sábado, 20 de marzo de 2010

Nanoparticles and its applications in field of pharmacy

Nanoscience is the study of phenomenon and manipulation of materials
at atomic, molecular and macromolecular scales, where properties
differ significantly from those at a larger scale.
Nanoelement can be defined as:
•A composite of other nanoelements, a (specially designed) molecule or
a sub-molecule.
•A nanoparticle in the usual sense, a composite of several different
•An (intellectually bound) small region of a material, an elementary particle.
•Any special construct on an atomic or subatomic level, any other
Nanotechnology can best be considered as a 'catch-all' description of
activities at the level of atoms and molecules that have applications
in the real world. Nanotechnology involves the use of man-made
materials so small; they are measured on the scale of a nanometer. The
word "Nano" is derived from the greek word for Dwarf. It means "a
billionth." A nanometer is a billionth of a meter, that is, about
1/80,000 of the diameter of a human hair, or 10 times the diameter of
a hydrogen atom.
2. Applications of Nanotechnology (1)
Applications of nanotechnology in the different field can be
summarized as follows:
Nanomedicnes: nanodrugs, medical devices, tissue engineering, etc.
Chemicals and cosmetics: nanoscale chemicals and compounds, paints,
coating, etc.
Materials: nanoparticles, carbon nanotubes, biopolymers, paints, coating
Food science: processing, nutracetical food, nanocapsules
Envirnoment and energy: water and air purification filters, fuel
cells, photovoltics
Military and security: bio-sensers, wepons, sensory enhancement
Electronics: semiconductor chips, memory storage, photonics, optoelectronics
Scientific tools: atomic force, microscopes and scanning tunneling microscope
Agriculture: pesticides, food production
Nanoparticles are often defined as particles of less than 100nm in
diameter. Nanoparticles can be also defined as particles less than
100nm in diameter that exhibit new or enhanced size-dependent
properties compared with larger particles of the same material.
Nanoparticles exist widely in the natural world: for example as the
products of photochemical and volcanic activity, and created by plants
and algae. They have also been created for thousands of years as
products of combustion and food cooking, and more recently from
vehicle exhausts.
3.1Classification of Nanoparticles (2)
3.1.1. In one dimensions (Thin surface coatings)
One-dimensional systems, such as thin films or manufactured surfaces.
3.1.2. In Two Dimensions
a) Carbon Nanotubes
Carbon nanotubes are a new form of carbon molecule. Wound in a
hexagonal network of carbon atoms, these hollow cylinders can have
diameters as small as 0.7 nm and reach several millimeters in length
(3). Each end can be opened or closed by a fullerene half-molecule.
These nanotubes can have a single layer (like a straw) or several
layers (like a poster rolled in a tube) of coaxial cylinders of
increasing diameters in a common axis (4).
Figure no. 1: Schematic representation of monolayer or multiplayer
carbon nanotube
3.1.3. In Three Dimensions
a) Fullerenes (Carbon 60)
Fullerenes are spherical cages containing from 28 to more than 100
carbon atoms (see schematic representation opposite Fullerenes are a
class of materials displaying unique physical properties. They can be
subjected to extreme pressures and regain their original shape when
the pressure is released. These molecules do not combine with each
other, thus giving them major potential for application as lubricants.
b) Dendrimers
Dendrimers represent a new class of controlled-structure polymers with
nanometric dimensions. They are considered to be basic elements for
large-scale synthesis of organic and inorganic nanostructures with
dimensions of 1 to 100 nm, displaying unique properties. Compatible
with organic structures such as DNA, they can also be fabricated to
interact with metallic nanocrystals and nanotubes or to possess an
encapsulation capacity (5).
c) Quantum Dots
It represents a special form of spherical nanocrystals from 1 to 10 nm
in diameter. They have been developed in the form of semiconductors,
insulators, metals, magnetic materials or metallic oxides.
4. Advantages of Nanoparticles
•Increased bioavailability
•Dose proportionality
•Decreased toxicity
•Smaller dosage form (i.e., smaller tablet)
•Stable dosage forms of drugs which are either unstable or have
unacceptably low bioavailability in non-nanoparticulate dosage forms.
•Increased active agent surface area results in a faster dissolution
of the active agent in an aqueous environment, such as the human body.
Faster dissolution generally equates with greater bioavailability,
smaller drug doses, less toxicity.
•Reduction in fed/fasted variability (6).
5. Nanoparticle production processes
Nanoparticles can be produced by either Dispersion-based processes
(which involves breaking larger micrometer-sized particles into
nanoparticles) or precipitation-based processes.
5.1 Dispersion-based processes
a) 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 (7,8).
b) 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.
The main advantage of high-pressure homogenization is that it is
suitable for both large- and laboratory-scale production because
high-pressure homogenizers are available in various sizes. In
addition, homogenization creates negligible nanoparticle
contamination, which is one of the most important objectives of a
nanoparticle production process.
A limitation of this process is that the pressure used is so high that
in some cases, the crystal structure changed.
c) Emulsification Technology
Emulsification also can be used to prepare nanoparticle suspensions.
In this method, the drug solution in an organic solvent is dispersed
in the aqueous phase containing surfactant. This step is followed by
the evaporation of organic solvent under reduced pressure, which
results in the precipitation of drug particles to form a nanoparticle
suspension which is stabilized by the added surfactant. The use of
microemulsion as templates for producing drug nanosuspensions (12).
5.2 Precipitation-based processes
a) Spray freezing into liquid (SFL)
In this process, developed at the University of Texas at Austin
(Austin, TX) and commercialized by Dow Chemical Company (Midland, MI),
an aqueous, organic, or aqueous–organic cosolvent solution;
aqueous–organic emulsion; or drug suspension is atomized into a
cryogenic liquid such as liquid nitrogen to produce frozen
nanoparticles which are subsequently lyophilized to obtain free
flowing powder (13-15).
b) Evaporative precipitation into aqueous solution (EPAS).
The EPAS process also was developed by the University of Texas at
Austin and commercialized by Dow Chemical Company. In this process,
the drug solution in a low boiling liquid organic solvent is heated
under pressure to a temperature above the solvent's normal boiling
point and then atomized into a heated aqueous solution containing
stabilizing surfactant (16).
c) Rapid expansion from a liquefied-gas solution (RESS)
In an RESS process, a solution or dispersion of phospholipids or other
suitable surfactant in the supercritical fluid is formed. Then, rapid
nucleation of drug is induced in the supercritical fluid containing
surfactant. This process allows rapid, intimate contact of the drug
dissolved in supercritical fluid and the surfactant which inhibits the
growth of the newly formed particles (17,18).
d) Precipitation with a Compressed Fluid Antisolvent (PCA)
In the PCA process (patented by RTP Pharmaceuticals and licensed to
SkyePharma Plc [London, UK]), supercritical carbon dioxide is mixed
with organic solvents containing drug compounds. The solvent expands
into supercritical carbon dioxide, thus increasing the concentration
of the solute in the solution, making it supersaturated, and causing
the solute to precipitate or crystallize out of solution (19,20).
6. Characterization of Nanoparticles
Table no. 1: Different parameters & characterization methods for nanoparticles
Characterization methods
Particle size & size distribution
photon correlation spectroscopy, Scanning electron microscopy (SEM),
Transmission electron microscopy (TEM), Atomic force microscopy (AFM),
Mercury porositometry, Laser defractrometry
Charge determination
Laser droplet anemometry, Zeta potentiometer
Surface hydrophobicity
Water contact angle measurements, rose bangle (dye) binding,
hydrophobic interaction chromatography, X-ray photoelectron
Chemical analysis of surface
Static secondary ion mass spectrometry, sorptometer
Carrier drug interaction
Differential scanning calorimetry
Nanoparticle dispersion stability
Critical flocculation temperature(CFT)
Release profile
In-vitro release characteristic under physiologic & sink condition
Drug stability
Bioassay of drug extracted from nanoparticle, chemical analysis of drug

7. Health implications of Nanoparticles
It is important to differentiate between 'free' and 'fixed'
nanoparticles. The former pose a more direct health threat because
they are more difficult to contain, easily become airborne and can be
inhaled (33).
Nanoparticles can enter the human body in several ways; (i) via the
lungs where a rapid translocation through the blood stream to vital
organs is possible, including crossing the BBB, and absorption by (ii)
the intestinal tract, or (iii) the skin (34).
a) Skin
Particles 500–1000 nm in size, theoretically beyond the realms of
nanotechnology, can penetrate and reach the lower levels of human
skin, 128 and smaller particles are likely to move deeper into the
TiO2 particles are often used in sunscreens to absorb UV light and
therefore to protect skin against sunburn or genetic damage. It has
been reported by Lademann et al in that micrometer-sized particles of
TiO2 get through the human stratum corneum and even into some hair
follicles – including their deeper parts (35).
b) Intestinal tract
The epithelium of the small and large intestines is in close contact
with ingested material so that nutrients can be utilized. A mixture of
disaccharides, peptides, fatty acids, and monoglycerides generated by
digestion in small intestine are further transformed and taken in the
The kinetics of particle translocation in the intestine depends on
diffusion and accessibility through mucus, initial contact with
enterocyte or M-cell, cellular trafficking, and post-translocation
Charged particles, such as carboxylated polystyrene nanoparticles or
those composed of positively charged polymers exhibit poor oral
bioavailability through electrostatic repulsion and mucus entrapment.
The smaller the particle diameter the faster they could permutate the
mucus to reach the colonic enterocytes; 14 nm diameter permeated
within 2 min, 415 nm particles took 30 min, while 1000-nm particles
were unable to translocate this barrier (36,37).
c) Lung
Based on three particle-types titanium dioxide (TiO2), carbon black,
and diesel particles, hazard studies in rats demonstrate that
ultrafine or nanoparticles administered to the lung produce more
potent adverse effects in the form of inflammation and subsequent
tumors compared with larger sized particles of identical chemical
composition at equivalent mass concentrations or
intratracheally-instilled doses. Surface properties, such as surface
chemistry and area, may play a significant role in nanoparticle
particle toxicity (38).
8. Clinical aspects
Several nanoparticle technologies are currently in clinical trials and
a few have progressed to clinical use. NanoCrystal™ technology from
Elan Pharmaceuticals International, Ltd. is one breakthrough
technology that is being licensed to pharma­ceutical companies for
specialized drug delivery systems. Cur­rently, there are some FDA
approved drug products employing this technology. Rapamune
(Wyeth-Ayerst Laboratories), an oral tablet dosage form containing
nanoparticles of the immu-nosuppressant drug Rapamycin, was approved
by the U.S. FDA during the year 2000. Some of the pharmaceutical
products based on nanotechnologies are summarized in Table 2.
Table no. 2: Examples of pharmaceuticals products based on
Brand name
(Merck & Co. Inc.)
Nanocrystal aprepiant (antiemetic) in a capsule
Enhanced dissolution rate & bioavailability
(Wyeth-Ayerst Laboratories)
Nanocrystallied Rapamycin (immunosuppressant) in a tablet
Enhanced dissolution rate& bioavailability
(American Biosciences, Inc.)
Paclitaxel (anticancer drug) bound albumin particles
Enhance dose tolerance and hence effect elimination of solvent
associated toxicity
(Epeius Biotechnology corporation)
A retroviral vector carrying cytotoxic gene
Effective in pancreatic cancer treatment
Olay Moisturizers
(Proctor and Gamble)
Contains added transparent, better protecting nano zinc oxide particles
Offer better UV protection
Trimetaspheres (Luna Nanoworks)
MRI images
enhanced MRI images at least 25 times better than current contrast agents
(Nucryst Pharmaceuticals)
Enhance the solubility and sustained release of silver nanocrystals
Better protection from infection

(Univ. of South Florida)
Nano-sized plastic spheres with drugs (active against
methicillin-resistant staph (MRSA) bacteria) chemically bonded to
their surface that allow the drug to be dissolved in water.
More powerful antibiotics


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