Nanoparticles & Nanocrystals

8/23/2019 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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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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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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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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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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1. Increase of dissolution velocity by surface area enlargement:


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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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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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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

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