upon the
nature of the continuous phase in the emulsion.
In Conventional, the continuous phase is aqueous (O/W)
In Inverse, the continuous phase is organic (W/O)
Two different mechanisms were proposed for the emulsion
polymerization process
a) Micellar nucleation & polymerization
b) Homogenous nucleation & polymerization math
18. A) MICELLAR NUCLEATION AND POLYMERIZATION
✓ In this the monomer is emulsified in non-solvent phase using surfactant
molecules.
✓ This leads to the formation of Monomer- swollen micelle & Stabilized
monomer droplets.
✓ Monomer-swollen micelle have sizes in nanometric range and have
much larger surface area compared to monomer droplet
✓ Polymerization reaction proceeds through nucleation and propagation
stage in presence of chemical or physical initiator.
✓ Energy provided by initiator creates free monomers in continuous
phase, which then collide with surrounding unreactive monomers and
initiate polymerization chain reaction.
✓ The monomer molecule reaches the micelle by diffusion from the
monomer droplets through continuous phase, thus allowing
polymerization to progress within micelles. Here monomer droplets act
as reservoirs of monomers.
19.
20. B) HOMOGENOUS NUCLEATION AND
POLYMERIZATION
✓ In this method monomer is sufficiently soluble in continuous
outer phase. Nucleation and polymerization can directly occur in
this phase leading to formation of primary chains called
oligomers.
✓ In this both micelle and droplets act as monomers reservoir
throughout polymer chain length.
✓ When oligomers reach certain length, they precipitate and form
primary particles and stabilized by surfactant molecules provided
by micelle and droplets in which the drug will be entrapped to
form nanoparticles.
21. ✓ The polymerization rate is dependent on the pH of the
medium.
✓ Anionic polymerization takes place in micelle after
diffusion of monomer molecules through the water phase
and is initiated by negative charged compound
✓ At neutral pH the rate of polymerization is extremely fast.
22.
23. 2) DISPERSION POLYMERIZATION:
In emulsion polymerization monomer is emulsified in an
immiscible phase using surfactant. In case of dispersion
polymerization monomer is dissolved in an aqueous medium
which acts as precipitant for polymer
The monomer is introduced into the dispersion medium.
Polymerization is initiated by adding a catalyst & proceeds
with nucleation phase followed by growth phase.
Nucleation is directly induced in aqueous monomer solution
and presence of stabilizer or surfactant is not necessary for the
formation of stable nanospheres.
25. 1) SOLVENT EVAPORATION METHOD :
Nanoparticles preparation using Emulsion solvent
evaporation method
This method involves the formation of a conventional O/W
emulsion between a partially water miscible solvent containing
the stabilizer. Ex: PLGA nanospheres
The polymer is solubilized in a solvent (chloroform) and
dispersed in gelatin solution by sonication to yield O/W
emulsion. The solvent is eliminated by evaporation. For
evaporation homogenizer is used which breaks the initial coarse
emulsion in nanodroplets yielding nanospheres.
27. 2) SOLVENT DISPLACEMENT METHOD
(Nanoprecipitation)
It is based on interfacial deposition of a polymer following
displacement of a semi polar solvent miscible with water from a
lipophilic solution
The organic solvent diffuses instantaneously to the external aq.
Phase inducing immediate polymer precipitation because of
complete miscibility of both the phases
If drug is highly hydrophilic it diffuses out into the external aq.
phase while if drug is hydrophobic it precipitates in aq. medium as
nanocrystals
29. 3) SALTING OUT TECHNIQUE:
Salting out is based on the separation of a water-miscible solvent
from aqueous solution via a salting-out effect.
Polymer and drug are initially dissolved in a solvent which is
subsequently emulsified into an aqueous gel containing the salting
out agent (electrolytes, such as magnesium chloride and calcium
chloride, or non- electrolytes such as sucrose) and a colloidal
stabilizer such as polyvinylpyrrolidone (PVP) or
hydroxyethylcellulose.
30. This O/W emulsion is diluted with a sufficient volume of
water or aqueous solution to enhance the diffusion of solvent
into the aqueous phase, thus inducing the formation of
nanospheres.
It is different from nanoprecipitation method as in
nanoprecipitation polymeric solution is completely miscible
with the external phase. But in this method the miscibility of
both the phase is prevented by the saturation of external aqueous
phase with PVA and Magnesium chloride.
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32. EVALUATION PARAMETER OF NANOPARTICLES:
1. Particle size
2. Density
3. Molecular weight
4. Structure and crystallinity
5. Specific surface area
6. Surface charge & electronic mobility
7. Surface hydrophobicity
8. In-vitro release
9. Nanoparticle yield
10.Drug entrapment efficiency
33. 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
Laser force microscope
Scanning electron microscope
34. 2.DENSITY:
Helium or air using a gas pycnometer
Density gradient 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
35. 5. SPECIFIC SURFACE AREA:
Sorptometer
Specific Surface Area, A = 6 / .d
Where, is the density & d is the diameter of the particle
6. SURFACE CHARGE & ELECTRONIC MOBILITY:
Surface charge of particle can be determined by
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 biodistribution of
nanoparticle.
Zeta potential can also be obtained by measuring the
electronic mobility
36. 7. SURFACE HYDROPHOBICITY:
Important influence on interaction of nanoparticles with
biological environment.
Several methods have been used,
1 Hydrophobic interaction chromatography.
2 Two phase partition.
3 Contact angle measurement.
8. INVITRO RELEASE:
Diffusion cell
Recently introduce modified Ultra-filtration tech.
Media used: phosphate buffer
37. 8. YIELD OF NANO PARTICLE:
The yield of nanoparticles was determined by comparing the
whole weight of nanoparticles formed against the combined
weight of the copolymer and drug
. % yield= ×100
9.DRUG ENTRAPMENT :
The nanoparticles were separated from the aqueous medium by
ultracentrifugation at 10,000 rpm for 30 min.
Then the resulting supernatant solution was decanted and
dispersed into phosphate buffer saline pH 7.4.
Actual weight of product
Total weight of excipient & Drug
38. The amount of drug present in clear supernatant after
centrifugation for 30 min at 10,000 rpm was determined by
UV spectroscopy.
The amount of drug in supernatant was then subtracted
from the total amount of drug added during preparation of
nanoparticle (W).
Drug entrapment %= * 100
Mass of drug in Nano particles
Mass of drug used in formulation
40. REFERENCES:
Vyas S.P., Khar R.K. Targeted & Controlled Drug Delivery,
Novel Carrier Systems, CBS Publication,2002, Page No.331-386.
Jain N. K., Controlled and novel Drug Delivery, 1st edition
2001, CBS Publication; 292-301
Nanotechnology in drug delivery - A Review, Indian
Drugs, Issue 11,november 2011.
