Nanoparticle

Presented by
Mr. Savale Sagar Kishor
(M.pharm First Year Student)
(Department of Pharmaceutics, North Maharashtra University, college of R.C.Patel Institute
of Pharmaceutical Education and Research, Shirpur, 425405, Dist.Dhule, Maharashtra.)
2015-016
[email protected]
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1. Nanoparticles are solid colloidal particles ranging in size from 10 to 1000 nm.

2. Nanoparticles are made of a macromolecular material which can be of synthetic or natural origin.

3. Depending on the process used for their preparation, two different types of nanoparticles can be obtained

4. Nanospheres: matrix type structure, drug is dispersed

5. Nanocapsules: membrane wall structure

6. Nanotechnology - Nanotechnology is the technology for design, fabrication and manipulation of nanometre scale systems, in the scale of

1-100 nm.

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 History
1. Nanoparticles as a drug delivery vehicle were first
•Have been documented to in use since the
use 9th century in Mesopotamia for ancient developed by Spieser and co-workers in the late 1960s.
pottery 2. In early 1970s the cross linked polyacrylamide nanoparticles were
produced.
3. Scheffel et al. developed a process for production of
radiolabelled albumin particles for imaging purpose in nuclear
medicines.
4. Widder et al incorporated magnetic particles into the
nanoparticles for targeting of these particles by means of magnetic
field.

•Gold particles nanosclaed have optical

properties that cause the luster

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Defination

Nanoparticles : Nanoparticles are particles made of natural or synthetic polymers ranging in size from 50 to 500 nm. They
consist of macromolecular materials in which the active principle ( drug or biologically active material ) is dissolved,
entrapped, and or to which the active principle is adsorbed or attached

there are mainly 2 type of nanoparticles

MATRIX RESERVIOR
type type

NANOSPHERES NANOCAPSULES

Nanospheres are solid core spherical particulates, which contain drug embedded within the matrix or adsorbed onto the
surface.(Matrix type)
Nanocapsules are vesicular system in which drug is essentially encapsulated within the central core surronded by a polymeric
sheath.(Reservoir type)

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 Properties of Nanomaterial's Size and Shape

1. Enhanced electrical and heat conductivity •Composites made from particles of nano-size ceramics or
metals smaller than 100 nanometers can suddenly become
2. Increased strength, tensile properties
much stronger than predicted by existing materials-science
3. Magnetic properties models.
4. Optical properties – color changes with size
•For example, metals with a so-called grain size of around 10
nanometers are as much as seven times harder and tougher
than their ordinary counterparts with grain sizes in the micro
meter range.

•The Nano particles affects many properties such as

Melting point
Boiling point
Band gap
Optical properties
Electrical properties
Magnetic properties
•.Even the structure of materials changes with respect to Size

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 Why Nano Particles

Noparticles are of interest because of the new properties (such as chemical reactivity and optical behaviour) that they
exhibit compared with larger particles of the same materials.

For example, titanium dioxide and zinc oxide become transparent at the nanoscale and have found application in sunscreens.

Nanoparticles have a range of potential applications:

In the short-term application such as in cosmetics, textiles and paints.

In the longer term applications such as drug delivery where they could be to used deliver drugs to a specific site in the body.

Nanoparticles can also be arranged into layers on surfaces, providing a large surface area and hence enhanced activity,
relevant to a range of potential applications such as catalysts.

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 Need of Nano Particles Examples
- Carbon Nanotubes
Noparticles are of interest because of the new properties - Proteins, DNA
(such as chemical reactivity and optical behaviour) that - Single electron transistors
they exhibit compared with larger particles of the same
materials.

For example, titanium dioxide and zinc oxide become

transparent at the nanoscale and have found application
in sunscreens.

Nanoparticles have a range of potential applications:

In the short-term application such as in cosmetics,

textiles and paints.
In the longer term applications such as drug delivery
where they could be to used deliver drugs to a specific
site in the body.
AFM Image of DNA Carbon Nanotubes
Nanoparticles can also be arranged into layers on
surfaces, providing a large surface area and hence
enhanced activity, relevant to a range of potential
applications such as catalysts. 8
Nanotechnology

Nanotechnology deals with the creation of USEFUL materials, devices and systems using the particles of nanometer
length scale and exploitation of NOVEL properties (physical, chemical, biological) at that length scale.
According to nanotechnology,
Based on the size and shape, the Nano materials are classified as follows ,

Nanoparticles Nanotubes

1. Nanocapsules 1. Nanosprings
2. Nanofibers 2. Nanobelts
3. Nanowires 3. Quantum dots
4. Fullerenes (carbon 60) 4. Nanofluidies

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 Morphology

Scientists have taken to naming their particles after the real-world

shapes that they might represent. Nanospheres, nanoreefs,
nanoboxes and more have appeared in the literature. These
morphologies sometimes arise spontaneously as an effect of a
templating or directing agent present in the synthesis such as
miscellar emulsions or anodized alumina pores, or from the innate
crystallographic growth patterns of the materials themselves. Some
of these morphologies may serve a purpose, such as long carbon
nanotubes used to bridge an electrical junction, or just a scientific
curiosity like the stars shown at right.
Amorphous particles usually adopt a spherical shape (due to their
microstructural isotropy), whereas the shape of anisotropic
microcrystalline whiskers corresponds to their particular crystal habit.
At the small end of the size range, nanoparticles are often referred to
as clusters. Spheres, rods, fibers, and cups are just a few of the
shapes that have been grown. The study of fine particles is called
micromeritics.

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Functionalization

The surface coating of nanoparticles is crucial to determining their properties. In particular, the surface coating can regulate
stability, solubility, and targeting. A coating that is multivalent or polymeric confers high stability. Functionalized nanomaterial-
based catalysts can be used for catalysis of many known organic reactions.

Characterization

Nanoparticle characterization is necessary to establish understanding and control of nanoparticle synthesis and applications.
Characterization is done by using a variety of different techniques, mainly drawn from materials science. Common techniques
are electron microscopy (TEM, SEM), atomic force microscopy (AFM), dynamic light scattering (DLS), x-ray photoelectron
spectroscopy (XPS), powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), matrix-assisted laser
desorption/ionization time-of-flight mass spectrometry (MALDI-TOF), ultraviolet-visible spectroscopy, Rutherford
backscattering spectrometry (RBS), dual polarisation interferometry and nuclear magnetic resonance (NMR).
While the theory has been known for over a century (see Robert Brown), the technology for nanoparticle tracking analysis
(NTA) allows direct tracking of the Brownian motion; this method. therefore, allows the sizing of individual nanoparticles in
solution.
The majority of these nanoparticle characterization techniques are light-based, but a non-optical nanoparticle characterization
technique called Tunable Resistive Pulse Sensing (TRPS) has been developed that enables the simultaneous measurement of
size, concentration and surface charge for a wide variety of nanoparticles.This technique, which applies the Coulter Principle,
allows for particle-by-particle quantification of these three nanoparticle characteristics with high resolution.
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Manufacture of nanoparticles

The choice of manufacturing method depends on:

1.The raw material intended to be used

2.The solubility characteristics of the active compound to be associated to the particles

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 Silver Nanoparticles

Size: 10nm-100nm
Chemical formula: Ag
Details: Silver nanoparticles are ultra fine particles of silver. They are ten to a hundred nanometers large, and differ
from the bulk silver as they have different colors such as yellow, as opposed to the silver.
This is due to plasmon absorbance:
Incident light rays create oscillation in free electrons on the surface of nanoparticles, causing them to absorb
electromagnetic radiation, creating different colors reflected.

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 Synthesis of Silver nanoparticles

Reduction method

Ag + → Ag (Reducing agent NaBH4)

Ag atoms will stick together to form small particles.

Addition of citrate-
Act as a buffer to control pH
Act as a binding agent to limit the growing of nanoparticls

Addition of hydrogen peroxide-

Act as a etching agent , remove silver atoms from less stable nanoparticles.

Silver nanoprism is formed.

Bromide is added to control the size of the nanoprisms.

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 Diffraction of light through a single slit

w sin Ɵ = n λ tan Ɵ = y / L

In this lab, a variation of single slit diffraction is used to measure the width of a human hair; instead of a single slit in
a wall.

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 Metallic nanoparticles

Reduction of metal complexes in dilute solution

Diffusion-limited process maintaining
Example: nano-gold particles
chlorauric acid (2.5 x 10-4 M) 20 ml boiling solution+ sodium citrate (0.5%) 1 ml
100°C till color change + water to maintain volume
uniform and stable 20 nm particles

Reduction reagents

Affect the size and size distribution

weak reduction reaction
larger particles
wider or narrower distribution (depends on “diffusion limited”)
Affect the morphology
type, concentration, pH value

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 Polymer stabilizer

To prevent agglomeration
surface interaction:
surface chemistry of solid, the polymer, solvent and temperature
Strong adsorbed stabilizers occupy the growth sites and reduce the growth rate
A. Henglein, Chem. Mater. 10, 444 (1998).
polyethyleneimine, sodium polyphosphate, sodium polyacrylate and poly(vinylpyrrolidone)

Semiconductor nanoparticles

Pyrolysis of organometallic precursor(s) dissolved in anhydrate solvents at elevated temperatures in an airless

environment in the presence of polymer stabilizer (i.e., capping material)
Coordinating solvent
Solvent + capping material
phosphine + phosphine oxide (good candidate)
controlling growth process, stabilizing the colloidal dispersion, electronically passivating the surface

Process

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 discrete nucleation by rapid increase in the reagent concentration -> Ostwald ripening during aging at increased
temperature (large particle grow)-> size selective precipitation
Ostwald ripening
A dissolution-growth processes
large particles grow at the expense of small particles
produce highly monodispersed colloidal dispersions

C.B. Murray (CdE, E=S, Se, Te), 1993

Dimethylcadmium (Me2Cd) + bis(trimethylsilyl) sulfide ((TMS)2S) or trioctylphosphine selenide (TOPSe) or
Trioctylphosphine telluride (TOPTe) + solvent (Tri-n-octylphosphine, TOP) + capping material (tri-n-octylphosphine oxide,
TOPO)
before aging (440 ~ 460nm), after aging at 230-260°C (1.5~11.5 nm)
Size-selective precipitation

Oxide nanoparticles

Several methods
principles: burst of homogeneous nucleation + diffusion controlled growth
most commonly: sol-gel processing
most studied: silica colloids

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 Doxil

Developed in 1995
Marketed by Ortho Biotech
Liposome-PEG doxorubicin HCl
Anti-cancer drug used
in the treatment of HIV-related Kaposi’s sarcoma
Also used to treat breast cancer, ovarian cancer, and other solid tumors
Administered intravenously every 4 weeks

Doxil is the drug doxorubicin HCl encapsulated in an antibody linked PEGylated liposome
Composed of multiple monoclonal antibodies to target cancer cells
PEG (polyethylene glycol) makes the liposome less vulnerable to immune system
Lipid composition: mainly diastearoylphospatidylcholine and cholesterol - increases liposomal rigidity

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Doxil works through passing through fenestrations in the vasculature and concentrating at
tumor sites
- Leads to reduced accumulation in other tissues
Able to deliver the drug at moderate concentrations over a longer period of time
-Half life: 54 hours
Result: An anticancer drug that is
delivered more effectively
- decreased side effects and dosage
Doxil acts by the intercalation of DNA

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 Side effects

Hand-Foot Syndome
Stomatitis
Fever
Neutropenia
Nausea, vomiting, tiredness, weakness, rash, shortness of breath, or mild hair loss
Loss of appetite
Diarrhea
Cardiotoxcity

DepoCyt

Approved by the FDA in 2004

Marketed by SkyePharma

Liposomal cytarabine

Anticancer drug used in the treatment of malignant neoplastic meningitis

Administered intravenously every 2 weeks

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 Neoplastic Meningitis

A common oncologic complication involving the spread of tumor cells to the subarachnoid
space (SAS)

Cancer cells in the subarachnoid space can :

-Settle in the dependent portions of the base of brain (cranial nerves, lower spinal canal)
-grow into the surface of the brain and fill the sulci
-block normal paths of CSF flow

Treatment options include chemotherapy and/or radiation

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 Cytarabine

Originally discovered in Europe in the

1960s
works by damaging the DNA in
cancerous cells
Short half-life in the body; requires
frequent dosage to attain cytotoxic levels
Clinical studies demonstrated that
encapsulation of cytarabine into
liposomes leads to sustained release of cytotoxic cytarabine
- improved therapeutic efficacy in patients with NM

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 Depofoam

Lipid composition: mainly dioleoyl phospahtidylcholine, triolein, and cholesterol

Depofoam results in a 55 fold increase in the terminal half life of cytarabine in the CSF
Composed of multiple monoclonal antibodies to target cancer cells
Larger liposome – high drug loading capacity; small enough to cross the blood brain barrier

Liposomes and Antibiotics

Drug targeting potential of liposomes and nanoparticles in the treatment of intracellular bacterial infections.
Poor penetration into cells and decreased activity intracellularly major reasons for limited activity of most antibiotics in
intracellular infections.

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 Polymer Synthesis

Initiator: n-carboxyamino acid anhydride

Growth : reaction with amino acid
monomers
Termination: reaction with n-carboxyamino
acid anhydride

Length can be controlled by monomer/initiator ratio

As long as the composition of polymer is the same, the physical and chemical properties will stay same (regardless of
sequence)

Cop 1 polymer related to myelin binding protein (MBP)

Binding to MHC leads to the activation of T-suppressor cells

Competes with several myelin-associated antigens to bind to MHC class II molecules

Low toxicity; however, copaxone can only slow the progression of the disease and reduce the relapse rate

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 Dendrimer

Highly branched, spherical nanoparticle

Core, highly branched layers of repeating units (polymers), and multiple active terminal groups

Pros and Cons

High level of activity as a result of multiple functional groups at surface; display strong surface activity with cell and virus
particle surfaces

limited information concerning physicochemical properties

Tough to synthesize

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 Solid lipid nanoparticles

The solid lipid nanoparticles are submicron colloidal carriers which are composed of physiological lipid ,dispersed in water or in
an aqueous surfactant solution

It combines the advantages of polymeric nanoparticles, fat emulsions & liposomes

The liquid lipid was replaced by a solid lipid which transformed into solid lipid nanoparticles

Advantages

Small size & narrow size distribution provides for site specific drug delivery by SLNs

Controlled release of active drug over a long period can be achieved

Protection of incorporated drug against chemical degradation

SLNs can be lyophilized & spray dried

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No toxic metabolites are produced

Sterilization can be done by autoclaving or gamma irradiation

Surface modification can be easily done

Preparation of SLN

Melting of the lipid

Dissolution of drug in melted lipid

Mixing of preheated dispersion medium & drug lipid melt

Premix using stirrer to form coarse pre-emulsion

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 High pressure homogenization at a temp. above the lipids melting point

o/w nanoemulsion

Solidification of the nanoemulsion by cooling down to room temp. to form SLN

Hot Homogenization Technique

Melting of the lipid

Dissolution /solubilization of drug in melted lipid

Solidification of drug loaded lipid in liquid nitrogen or dry ice

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 Grinding in a powder mill(50-100µm particles)

Dispersion of lipid in the cold aqueous dispersion medium

Solid lipid nanoparticles

Cold Homogenization Technique

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 Comparison of SLN with other colloidal sytems
Drug delivery system SLN Liposomes Nano suspensions Polymeric nanoparticles Emulsions

Parenteral delivery Possible Possible Possible Possible Possible

Oral delivery Possible Not possible Possible Possible Possible

Ability to deliver hydrophobic Yes Yes Can deliver only Yes Yes
and hydrophilic drugs hydrophobic drugs

Physical stability +++ + +++ +++ ++

Biocompatibility +++ +++ ++ ++ +++

Drug targeting ++ ++ + ++ +

Drug loading Low to moderate Low to moderate High Moderate High

(SLN)
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 Pharmaceutical aspects of nanoparticles

 The important process parameters performed are Purification, Freeze drying, Sterilization

 Purification of nanoparticles:-Toxic impurities includes organic solvents, residual monomers, polymerization initiators,
electrolytes, stabilizers & large polymer aggregates. Most commonly used method is gel filtration & ultra filtration

 Freeze drying of nanoparticles

It includes freezing of nanoparticle suspension & sublimation of water to produce free flowing powder.

Advantages are

 Prevention from degradation & or solubilization of the polymer

 Prevention from drug leakage, drug desorption, drug degradation

 Nanocapsules containing oily core may be processed in the presence of mono or disaccharides (glucose or sucrose)
 Readily dispersible in water without modifications in their physicochemical properties

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Sterilization of Nanoparticles

Nanoparticles for parenteral use should be sterilized to be pyrogen free before animal or human use.

Sterilization in nanoparticles is achieved by using aseptic tech.throughout their preparation & processing & formulation
& by sterilizing treatments like autoclaving or γ- irradiation

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 Characterization of nanoparticles
Parameter Characterization method
Particle size & size distribution Photon correlation spectroscopy,Laser defractometry,Transmission electron
microscopy,SEM,Atomic force microscopy,Mercury porosimetry

Charge determination Laser doppler anemometry, Zeta potentiometer

Surface hydrophobicity Water contact angle measurements, rose bengal binding X-ray photoelectron spectroscopy

Chemical analysis of surface Static secondary ion mass spectrometry, sorptometer

Carrier-drug interaction Differential scanning calorimetry

Nanoparticle dispersion stability Critical flocculation temp (CFT)

Release profile In vitro release charac.under physiologic & sink conditions

Drug stability Bioassay of drug extracted from nanoparticles

Chemical analysis of drug
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 Therapeutic applications of nanoparticles

1. Biodegradable polymers like gelatin, albumin, casein, polysaccharide,lectin & synthetic polymers like polycaprolactone,
polyesters, polyanhydrides, polycyanoacrylates with various drug release charac. have been used to formulate sustained
release nanoparticles.

2. Intracellular targeting:-available antibiotics has following limitations

3. Poor intracellular diffusion

4. Most intracellular infections are difficult to irradicate because bacteria inside phagosome are protected from antibiotics

5. The need for antibiotics with greater intracellular efficacy led to the development of endocytosable drug carriers including
nanoparticles

Prolonged systemic circulation can be achieved by surface modification of nanoparticles with different block polymers
(pluronics) or polyethylene glycols

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 Application Material Purpose

Cancer therapy Poly(alkylcyanoacrylate)nanoparticleswith anticancer Targeting,reduced toxicity, enhanced uptake

agents,oligonucleotides of antitumour agents, improved in vivo & in
vitro stability

Intracellular targeting Poly(alkylcyanoacrylate) Target RES for intracellular interactions

Polyester nanoparticles with anti parasitic or antiviral
agents

Prolonged systemic circulation Polyesters with adsorbed polyethylene glycols or pluronics Prolong systemic drug effect,avoid uptake by
RES

Vaccine adjuvant Poly (methylmetghacrylate)nanoparticles with Enhances immune response

vaccines(oral & IM injection)

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 Application Material Purpose
Peroral absorption Poly(methylmetghacrylate)nanoparticles with Enhanced bioavailability &protection from GI
proteins & therap.agents enzymes

Ocular delivery Poly(alkylcyanoacrylate)with Improved retention of drugs/reduced wash out

steroids,antiinflammatory agents,antibacterial agents
for glaucoma

DNA delivery DNA gelatin nanoparticles, DNA chitosan Enhanced delivery & higher expression levels
nanoparticles,

Oligonucleotide delivery Alginate nanoparticles, poly(D,L)lactic acid Enhanced delivery of oligonucleotide

nanoparticles

Other applications Poly(alkylcyanoacrylate)nanoparticles with peptides Crosses blood brain barrier

For transdermal application
Nanooparticles with radioactive or contrast agents Improved absorption & permeation
Copolymerized peptide nanoparticles of n-butyl Enzyme immunoassays,Radioimaging
cyanoacrylate & activated peptides
Oral delivery of peptides

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 Nanoparticles for Drug Delivery

Metal-based nanoparticles

Lipid-based nanoparticles

Polymer-based nanoparticles

Biological nanoparticles

Nanobiopharmaceuticals

In biopharmaceuticals, in addition to the main technologies covered-liposomal, monoclonal antibody-

based, and polymer-based technologies host of newer technologies such as nanoparticles including
various nanodimensional entities such as molecular imprinted polymers, metallofullerenes, prodrug
delivery, oral, injectable and implantable, pulmonary, and transdermal and transmucosal delivery
have come up.

Drug Delivery Technology Important to Pharma Industry

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Drug delivery formulations involve low cost research compared that for discovery of new molecule,

Minimizing the drug use would significantly reduce the effective cost of drug which would give financial relief to the
patients,

Delivery systems increase commercial opportunity by distinguishing a drug from competitive threats posed by “me too”
drugs and

Novel means of delivery particularly using nano-carriers, can allow branded drugs to be rescued from abyss of generic
competition (may be called “resurrection of drug”).

SOME SIGNIFICANT ACHIEVEMENTS OF NANODEVICES

Development of one dose a day ciprofloxacin using nanotechnology

Tumor targeted taxol delivery using nanoparticles in Phase 2 clinical trial stage
Improved ophthalmic delivery formulation using smart hydrogel nanoparticles
Oral insulin formulation using nanoparticles carriers.
Liposomal based Amphotericin B formulation

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 PRIORITY AREAS

Cancer Nanotechnology

(i) Diagnosis using Quantum

Dots

(ii) Tumor Targeted Delivery

(iii) Imaging

(iv) Cancer Gene Therapy

DNA Vaccines for parasitic, bacterial and viral diseases

Oral and pulmonary routes for systemic delivery of proteins and peptides

Nanotechnology in Tissue Engineering

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 Liposome's

Their exterior lipid bilayer is very chemically reactive, thereby providing a means to conveniently couple “tags” on a covalent
basis.
Such “tags” can be antibodies, antigens, cell receptors, nucleic acid probes, etc.
This provides significant versatility in assay formats (i.e., immunoassay, receptor-based, nucleic acid probe, etc.) possible.
With diameters ranging in size from approximately 50 nm to 800 nm, their aqueous core encapsulates up to millions of
molecules of signal generating “markers” that can be detected in a variety of different way.
A variety of different encapsulants are possible including visually detectable dyes (since the lipid bilayer is transparent), optically
and fluorometrically detectable dyes, enzymes, and electroactive compounds.
This provides significant versatility in the detection schemes possible.

Niosomes

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 Niosomes

Niosomes, non-ionic surfactant vesicles, are widely studied as an alternative to liposomes

These vesicles appear to be similar to liposomes in terms of their physical properties
They are also prepared in the same way and under a variety of conditions, from unilamellar or multilamellar structures.
Niosomes alleviate the disadvantages associated with liposomes, such as chemical instability, variable purity of phospholipids
and high cost.
They have the potential for controlled and targated drug delivery
Niosomes enhanced the penetration of drugs

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Equipments for Nanoparticles

1.Homogenizer
2.Ultra Sonicator
3.Mills
4.Spray Milling
5.Supercritical Fluid Technology
6.Electrospray
7.Ultracentrifugation
8.Nanofiltration

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 Reference

 Zhang, L. "Nanoparticles in Medicine." Translational Medicine.

 Patel, Priyal. "Nanotechnology." Drug Delivery Technology.
 Patel, Priyal. “Nanoparticles in cancer research: a novel drug delivery&pharmacologicalapproach” Drug Delivery Technology.
 Murry, R.“Clinicalpharmacology of encapsulated sustained-release cytarabine” The Annals of pharmacotherapy
 J. Israelachvili, “Intermolecular and Surface Forces, 2nd Ed. 1991, Academic Press, London, pp.378 et seq.
 http://www.k2.ims.ac.jp/Movies.html See this site for amazing movies of big biomolecules in action.
 Vesicles, ed. M. Rosoff, Surfactant Sci. Series vol. 62, Dekker, New York 1996. (BJL RS201 L55 V5)
 Liposmes - A practical approach, Ed. RRC New, OUP, Oxford, 1990. (BJL OWL QH 601 L7)
 Liposomes: the next generation. H. Jamil, S. Sheikh and I. Ahmad, Modern Drug Discovery, Jan 2004, 37. (PDIF has copy, also
on web).
 Search GOOGLE on the web for “liposomes” or “vesicles” to find a variety of companies developing liposomal drug delivery
systems.

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