Nanoparticles

Presented to: Dr Shahiq U Zaman

Presented by: Dr Aliha Akhtar (6123)
Dr Dania Hassan (6174)

Riphah Institute of Pharmaceutical Sciences, Islamabad

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Contents to be covered

● Introduction
● Composition
● Characterization
● Advantages & disadvantages
● Classification
● Method of preparation
● Applications
● Recent advancements

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Dr. Aliha Akhtar (6123)

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 Introduction

Nanoparticle are the solid colloidal particles consisting of macromolecular substances that vary in size from 10
nm to 1000 nm.

●The drug of interest is dissolved, entrapped absorbed, attached or encapsulated into the nanoparticle
matrix.

●They are composed of synthetic and semisynthetic polymers carrying drugs or proteinaceous substances
i.e. antigen.

●Drugs are entrapped in the polymeric matrix particulates or solid solutions or may be bound to particle
surface ny physical adsorption or in chemical form.

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Structure of Nanoparticle

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Nanomedicine

● Nanomedicine involves utilization of nanotechnology for the benefit of human health and
well being.
● Nanomedicine was defined by European Science Foundation as

‘the science and technology of diagnosing, treating and preventing disease and traumatic injury, of
relieving pain, and of preserving and improving human health, using molecular tools and molecular
knowledge of the human body.

● This definition was revised by the US NIH as:

‘Nanomedicine refers to highly specific medical intervention at the molecular scale for curing
diseases or repairing damaged tissues, such as bone, muscle, or nerve’.

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 Need for nanoparticle dds:
Conventional drug delivery system

Conventional utilization of drugs is characterized by

● Poor biodistribution.
● Limited effectiveness.
● Undesirable side effects.
● Lack of selectivity.

❏ To overcome these limitations one of the best method is nanosizing. Size reduction of targeted
formulation and designing its pathways for suitable drug delivery system is a more fundamental
and successful approach that forms the basis of nanotechnology.

❏ In addition these methods help in reducing toxicity, enhancing release, improving solubility and
bioavailability and provide better formulation opportunities for drugs.

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Advantages:

Nanotechnology offers drugs in the nanometer size range which enhances the performance in a variety of
dosage forms. Various advantages of nano sizing are mentioned below:

• Decreased fed/fasted variability

• Decreased patient-to-patient variability

• Enhanced solubility

• Increased oral bioavailability

• Increased rate of dissolution

• Increased surface area

• Less amount of dose required

• More rapid onset of therapeutic action

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Characterization
Characterization refers to the study of materials features such as its composition,
structure and various properties like physical, chemical, electric and magnetic etc

● Characterization of nanoparticles is based on the size, morphology and surface charge,

using such advanced microscopic techniques as atomic force microscopy (AFM), scanning
electron microscopy (SEM) and transmission electron microscopy (TEM).

● Properties such as the size distribution, average particle diameter, charge affect the
physical stability and the in vivo distribution of the nanoparticles

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Characterization
1. Particle Size
● Characterizations of nanoparticles are primarily evaluated by the particle size distribution and
morphology.

● Application of nanoparticles in drug release and drug targeting can be conveniently determined by
various tools. It has already been reported that particle size of nanoparticles has profound effect on the
drug release.

● Smaller the size of nanoparticles larger surface area, which results in to fast drug release. Loaded drug
when exposed to the particle surface area causes significant drug release.

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Characterization

● In contrast, inside the nanoparticles drugs slow diffusion of larger particles occurs. Consequently smaller
particles tend to aggregate during storage and transportation of nanoparticle dispersion.

● Therefore there is a mutual compromise between maximum stability and small size of nanoparticles

● In addition degradation of the polymer can also be affected by the particle size e.g. the extent of poly
(lactic-co-glycolic acid) degradation was found to increase with increasing particle size in vitro

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Importance of evaluation of particle size

Small size of nanoparticles is important for:

1) Drug release
2) Diffusion rate
3) Stability
4) Polymer degradation

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Techniques to determine size of nanoparticles:

With the advancement in analytical tools various techniques are now available for determining
nanoparticle size as discussed below:

● Photon-Correlation Spectroscopy (PCS) or Dynamic Light Scattering (DLS)

● Scanning Electron Microscopy (SEM)
● Transmission Electron Microscope

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Photon correlation spectroscopy:

Principle:

Dynamic light scattering (DLS) is based on the Brownian motion of dispersed

particles. When particles are dispersed in a liquid they move randomly in all
directions. The principle of Brownian motion is that particles are constantly
colliding with solvent molecules.

Instrumentation:

1) Light source
2) Optical systems
3) Detectors
4) Digital correlator

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 Working:

In a dynamic light-scattering instrument, when laser light encounters macromolecules the incident light scatters in
all directions and scattering intensity is recorded by a detector. The monochromatic incident light will undergo a
phenomenon called Doppler broadening as the macromolecules are in continuous motion in solution

The scattered light will either result in mutually destructive phases and cancel each other out, or in
mutually constructive phases to produce a detectable signal.

The digital autocorrelator then correlates intensity fluctuations of scattered light with respect to
time (ns-μs) to determine how rapidly the intensity fluctuates, which is related to the diffusion
behaviour of macromolecules.

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Scanning electron microscopy:

SEM is the most important technique for the analysis of morphological characteristics like
size and shape, topography, and surface composition.

Scanning electron microscopy (SEM) is used to examine the morphology of the powder
before consolidation.

This electron microscopy based technique determines the size, shape and surface
morphology with direct visualization of the nanoparticles. Therefore scanning electron
microscopy offer several advantages in morphological and sizing analysis.

However they provide limited information about the size distribution and true population
average.

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 Scanning electron microscopy:

Procedure:

During the process of SEM characterization, solution

of nanoparticles should be initially converted into a
dry powder.

This dry powder is then further mounted on a sample

holder followed by coating with a conductive metal
(e.g. gold) using a sputter coater.

Whole sample is then analyzed by scanning with a

focused fi ne beam of electrons.

Secondary electrons emitted from the sample surface

determine the surface characteristics of the sample.
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Characterization

2) Surface Charge:

Zeta Potential:

Surface charge and intensity determines the interaction of nanoparticles with the biological
environment as well as their electrostatic interaction with bioactive compounds.

Zeta potential is an indirect measure of the surface charge.

Thus zeta potential of colloidal based dispersion assists in directly evaluating its storage stability.
Zeta potential values (high zeta potential values, either positive or negative) are achieved in
order to ensure stability and avoid aggregation of the particles.

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Characterization

3) Hydrophobicity: Hydrophobicity is an important parameter to determine for the risk assessment

of chemicals and in particular of nanomaterials.

Why?

Because hydrophobicity plays a critical role in various biological processes such as:

● protein adsorption
● interaction with biological membranes
● cellular uptake
● immune response
● hemolytic effects.

It is also recognized as key quality attribute for nanomedicines.

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Surface Area

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Density:

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Methods to find hydrophobicity of Nps:

Existing methods for characterizing the hydrophobicity of substances have been applied to
NPs and met with varying degrees of success.

Examples of these methods include

1) Contact angle, which is typically used to evaluate the hydrophobicity of solid surfaces.
2) Octanol-water partitioning, which is commonly used for chemicals.
3) Hydrophobic interaction chromatography, which provides a relative measure of the
hydrophobicity of proteins.

In some cases, these methods have been modified for NP specific behavior.

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Drug Release:

Drug loading capacity of the nanoparticles is defined as the amount of drug bound per mass of
polymer or in another term it is the moles of drug per mg polymer or mg drug per mg polymer or
it could also be given as percentage relative to the polymer.

It’s very essential to determine extent of the drug release and in order to obtain such
information most release methods require that the drug and its delivery vehicle be separated.

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Methods of preparation:

Nanoparticles can be prepared from a variety of materials such as proteins, polysaccharides and
synthetic polymers. The selection of matrix materials is dependent on many factors including

• Biocompatibility and toxicity.

• Degree of biodegradability

• Drug release profile desired

• Inherent properties of the drug (aqueous solubility and stability)

• Size of nanoparticles required

• Surface characteristics (charge and permeability)

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Methods of preparation:

Nanoparticles have been usually prepared by three methods:

Dispersion of preformed polymers

Ionic gelation or coacervation of hydrophilic polymers

Polymerization of monomers

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 Dispersion of preformed polymers

Spontaneous Double
Solvent
Emulsification or emulsification and
evaporation Salting out method
Solvent Diffusion evaporation
method
Method method

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Solvent evaporation method:

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Spontaneous Emulsification:

Water miscible solvent along with a small amount of the organic solvent (water
immiscible) is used as an oil phase.

During the spontaneous diffusion of solvents between the two phases an interfacial
turbulence is generated which may ultimately leads to the formation of small particles.

Smaller particle size can be achieved by increasing the concentration of water

miscible solvent increases.

This method can be used for hydrophobic or hydrophilic drugs. In the case of
hydrophilic drug, a multiple w/o/w emulsion needs to be formed with the drug
dissolved in the internal aqueous phase.

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Double emulsification method:

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Salting out method: Polymer and drug are dissolved in a
solvent

Subsequently emulsified into an

aqueous gel containing the salting out
agent and a colloidal stabilizer.

Polymer and drug are dissolved in a

solvent

This lead to formation of oil/water

emulsion which is further diluted with a
sufficient volume of water or aqueous
solution to enhance the diffusion of
solvent into the aqueous phase,
ultimately induce the formation of
nanosphere. 35
Salting out method:

Types of salting out agents Colloidal stabilizer

electrolytes, such as
magnesium chloride Polyvinylpyrrolidone
and calcium or
chloride, or non- hydroxyethylcellulo
electrolytes such as se
sucrose

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Emulsions-Diffusion Method

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Solvent Displacement/Precipitation Method

In solvent displacement method, the polymer is precipitated from an organic solution and the
organic solvent diffuses in the aqueous medium in the presence or absence of surfactant.

Semipolar water miscible solvent (acetone, ethanol) is used to dissolve polymers, drug, and or
lipophilic surfactant. Thereafter under magnetic stirring conditions, the prepared solution is
added into an aqueous solution containing stabilizer.

By rapid solvent diffusion, nanoparticles are formed instantly. Under reduced pressure
the solvent is removed from the suspension.

The particle size depends upon the rate of addition of organic phase in aqueous medium. The
particle size and drug entrapment is decreased as the rate of mixing of the two phases
increases
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Solvent Displacement/Precipitation Method

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Supercritical Fluid Technology

Supercritical fluids are those fluids which are at a temperature above its critical temperature
remains in a single phase regardless of pressure.

CO 2 (SC CO 2 ) is the most widely used supercritical fluid because of its mild critical conditions,
non-flammability, low price and non toxicity.

Among the various processing techniques involving supercritical fluids

❏ Supercritical anti-solvent (SAS)

❏ Rapid expansion of critical solution (RESS) are the most common one.

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Supercritical Fluid Technology

Supercritical anti-solvent (SAS)

A liquid solvent (methanol) is selected on the basis of it’s completely miscibility with the
supercritical fluid (SC CO 2 ).

This is done to dissolve the solute to be micronized at the process conditions.

Since the solute is insoluble in the supercritical fluid, the extract of the liquid solvent by
supercritical fluid leads to the instantaneous precipitation of the solute, results in the formation of
nanoparticles.

This process is reported for formation of hydrophilic drug dexamethasone

phosphate drug nanoparticles for microencapsulation purpose.

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Rapid expansion of critical solution (RESS)

Solute is dissolved in a supercritical fluid such as supercritical methanol

then the solution is rapidly expanded through a small nozzle into a

region lower pressure

This dramatically affects the solvent power of supercritical fluids which

is ultimately decreases and the solute eventually precipitates

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Types of Nanoparticles:

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NIOSOMES

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Introduction

Niosomes are synthetic microscopic vesicles consisting of an aqueous core enclosed in

bilayer consisting of cholesterol and one or more non ionic surfactants. Their size range
is 10-100 nm.

They are vesicular systems similar to liposomes that can be used as carriers of
amphiphilic and lipophilic drugs.

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Characteristics of niosomes:

● Biocompatible, biodegradable, non-toxic, non-immunogenic and non-carcinogenic.

● The ability of non-ionic surfactant to form bilayer vesicle is dependent on HLB value of surfactant and
chemical structure of components.
● High resistance to hydrolytic degradation.
● The properties of niosomes depends both on composition of the bilayer and on method of their production.

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Components of Niosomes:
Major components of niosomes include:

● Non-ionic surfactants (Tweens, Spans,ester linked poly-sorbates, sorbitan esters)

● Cholesterol

Cholesterol provides rigidity and proper shape to the niosomes.

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 Comparison of liposomes and niosomes

Similarities:
● Both act as drug carriers
● Both increase bioavailability of drugs and reduce the clearance
● Both are used for targeted drug delivery
● Entrapment efficiency increases with increase in concentration and lipophilicity of
surfactant.
● Properties of both niosomes and liposomes depends on composition of bilayer and
method of production used

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Differences:
Niosomes:
● Vesicles made up of
surfactants with or without
incorporation of cholesterol.
● Size ranges 10-100 nm
● Less expensive
● Chemically more stable
● Increased permeability and
fluidity
Liposomes:
● Vesicles made up of concentric
bilayer of phospholipids
● Size ranges 10-100 um
● More expensive
● Chemically less stable
● Decreased permeability and
fluidity
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● Non-ionic surfactants
● Non toxic
● No aggregation, fusion,
sedimentation
● Methods of preparation
include:
1. Reverse phase evaporation
technique
2. Lipid layer hydration method
3. Transmembrane pH gradient
uptake technique
● Ionic surfactants
● Toxic
● Aggregation, fusion and
sedimentation can occur
● Methods of preparation
include:
1. Physical dispersion
2. Solvent extraction
3. Detergent solubilization
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● Due to increased cholesterol,
release of active is good
● Less products in market
● No handling and storage
conditions are required
● Oral route is possible
● Due to increased cholesterol,
rigidity increases
● More products in market
● Handling and storage
conditions are necessary
● Not possible due to
instability to bile acids
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Advantages:

● They are osmotically active and they increase the stability of entrapped drug.
● Targeted drug delivery can be achieved using niosomes.
● Reduced dose is required to achieve the desired effect.
● Can enhance the skin permeation of drugs.
● They can be used for oral, parenteral as well as topical use.
● Improve the therapeutic performance of the drug by protecting it from the biological
environment and restricting effects to target cells, thereby reducing the clearance of
the drug.

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Advantages:

● Handling and storage of niosomes requires no special

conditions.
● They improve the oral bioavailability of poorly absorbed drugs.
● Biodegradable, biocompatible and non immunogenic.
● Characteristics of the vesicle formulation are variable and
controllable.

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Disadvantages:

● Aggregation.
● Fusion.
● Hydrolysis of encapsulated drugs which limiting the shelf life of
the dispersion.
● Leaking of entrapped drug.

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 Classification of niosomes:
On the basis of;

1) Lamellarity

2) Size

3) Composition

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On the basis of
lamellarity:
Small unilamellar

Large unilamellar

Multilamellar

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 On the basis of size:

Small Large Big/ Giant

Size: 100nm-200nm Size: 800nm-900 nm Size: 2um-4um

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On the basis of composition:
❖ Proniosomes.
❖ Aspasomes.
❖ Vesicle in water and oil system (v/w/o).
❖ Niosomes in carbopol gel.
❖ Niosomes of HPMC.
❖ Bola niosomes.
❖ Discomes.
❖ Deformable / elastic niosomes.

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Proniosomes

What are proniosomes?

Proniosomes are self-assembled vesicular nanocarriers composed of non-ionic

surfactants, helper lipids and charge modifiers that have recently emerged as
promising nonviral gene delivery systems.
OR
Proniosomes are dry formulation of water-soluble carrier particles that are
coated with surfactant.

Which requires to be hydrated before being used to form aqueous niosome dispersion

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 proniosomes :

Carrier Surfactant Proniosome

H2O
Commonly used carriers: Commonly surfactants:
a) Maltodextrin. a) Alkyl ethers
b) Sorbitol. b) Alkyl esters
c) Spray dried lactose. c) Alkyl amides
d) Glucose monohydrate. d) Esters of fatty acid
e) Lactose monohydrate.
f) Sucrose stearate.

Niosomes 60
Advantages of proniosomes:

● Avoiding the problem of physical stability like fusion, aggregation,sedimentation and leakage on
storage.
● Avoiding hydrolysis of encapsulated drugs which limiting the shelf life of the dispersion.
● Ease on storage and handling.
● Drug delivery with improved bioavailability, reduced side effects.
● Entrapment of both hydrophilic and hydrophobic drugs.

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Aspasomes:

Niosomes that are the combination of ,ascorbyl palmitate, cholesterol and diacetyl
phosphate, are known as aspasomes.

Ascorbyl Diacetyl Aspasomes

Cholesterol
palmitate phosphate

Provides Bilayer Negatively

rigidity to the vesicle charged
niosome forming lipid
material

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Aspasomes:

Formation of aspasomes:

Aspasomes are formed by film hydration method, followed by sonication.

Advantages:
● Increase the transdermal penetration of drugs.
● Drugs that get oxidized can be protected by making aspasomes, as
they carry an inherent antioxidant property.

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Vesicle in water in oil system

The formulation in which the niosomes are dispersed in an aqueous phase which then added into
the non-aqueous phase.
● The resultant vesicle-in-water-in-oil (v/w/o) system allows the delivery of vcsiclcs in a non-
aqueous vehicle.

Niosome
W/O emulsion Vesicle/w/o emulsion

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Vesicle in water in oil system

● The emulsion will be in gel like consistency.

Method of preparation:

● This can be prepared by adding niosome dispersion into oil phase at 60 c. As a result vesicle
in water in oil emulsion formed. Upon cooling we obtained vehicles-in-water-in-oil gel.

Advantages:

● Can encapsulate proteinous drugs.

● Can protect stomach sensitive drugs.
● Provide controlled release after oral administration of drug.

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Niosomes in carbopol gel:

Niosomes prepared by the combination of cholesterol, drug and non-ionic surfactant.

These prepared niosomes are then incorporated into carbopol-934 gel.

● This type of formulation is very important for transdermal drug delivery system.

why?

Because this carbopol gel is:

● Very non greasy

● A good carrier of drug
● Enhances the penetration of a drug
● Hydrate the skin

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Niosomes of HPMC

1ST step:

● Prepare base containing 10% glycerin of HPMC

2nd step:

● Prepare simple niosome by using cholesterol and nonionic surfactant.

● Then incorporate niosomes in the base

Importance :

● For delivery of niosomes through oral administration as hpmc is biodegradable act as good
carrier of niosome

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BOLA-NIOSOMES

BOLA- surfactant:

● bola surfactant compound, unique as it contain two hydrophilic heads that are connected by one
or two long lipophilic spacers.they could have single or double hydrophobic tail.
● They are naturally present in archaebacteria
● They have much lower surface activity but have strong assembling ability i-e they have rigid
structure, cause less leakage of drug, better entrapment of drug
● Suitable tolerability both in-vivo and in-vitro

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Bola niosomes

● This group of vesicles are made of alpha omega-hexadecyl-bis-(1-aza-18-crown-6-)(bola), span 80

and cholesterol (2:5:2) molar ratio was proposed as topical DDS for 5-flurouracil. Largely used in
the treatment of cancer.

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Discomes (large disc like) niosomes

● Organic solvent(hexadecyl diglycerol ether) +cholesterol+dicetyl phosphate

by mechanical shaking form disc like niosomes

● Gradually increase size upon sonication

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Discosomes

● Discomes are flattened disc like

● Have more ability to carry drug mostly act as drug reservoir systems
● Leak drug when come in contact with water
● Discomes are thermoresponsive as they become leaky when temperature raised above 37C so
have potential for ocular DDS.

e.g naltrexone HCl in the treatment of diabetic keratopathy

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Deformable niosomes or elastic niosome

● Nonionic surfactant + ethanol + water also called ethosomes.

● Superior to conventional niosomes because they increase penetration efficiency of compound
through intact skin by passing through pores in stratum corneum, which are smaller than
vesicles(niosomes)

How?

Because of their structural flexibility(cause bending) they passed from pores that are less than
one tenth of vesicles.

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Deformable niosomes

● Example: manosroi prepared niosomes from tween 61, span 60 and ethanol for entrapment of
diclofenac diethylammonium so that there deformability index value increases 13.75 times higher
than conventional niosomes

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Polymeric Nanoparticles

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Polymeric NPS:

“Polymeric nanoparticles (NPs) are particles within the size range from 1 to 1000 nm
and can be loaded with active compounds entrapped within or surface-adsorbed onto
the polymeric core.”

•Polymeric nanoparticles (NPs) have attracted considerable interest over recent years
due to their properties resulting from their small size.

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Polymeric Nps:

● Natural polymer based nanoparticles are usually biocompatible and non toxic, although often suffer
from stability problems when delivered across the various biological membranes. Such delivery
exposed nanoparticles against various pH.

● This variation in pH and certain other problems limit their use sometime.

● Polymeric nanoparticles consist of a biodegradable polymer which is biocompatible and non toxic.
Feature such as biocompatibility is required for potential application in tissue engineering, drug and
gene delivery and new vaccination strategies.

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 Polymeric Nps:

•The term “nanoparticle” comprises both nanocapsules and

nanospheres, which differ with respect to their morphology.
•Nanocapsules are composed of an oily core in which the drug is
usually dissolved, surrounded by a polymeric shell which controls
the release profile of the drug from the core.
Nanospheres are based on a continuous polymeric network in
which the drug can be retained inside or adsorbed onto their
surface.
•These two types of polymeric NPs recognized as a reservoir
system (nanocapsule), and matrix system (nanosphere) [8] are
shown in Figure

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Advantages of polymeric nanoparticles:

There are many advantages of using polymeric nanoparticles in drug delivery:

• Biocompatable and biodregerable

• Increase the stability of any volatile pharmaceutical agents

• Less toxic •

They are easily cheaply fabricated in large quantities by a multitude of methods

• Have engineered specificity, allowing them to deliver a higher concentration of pharmaceutical agent to a
desired location

• Nonimmunogenicity and nontoxicity

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Polymers used:

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Nanocapsules:

Nanocapsules are systems in which the drug is confined to a cavity surrounded by unique polymeric
membrane.

Nanocapsules have been one of the most widely studied nanosystems for the delivery of functional
compounds.

Nanocapsules (which are also known as nanoparticles in food science) are constituted by an external
polymeric membrane and an inner part composed of a liquid or polymeric matrix that contains the
bioactive compound.

During their production, different techniques can be applied (such as ionic pregelation/coacervation,
polymerization, and dispersion of preformed polymers), which may affect their final properties.

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Structure of nanocapsules:

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Methods of preparation:

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Nanoprecipitation method:

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Double emulsification method:

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Polymer coating method:

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Advantages of nanocapsules:

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