Nanoparticles
Targeted
drug delivery systems
Session objectives
By the end of this session, students will be able to:
• Explain
the importance of nanoparticles
• Explain
the advantages and limitations of
nanoparticles
• Describe
different methods used for preparation of nanoparticles
• Describe
the applications of nanoparticles
• Explain
the methods used for the characterization of nanoparticles
Definitions
• Nanosuspensions
:
– Are
colloidal dispersions of nano sized drug particle that are produced by suitable method and stabilized by
suitable stabilizer
• Nanoparticles
:
– They
are solid colloidal particles sized from 1-1000
nm
• Nanospheres
:
– Polymer
matrices in which drug is dissolved or dispersed
• Nanocapsules
:
– Consists
of polymer wall entrapping an oily core in which the drug is dissolved
Introduction
• Nanoparticles
are subnanosized colloidal drug delivery
systems ranging in size 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
Types of nanoparticles
• Monolithic
type
• Capsule
type
Importance of nanoparticles
• Selective
and Effective Localization of pharmacologically
active moiety at preselected target(s) in
therapeutic concentration
• Restricted
access to non-target normal tissues and cells.
• Nanoparticles
are mainly taken by the RES after the
administration and are useful to carry drugs to the liver and to cells that are phagocytically active
• 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
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
Disadvantages
• 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
Ideal characteristics
• It should be
biochemical inert, non-toxic and non-immunogenic
• It should
be stable both physically and chemically in In vivo & in vitro conditions
• Restrict
drug distribution to non-target cells or tissues or organs & should have
uniform distribution
• Controllable
& Predicate rate of drug release
• 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
• The preparation
of the delivery system should be easy or reasonable
• Simple,
reproducible & cost effective
Polymers used
• Polymethyl
methacrylate copolymers,
• Polymethyl
cyanoacrylate,
• Polybutyl
cyanoacrylate & Polyisobutyl cyanoacrylate,
• Polyhexyl
cyanoacrylate & polyisohexyl cyanoacrylate,
• Poly(Nα,NÎ-L-lysinedylterephthalamide
• Polyisobutyl
cyanoacrylate
• Poly-D,L-lactide
• Serum
albumin
• Gelatin
• Polyacryl
dextran
• Polyacryl
starch
• Albumin
• Polylactic
acid-poly glycolic acid copolymer
• Poly(b-hydroxy
butyrate)
• Ethyl
cellulose
• Eudragit
RL,RS
Methods of preparation
A. Cross Linking Methods
1) By
Cross-linking of Amphiphilic Macromolecules
2) By Crosslinking
in W/O Emulsion
3) By Emulsion
chemical dehydration
4) By Phase
Separation
5) By pH
lnduced Aggregation
B. Polymerization Methods
1) Emulsion
polymerization
2) Dispersion
polymerization
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
• Emulsification using high-
pressure homogenization or high frequency sonication
W/O emulsion
• Dilution with preheated oil (100oC) (Heat cross-linking) or Addition of crosslinking agent (Chemical
cross-linking)
• Centrifugation and isolation of
nanoparticles
3) Emulsion chemical
dehydration
• Stabilization
can also be achieved by emulsion chemical
dehydration
• Hydroxy
propylcellulose 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
• This method
avoids coalescence of droplets and could
produce nanoparticles of smaller size (300nm)
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
Aqueous
phase (protein aqueous solution)
Heat to 40o
C, subsequent cooling to 4O C for 24h. â Desolvation
Protein
aggregates (Coacervates)
â Resolvation
Protein
colloidal dispersion
â Cross-linking
Nanoparticles
dispersion (External aqueous phase) 200nm
5) pH induced aggregation
• Gelatin
Nanospheres were prepared by :
• Gelatin
& tween 20 were dissolved in aq. phase & pH of the solution was
adjusted to optimum value.
• The clear
solution so obtained was heated to 400C followed by its quenching at
40C for 24hrs & subsequently left at ambient temperature for
48hrs.
• The
sequential temperature treatment resulted into a colloidal dispersion of
aggregated gelatin. The aggregates were finally cross linked using glutaraldehyde as cross linking
agent the optimum pH was 5.5- 6.5.values
• pH below
5.5 produced no aggregation while above 6.5 an
uncontrolled aggregation led to the formation of larger nanospheres
Polymerization based methods
1) Emulsion polymerization :
It consists of:
a) Micellar nucleation and polymerization :
Monomer is
insoluble in continuous phase-(O/W phase) – Aqueous phase
b) Homogenous nucleation and polymerization :
Monomer is soluble in continuous phase- (W/O phase) – Organic
phase
2] Dispersion polymerization
(Acrylamide
or Methyl methacrylate) Monomer is dissolved in an aqueous medium
â
Further, by
chemical initiation (ammonium or potassium per oxo disulphate)
â
Heated to
above 650C
â
Oligomers
aggregate & precipitates
â
lsolation
of nanospheres
Characterization and evaluation
of nanoparticles
|
Parameter |
Method |
|
Particle |
– Photon – Laser – Scanning |
|
Molecular |
– Gel |
|
Charge |
– Laser – Zeta |
|
Density |
– Helium |
|
Crystallinity |
– X-ray – Thermogravimetry |
|
Hydrophobicity |
– Hydrophobic – Chromatography |
|
Surface element analysis |
– X-ray – Photo |
|
Specific Surface Area |
Specific surface area( A) = 6/Density x diameter |
|
Invitro Release : |
-Diffusion -Modified -Media Used |
|
Nanoparticle Yield : |
% Yield = Actual weight of Product X 100 Total weight |
Applications
1) Cancer
Therapy
2) In
lntracellular Targeting
3) Used for
Prolonged Systemic Circulation
4) As a
Vaccine Adjuvant
5) In Case of
Ocular delivery
6) Used in DNA
Delivery
7) It is used
in case of Oligonucleotide delivery
8) Enzyme
immunoassays
9) Radio-imaging
10) To cross BBB
|
Application |
Purpose |
Material |
|
Cancer |
Targeting, Reduced toxicity, enhance uptake of anti-tumor agent |
Polyalkylcyanoacrylate with anticancer agent |
|
Intra |
Target reticuloendothelial |
Poly alkyl cyanoarylate |
|
Vaccine |
Prolong systemic drug effect. Enhance immune response |
Poly methyl metha acrylate |
|
DNA |
Enhanced bioavailability and significantly higher expression level |
DNA gelatin nanoparticles, DNA chitosan nanoparticles |
|
Ocular |
Improved retention of the drug and reduced washed out. |
Poly alkyl cyanoacrylate |
Summary
- Nanoparticles are subnanosized colloidal drug delivery systems ranging in size from 10-1000 nm in
diameter - Selective
and Effective Localization of drug to
target sites - The
methods of preparation include
A. Cross
Linking Methods
1) By
Cross-linking of Amphiphilic Macromolecules
2) By Cross-linking
in W/O Emulsion
3) By Emulsion
chemical dehydration
4) By Phase
Separation
5) By pH
lnduced Aggregation
B. Polymerization Methods
1) Emulsion
polymerization
2)
Dispersion polymerization
- Nanoparticles
can be characterized for their particle size , molecular weight, surface charge, surface texture,
density, crystallinity,
hydrophobicity, surface area, drug release and drug entrapment - The
polymers used can be synthetic or natural polymers - Nanoparticles
can be Metal-based, Lipid-based or Polymer-based in nature
- Carbon
nanotubes (CNTs) are allotropes of carbon, made of graphite and constructed in cylindrical tubes
with nanometer in diameter and
several millimeters in length
Based on the number of layers,
structures of CNTs are classified into two types:
– Single-walled
Carbon Nanotubes (SWCNTs)
–
Multi-walled Carbon Nanotubes (MWCNTs)
- Three
main techniques used for SWCNTs and MWCNTs production are
1) Arc-Discharge
method (using arc vaporization of two carbon rods)
2) Laser
Ablation method (using graphite)
3) Chemical
Vapor Deposition (using hydrocarbon sources such as CO, methane, ethylene, acetylene)
