Nanoparticles & Nanocrystals
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Transcript of Nanoparticles & Nanocrystals
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Nanoparticles and
Nanocrystals
Supervised by: Prof. Ashok Kumar
Done by: Hussein Talal Ashur
ID: 201117011
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Definitions
Nanoparticle is a microscopic particle with at least one
dimension less than 100 nm.
Polymeric Nanoparticles are also defined as polymeric particles
made of natural or synthetic polymers ranging from 10-100 nm in
which drug may be bound in solid solution or dispersion,
adsorbed or chemically attached
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Definitions
Nanoclusters have at least one dimension between 1 and 10 nm
and a narrow size distribution.
Nanopowders are agglomerates of ultrafine particles,
nanoparticles, or nanoclusters.
Nanometer-sized single crystals, or single-domain ultrafine
particles, are often referred to as Nanocrystals.
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Advantages of Nanoparticles
a) Longer shelf-stability
b) High carrier capacity
c) Ability to incorporate hydrophilic and hydrophobic drug molecules
d) Can be administered via different routes
e) Longer clearance time
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Advantages of Nanoparticles
f) Ability to sustain the release of drug
g) Can be utilized for imaging studies
h) Increase the bioavailability of drugs
i) Targeted delivery of drugs at cellular and nuclear level
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Advantages of Nanoparticles
j) Development of new medicines which are more safe
k) Prevent the multi-drug resistance mediated efflux of
chemotherapeutic agents
l) Product life extension
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Disadvantages of nanoparticles
a) Involves higher manufacturing costs which may in turn lead to
increase in the cost of formulation
b) Involves use of harsh toxic solvents in the preparation process
c) May trigger immune response and allergic reactions
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Nanoparticles production processes
Nanoparticles can be produced by either
1. Dispersion-based processes (which involves breaking larger
micrometer-sized particles into nanoparticles) or
2. precipitation-based processes
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1-Dispersion-based processes
a) Wet milling
b) High-pressure Homogenization (Air jet milling)
c) Emulsification Technology
2-precipitation-based processes
a) Spray freezing into liquid (SFL)
b) Evaporative precipitation into aqueous solution (EPAS).
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Nanoparticles
Wet milling
Wet milling
is an attrition-based process in which the drug is dispersed first in an
aqueous-based surfactant solution. The resulting suspension is
subjected to wet milling using a pearl mill in the presence of milling
media.
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Wet milling provides a method to reduce
the particle size of poorly soluble API.
Intensive
process
Particle
recovery
required
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Particle-particle
collisionsNo heat or moving
parts
Air jet milling ( High pressure homogenization)
High-pressure homogenization is based on the principle of
cavitation (i.e., the formation, growth, and implosive collapse of
vapor bubbles in a liquid (9-11). In this process, a drug
presuspension (containing drug in the micrometer range) is
prepared by subjecting the drug to air jet milling in the presence of
an aqueous surfactant solution.
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Spray freezing into liquid (SFL)
An aqueous, organic, or aqueousorganic cosolvent solution;
aqueousorganic emulsion; or drug suspension is atomized into a
cryogenic liquid such as liquid nitrogen to produce frozen
nanoparticles which are subsequently lyophilized to obtain freeflowing powder
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Table 1 Overview of nanoparticles and their applications in Life Sciences
Particle class Materials Application
Natural Chitosan Drug/Gene delivery
materials or Dextrane
derivatives Gelatine
Alginates
Liposomes
Starch
Dendrimers Branched polymers Drug delivery
Fullerenes Carbon based carriers PhotodynamicsDrug delivery
Polymer carriers Polylactic acid Drug/gene delivery
Poly(cyano)acrylates
Polyethyleinemine
Block copolymers
Polycaprolactone
Ferrofluids SPIONS Imaging (MRI)
USPIONS
Quantum dots Cd/Zn-selenides Imaging
In vitro diagnostics
Various Silica-nanoparticles Gene deliveryMixtures of above
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Classification of Nanoparticles
Liposomes
Micelles
Polymeric nanoparticles
Dendrimers
Fullerenes
Nanoshells Carbon Nanotubes
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Liposomes (Lipid based drug carriers)
A self-closing spherical particle that is composed of natural orsynthetic amphiphilic lipid molecules (lipid bilayer)
Microscopic spherical vesicles that form when phospholipids arehydrated.
Doxorubicin liposomal ( Doxil)
is used to treat metastatic ovarian
cancer and AIDS-related
Kaposi's sarcoma.
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Liposomes Doxil is the drug doxorubicin HCl encapsulated in an antibody
linked PEGylated liposome
PEG (polyethylene glycol) makes the liposome less vulnerable toimmune system
PEGylation, by increasing the molecular weight of a molecule, canimpart several significant pharmacological advantages over theunmodified form, such as:
1. Improved drug solubility
2. Reduced dosage frequency,3. Extended circulating life
4. Increased drug stability
5. Enhanced protection from
proteolytic degradation
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Micelles
Micelle is an aggregate of amphipathic molecules in water, with
the nonpolar portions in the interior and the polar portions at the
exterior surface, exposed to water.
Hydrophobic drugs can be encapsulated, into inner core.
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Block copolymers self assemble in
solution to form micelles.
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Polymeric Nanoparticles
As name only suggest polymeric nanoparticles are nanoparticleswhich are prepared from polymers
The drug is dissolved, entrapped, encapsulated or attached to ananoparticles and depending upon the method of preparation,nanoparticles, nanospheres or nanocapsules can be obtained.
Nanocapsules are vesicular systems in which the drug is confined toa cavity surrounded by a polymer membrane, while nanospheres arematrix systems in which the drug is physically and uniformlydispersed.
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Polymeric Nanoparticles Biodegradable polymeric nanoparticles have attracted considerable
attention as potential drug delivery devices in view of their
applications in drug targeting to particular organs/tissues, as carriers
of DNA in gene therapy, and in their ability to deliver proteins,
peptides and genes through oral route of administration.
In cancer, targeted polymeric NPs can be used to deliver
chemotherapies to tumor cells with greater efficacy and reduced
cytotoxicity on peripheral healthy tissues.
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Polymeric Nanoparticles Recently, a nanoparticle formulation of paclitaxel, in which serum
albumin is included as a carrier [nanometer-sized albumin-bound
paclitaxel (Abraxane) has been applied in the clinic for the treatment
of metastatic breast cancer.
Besides metastatic breast cancer, Abraxane has also been evaluated
in clinical trials involving many other cancers including nonsmall-celllung cancer (phase II trial) and advanced nonhematologic
malignancies.
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Polymeric Nanoparticles
Some examples of biodegradable polymers involved in polymeric NPsproduction
1. Polylactides (PLA).
2. Polyglycolides (PGA).
3. Poly(lactide-co-glycolides) (PLGA).
4. Polyanhydrides.
5. Polyorthoesters.
6. Polycyanoacrylates
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Polymeric Nanoparticles During the 1970, scientists first began to encapsulate and entrap
drugs within polymers
Encapsulation involves surrounding drug molecules with a solidpolymer shell
Entrapment involves the suspension of drug molecules within a
polymer matrix.
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Polymeric Nanoparticles
Drug release from nanoparticles is achieved either by Diffusion
and/or Erosion
In case of diffusion:
1. polymer absorbs water it and swells in size
2. Swelling created voids throughout the interior polymer
3. Smaller molecule drugs can escape via the voids at a known rate
controlled by molecular diffusion (a function of temperature and
drug size)
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Dendrimers
Dendrimers are a highly branched type of nanoparticle that can
target specific cells based on the molecular "hooks" on the ends of
the polymers that make up their outer surface. There are two basic structural types:
1. One is the globular structure with a central core from which
polymer branches radiate;
2. The second type has no central core and consists simply of aseries of highly branched polymers.
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Dendrimers
The manufacturing process is a series of repetitive steps starting
with a central initiator core.
Each subsequent growth step represents a new "generation" of
polymer with a larger molecular diameter, twice the number
of reactive surface sites, and approximately double the molecular
weight of the preceding generation.
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DendrimersProduct Application Company
Vivagel Vaginal Gel for
preventing HIV
Starpharm
a
Stratus CS Cardiac Marker Dade
Behring
SuperFect Gene Transfection Qiagen
Alert
Ticket
Anthrax Detection US Army
Research
Laboratory
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Fullerenes (Carbon 60)
are spherical cages containing from 28 to more than 100 carbonatoms.
They can be subjected to extreme pressures and regain their
original shape when the pressure is released.
Hence they find application as NanoPharmaceuticals with largedrug payload in their cage like structure.
They are being explored as potential new antimicrobial
agents in view of their potency for induction of reactive
oxygen species after photoexcitation
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Fullerenes (Carbon 60)
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Nanoshells
Nanoshells have a core of silica and a metallic outer layer.
These nanoshells can be injected safely, as demonstrated inanimal models.
Because of their size, nanoshells will preferentially concentrate incancer lesion sites.
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Nanoshells
This physical selectivity occurs through a phenomenon calledenhanced permeation retention (EPR).
Can further decorate the nanoshells to carry molecular conjugatesto the antigens that are expressed on the cancer cells themselvesor in the tumor microenvironment.
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For example, tumor accumulation via
enhanced permeability and retention.
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Nanoshells
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Carbon Nanotube Carbon nanotubes are carbon cylinders composed of benzene
rings that have been applied in biology as sensors for detectingDNA and protein, diagnostic devices for the discrimination ofdifferent proteins from serum samples, and carriers to deliver
vaccine or protein .
Carbon nanotubes are completely insoluble in all solvents,generating some health concerns and toxicity problems.
However, the introduction of chemical modification to carbonnanotubes can render them water-soluble and functionalized sothat they can be linked to a wide variety of active molecules suchas peptides, proteins, nucleic acids, and therapeutic agents.
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Carbon Nanotube Antifungal agents (amphotericin B) or anticancer drugs
(methotrexate) have been covalently linked to carbon nanotubes
with a fluorescent agent.
In an in vitro study, drugs bound to carbon nanotubes were shown
to be more effectively internalized into cells compared with free
drug alone and to have potent antifungal activity.
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Carbon Nanotube
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Targeted delivery of nanoparticles For anticancer drugs to be effective in cancer treatment,
1. they should after administration, be able to reach the desired
tumor tissues through the penetration of barriers in the bodywith minimal loss of their volume or activity in the blood
circulation. (Penetrability)
2. after reaching the tumor tissue, drugs should have the ability toselectively kill tumor cells without affecting normal cells with a
controlled release mechanism of the active form. (Selectivity)
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Targeted delivery of nanoparticles
These two basic strategies are also associated with improvements
in patient survival and quality of life by increasing the intracellular
concentration of drugs and reducing dose-limiting toxicitiessimultaneously.
Increasingly, nanoparticles seem to have the potential to satisfyboth of these requirements for effective drug carrier systems.
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Size and Surface Characteristics of Nanoparticles
To effectively deliver drug to the targeted tumor tissue,
nanoparticles must have the ability to remain in the bloodstream
for a considerable time without being eliminated.
Conventional surface nonmodified nanoparticles are usually
caught in the circulation by the reticuloendothelial system, such
as the liver and the spleen, depending on their size and surface
characteristics. The fate of injected nanoparticles can be controlled by adjusting
their size and surface characteristics.
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Size of Nanoparticles
One of the advantages of nanoparticles is that their size is tunable.
The size of nanoparticles used in a drug delivery system should be
large enough to prevent their rapid leakage into blood capillaries
but small enough to escape capture by fixed macrophages that are
lodged in the reticuloendothelial system
The size of nanoparticles should be up to 100 nm to reach tumor
tissues by passing through these particular vascular structures.
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Surface Characteristics of Nanoparticles
Nanoparticles should ideally have a hydrophilic surface to escape
macrophage capture. This can be achieved in two ways:
1. coating the surface of nanoparticles with a hydrophilic polymer,
such as PEG
2. alternatively, nanoparticles can be formed from block co-
polymers with hydrophilic and hydrophobic domains
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Drug nanocrystals are crystals with a size in the nanometer range,
which means they are nanoparticles with a crystalline character.
A further characteristic is that drug nanocrystals are composed of
100% drug; there is no carrier material as in polymeric
nanoparticles.
Dispersion of drug nanocrystals in liquid media leads to so callednanosuspensions .
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In general the dispersed particles need to be stabilized, such as by
surfactants or polymeric stabilizers.
Dispersion media can be water, aqueous solutions or nonaqueous
media (eg, liquid polyethylene glycol [PEG], oils).
Depending on the production technology, processing of drug
microcrystals to drug nanoparticles can lead to an either
crystalline or to an amorphous product, especially when applying
precipitation.
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Properties of nanocrystals
1. Increase of dissolution velocity by surface area enlargement:
The size reduction leads to an increased surface area and thusaccording to the Noyes-Whitney equation (Noyes and Whitney
1897) to an increased dissolution velocity.
Therefore micronization is a suitable way to successfully enhance
the bioavailability of drugs where the dissolution velocity is therate limiting step.
By moving from micronization further down to nanonization, the
particle surface is further increased and thus the dissolution
velocity increases too
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Properties of nanocrystals
1. Increase of dissolution velocity by surface area enlargement:
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Properties of nanocrystals
2. Increase in saturation solubility
(cs- saturation
solubility,
cx - bulk
concentration,
h - diffusional
distance).
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Production of nanocrystals
1. Precipitation methods
2. Milling methods
3. Homogenization methods
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echnology Advantages Disadvantages
recipitation- finely dispersed drug
- good control of desired size
- needs to be stabilized
- organic solvent residue
- not universally applicable, only
drugs with certain properties are
possible (eg, soluble in at least one
solvent)
illing- low energy technique
- proven by 4 FDA approved drugs
- residue from milling media
- can be a slow process (several
days)
- needs to be stabilized
- large batches difficult to produce
due to size of milling chamber
omogenization
- universally applicable
- no problem with large batches
- fast method (several minutes
possibly)
- water free production possible
- high energy technique
- great experience needed
Table: Advantages and disadvantages of different methods for the production of nanocrystals
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Products in the market
1. Rapamune Sirolimus (immunosuppressive agent)was the first
marketed product introduced in 2000 by Wyeth Pharmaceuticals,
Comparing the oral bioavailability of solution and nanocrystal
tablet, the bioavailability of the nanocrystals is 21% higher
compared to the solution.
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Products in the market
2. Emendintroduced in 2001 by Merck. The drug is aprepitant,
used for treatment of emesis. Aprepitant will only be absorbed in
the upper gastrointestinal tract. Bearing this in mind
nanoparticles proved to be ideal to ideally exploit this narrow
absorption window. The drug nanocrystals are contained within a
hard gelatin capsule as pellets
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Products in the market
3. Tricoris being marketed by Abbott Laboratories and the active
ingredient is fenofibrate. The absorption of fenofibrate in fed
patients is up to 35% higher than in nonfed patients. The
nanocrystal technology makes the fenofibrate independent of
meals. Plasma levels in fed and fasting condition are
bioequivalent (data on file, Abbott Labs).
Table: Examples of pharmaceuticals products based on nanotechnologiesBrand name Description Advantages
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Brand name Description Advantages
Emend
(Merck & Co. Inc.)
Nanocrystal aprepiant (antiemetic) in a
capsule
Enhanced dissolution rate &
bioavailability
Rapamune
(Wyeth-Ayerst Laboratories)
Nanocrystallied Rapamycin
(immunosuppressant) in a tablet
Enhanced dissolution rate&
bioavailability
Abraxane
(American Biosciences, Inc.)
Paclitaxel (anticancer drug) bound
albumin particles
Enhance dose tolerance and hence
effect elimination of solvent
associated toxicity
Rexin-G(Epeius Biotechnology
corporation)
A retroviral vector carrying cytotoxicgene
Effective in pancreatic cancertreatment
Olay Moisturizers
(Proctor and Gamble)
Contains added transparent, better
protecting nano zinc oxide particles
Offer better UV protection
Trimetaspheres(LunaNanoworks)
MRI images enhanced MRI images at least 25
times better than current contrast
agents
SILCRYST
(Nucryst Pharmaceuticals)
Enhance the solubility and sustained
release of silver nanocrystals
Better protection from infection
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Future Direction and Opportunities
Together with the progression of nanoscale drug delivery systems,
advances in nanoscale imaging suggest the potential for the
development of multifunctional smart nanoparticles that may
facilitate the realization of individualized cancer therapy.
Almost all types of nanoparticles including polymeric
nanoparticles, nanocrystals, polymeric micelles, dendrimers and
carbon nanotubes have been evaluated for their suitability as
multifunctional nanoparticles that can be applied for
simultaneous in vivo imaging and treatment of cancers.
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Future Direction and Opportunities
Eventually, multiplex nanoparticles may be capable of:
1. detecting malignant cells2. visualizing their location in the body (real-time in vivo imaging),
3. killing the cancer cells with minimal side effects by sparing
normal cells (active targeting and controlled drug release or
photothermal ablation), and4. monitoring treatment effects in real time.
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Multifunctional nanoparticle.
References:
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References:
1. http://clincancerres.aacrjournals.org/content/14/5/1310.full#F1
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626933/
3. http://www.nanopharmaceuticals.org/Polymeric_nanoparticles.html
4. http://www.pharmainfo.net/reviews/nanoparticles-and-its-applications-field-pharmacy
5. http://www.authorstream.com/Presentation/issra-366349-nanoparticles-science-technology-ppt-powerpoint/
6. http://www.authorstream.com/Presentation/aSGuest115913-1207997-
nanoparticles-in-drug-delivery/
7. Drug delivery and nanoparticles: Applications and hazards
Wim H De Jong, Paul JA Borm
8 http://www nanoparticles org/pdf/Berkland pdf