Nanoparticles

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
size

– Photon
correlation spectroscopy

– Laser
defractometry

– Scanning
electron microscopy

Molecular
weight

– Gel
Chromatography

Charge
determination

– Laser
Doppler Anemometry

– Zeta
potentiometer

Density

– Helium
pycnometer

Crystallinity

– X-ray
diffraction & DSC

– Thermogravimetry

Hydrophobicity

– Hydrophobic
interaction

– Chromatography

Surface element analysis

– X-ray

– Photo
emission Spectroscopy

Specific Surface Area

Specific surface area( A) = 6/Density x diameter
of particle

Invitro Release :

 

-Diffusion
Cell

-Modified
Ultra Filtration Technique.

-Media Used
: Phosphate Buffer

Nanoparticle Yield :

% Yield =

Actual weight of Product        X 100 

Total weight
of Drug and Excipients

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
therapy

Targeting, Reduced toxicity,  enhance uptake of anti-tumor  agent

Polyalkylcyanoacrylate with

anticancer agent

Intra
cellular targeting

Target reticuloendothelial 
system for intracellular 
infection

Poly alkyl cyanoarylate

Vaccine
adjuvant

Prolong systemic drug effect.  Enhance immune response

Poly methyl metha acrylate 
nanoparticles with vaccines

DNA
delivery

Enhanced bioavailability and  significantly higher expression  level

DNA gelatin nanoparticles,

DNA chitosan nanoparticles

Ocular
delivery

Improved retention of the drug and reduced washed out.

Poly alkyl cyanoacrylate 
nanoparticles , anti- 
inflammatory agent

Summary

  1. Nanoparticles  are subnanosized colloidal drug delivery systems  ranging in size from 10-1000 nm in
    diameter

  2. Selective
    and Effective Localization of drug  to
    target sites

  3. 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

  1. Nanoparticles
    can be characterized for their particle size , molecular  weight, surface charge, surface texture,
    density, crystallinity, 
    hydrophobicity, surface area, drug release and drug entrapment

  2. The
    polymers used can be synthetic or natural polymers

  3. Nanoparticles
    can be Metal-based, Lipid-based or Polymer-based in nature

  1. 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)

  1. 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)

 

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