IJRPC 2016, 6(3), 491-500 Rashmi et al.

ISSN: 22312781

INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY

Available online at www.ijrpc.com Review Article

NANOPARTICULATE DRUG DELIVERY SYSTEM - REVIEW

Rashmi .C*, J. Adlino Jino Nesalin and T. Tamizh Mani
Department of Pharmaceutics, Bharathi College of Pharmacy, Bharathinagar,
Maddur Taluk, Mandya District, Karnataka, India.

ABSTRACT
Nanotechnology has many implications in our day today life with its core being the synthesizing of
nanoparticles. Nanoparticle can easily enter most cells and circulate through the body, are suitable for
targeted delivery vehicles to carry large doses of chemotherapeutic agents or therapeutic genes into
the target site. Nanoparticles have been improving the therapeutic effect of drugs and minimize the
side effects. It possess numerous properties of a suitable and supreme drug carriers, which comprise
its high stability, feasibility of incorporation, high carrier capacity, reduce toxicity. The present review
focuses on the advantages and disadvantages of nanoparticles, preparation of nanoparticles, carriers
used, characterization and applications of nanoparticulate drug delivery system. In conclusion,
nanoparticles are one of the promising drug delivery systems, which can be of potential use in
controlling and targeting drug delivery.

Keywords: Nanoparticles, Preparation methods, Polymers, Drug release.

INTRODUCTION
An essential requirement of modern drug Nanoparticles are solid colloidal particles
therapy is the controlled delivery of a drug with diameters ranging from 1-1000 nm.
or an active substance to the site of action They consist of macromolecular materials
in the body in an optimal concentration and can be used therapeutically as
versus time profile. One attempt to achieve adjuvant in vaccines or drug carriers in
this goal was the development of colloidal which the active ingredient is dissolved,
drug carriers known as nanoparticles, entrapped, encapsulated, adsorbed or
chiefly because of their small particle size. chemically attached. Polymers used to form
Colloidal drug delivery systems offer a nanoparticles can be both synthetic and
number of advantages over conventional natural polymers. There are two types of
dosage forms. Due to their small particle nanoparticles depending on the preparation
size, colloidal preparations lend themselves process: nanospheres and nanocapsules
to parenteral preparations and may be (Allemann et al., 1993). Nanospheres have
useful as sustained release injections for a monolithic-type structure (matrix) in which
the delivery to a specific organ or target drugs are dispersed or adsorbed onto their
site. Targeting the drug to the desired site surfaces (Figure 1). Nanocapsules exhibit a
of action would not only improve the membrane-wall structure and drugs are
therapeutic efficiency but also enable a entrapped in the core or adsorbed onto
reduction of the amount of drug which must their exterior (Figure 1).The term
be administered to achieve a therapeutic “nanoparticles” is adopted because it is
response, thus minimizing unwanted toxic often very difficult to unambiguously
1
effects . establish whether these particles are of a
2
matrix or a membrane type .

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Nanoparticulate system can be formed by  The matrix must be non-toxic and must
entrapped and encapsulated with matrix. By not exhibit any antigenic behaviour to
these method we can prepared the the body.
nanoparticle, nanosphere or nanocapsules.  Targeted and drug delivery.
Now a day’s biodegradable and inert polymer  Good control over size and size
used as coating agent upon nanoparticle. distribution.
These coating improve the potential of the  Good protection of the encapsulated
drug delivery system. The aim of drug.
nanoparticulate drug delivery system is to  Retention of drug at the active site.
control the release of drug at the specific site  Increased therapeutic efficacy.
for longer action. This is achieving by liposome  Increased bioavailability.
formation which is used as carriers. Carriers
 Dose proportionality.
have many advantages like protect from the
degradation, reduce the toxicity and targeting
DISADVANTAGES OF NANOPARTICLES
site of action. Nanoparticles enhance the
 Extensive use of polyvinyl alcohol as a
stability of drug and have the control release
3. detergent –issues with toxicity.
property The proper selection of the
polymeric matrix is necessary in order to  Limited targeting abilities.
develop a successful nanoparticulate delivery  Discontinuation of therapy is not
system .
4 possible.
Recent developments in nanotechnology have  Cytotoxicity.
shown that nanoparticles (structures smaller  Pulmonary inflammation and
than 100 nm in at least one dimension) have a pulmonary carcinogenicity.
great potential as drug carriers. Due to their  Alveolar inflammation. The
small sizes, the nanostructures exhibit unique disturbance of autonomic imbalance
physicochemical and biological properties by nanoparticles having direct effect
(e.g., an enhanced reactive area as well as an on heart and vascular function.
ability to cross cell and tissue barriers) that 8
make them a favourable material for NEED FOR DEVELOPING NANOPARTICLE
5 The major goals in designing nanoparticles as
biomedical applications .
Modification and fabrication of polymers is very a delivery system are to control particle size,
effective technology which provides the better surface properties and release of
drug delivery to the system for the treatment of pharmacologically active agents so as to
disease. The materials which are used in achieve the site of action of the drug at the
fabrication are polymers nanostructures. rationate rate and dose. Polymeric
These polymers used with the combination of nanoparticles offer some specific advantage
drug particle and targeted to the site of action. over liposomes. For instance, they help to
Targeted drug can be conjugated to tissue, increase the stability of drugs/proteins and
ligands or macromolecules to the site of possess useful controlled release properties.
action. Targeted nanoparticulate drug delivery
systems are to delivery of anti-cancer, anti- MECHANISM OF DRUG DELIVERY VIA
9
microbial agent, vascular endothelial, brain NANOPARTICLE
drug targeting, insulin delivery and neuro Nanoparticles exerts its site-specific drug
3 delivery by avoiding the reticuloendothelial
disorders .
system, utilizing enhanced permeability and
6,7 retention effect and target-specific targeting.
ADVANTAGES OF NANOPARTICLES
 NPs is a better carrier than the Two types of approaches are applied with drug
emulsion if a prolonged and a sustained using nanoparticle as carrier:
delivery of the drug is desired.
 Longer clearance time.

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a. Surface bound: The drug molecules The polymers used for the preparation of
are adhered to the surface of nanoparticles are either amphiphilic
nanoparticles macromolecules, obtained from natural
b. Core bound: In such methodology the sources, hydrophobic polymers or synthesized
drug particles are concentrated to the chemically. Some of the polymers were
matrix of the nanoparticle and carried originally investigated for biomedical
to the target in the body. applications, consequently fortheir safety and
Drugs can be loaded onto Nanoparticles by biodegradation. Various natural hydrophilic
adding them to a solution that contains and synthetic hydrophobic polymers are used
previously prepared Nanoparticles or by for the preparation of nanoparticles.
adding them to the reaction mixture during the The use of natural biopolymers specifically
polymerization process. Nature of interaction polysaccharides in drug delivery has attracted
of nanoparticle to the drug may be chemical, particular interest due to their desirable
surface adsorption, and no binding or biocompatible, biodegradable, hydrophilic and
interaction at all. The amount of bound drug protective properties (Barichello JM, 1999).
and the type of interaction of drug and The interaction between biodegradable
Nanoparticles depend on the chemical cationic and anionic biopolymers leads to the
structure of the drug and the polymer and the formation of polyionic hydrogels, which have
conditions of drug loading. demonstrated favourable characteristics for
drug entrapment and delivery (Chella F, 2000).
CARRIERS USED IN PREPARATION OF Chitosan and Alginate are two biopolymers
NANOPARTICLES that have received much attention and have
The polymers should be compatible with the been shown to maintain their structure and
body in the terms of adaptability (non-toxicity) activity and protect them from enzymatic
12
and (non-antigenicity) and should be degradation (Madan T, 1997) .
biodegradable and biocompatible.
The polymeric drug carriers deliver the drug at ADJUVANT USED IN THE PREPARATION
11
the tissue site by any one of the three general OF NANOPARTICLES
physico-chemical mechanisms.  Cross linking agent – gluteraldehyde
1. By the swelling of the polymer  Desolvating agents – sodium
nanoparticles by hydration followed by sulphate,ethanol, isopropyl alcohol
release through diffusion.  Counter ions – tripolyphosphate
2. By an enzymatic reaction resulting in  Surfactants – tween-80, span-80
rupture or cleavage or degradation of  Stabilizer – poly vinyl alcohol
the polymer at site of delivery, there by  Solvents – methanol, isopropyl
releasing the drug from the entrapped alcohol, chloroform, dichloromethane,
inner core. water etc.
3. Dissociation of the drug from the
polymer and its de-adsorption/release
10
from the swelled nanoparticles .

11
Table 1: Polymers used for the preparation of nanoparticles

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PREPARATION OF NANOPARTICLES particle replication in non-wetting

Nanoparticles can be prepared from a templates (PRINT) have also been
variety of materials such as proteins, described in the literature for production
polysaccharides and synthetic polymers. of nanoparticles.
The selection of matrix materials is
dependent on various factors which A) DISPERSION OF PREFORMED
include: POLYMERS:
a. Size of nanoparticle required Is the most common technique used to
b. Inherent properties of the drug, prepare biodegradable nanoparticles from
e.g., aqueous solubility and poly (lactic acid) (PLA); poly (D,L glycolide),
stability PLG; poly (D, L-lactide-co-glycolide)
14
c. Surface characteristics such as (PLGA) and poly (cyanoacrylates) (PCA) .
charge and permeability
15
d. Degree of biodegradation, 1. Solvent Evaporation Method:
biocompatibility and toxicity Solvent evaporation method has been widely
e. Drug release profile desired used in the preparation of both micro and
13
f. Antigenicity of the final product . nanosuspension. Briefly, drug and polymer
were dissolved in water non-miscible organic
Nanoparticles have been prepared most solvent, which was then added to the
frequently by three methods: aqueous phase containing
A) Dispersion of preformed polymers copolymer/surfactants (e.g. Poloxamer,
1. Solvent evaporation method Tween 80, and sodium dodecyl sulphate)
2. Spontaneous emulsification or under high energy homogenization to form
solvent diffusion method an emulsion. Subsequently, the polymer in
B) Polymerization of monomers the emulsion undergoes precipitation, which
C) Ionic gelation or coacervation of encapsulates the drug in the polymer matrix
hydrophilic polymers resulting in the formation of nanospheres.
D) Supercritical fluid technology The residual solvent in the formulation was
However, other methods such as then removed by increasing the temperature
supercritical fluid technology39 and under reduced pressure.

16
Fig. 2: Schematic representation of the solvent-evaporation technique

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2. Spontaneous Emulsification Or employed for polymerization by

17
Solvent Diffusion Method: ultracentrifugation and resuspending the
El-Shabouri reported chitosan NP prepared particles in an isotonic surfactant-free
by emulsion solvent diffusion method, medium. This technique has been reported
(which originally developed by Niwa et for making polybutylcyanoacrylate or poly
al.employing PLGA. This method is based (alkylcyanoacrylate) nanoparticles.
on the partial miscibility of an organic
solvent with water. An o/w emulsion is C) IONIC GELATION OR
obtained upon injection an organic phase COACERVATION OF
16
into chitosan solution containing a HYDROPHILLIC POLYMER
stabilizing agent (i.e. poloxamer) under Polymeric nanoparticles are prepared by
mechanical stirring, followed by high using biodegradable hydrophilic polymers
pressure homogenization. The emulsion is such as chitosan, gelatin and sodium
then diluted with a large amount of water to alginate. Calvo and co-workers developed
overcome organic solvent miscibility in a method for preparing hydrophilic chitosan
water. Polymer precipitation occurs as a nanoparticles by ionic gelation. Amir
result of the diffusion of organic solvent into Dustgani et al prepared Dexamethasone
water, leading to the formation of Sodium Phosphate loaded chitosan
nanoparticles. This method is suitable for nanoparticles by ionic gelation method. The
hydrophobic drug and showed high method involves a mixture of two aqueous
percentage of drug entrapment. The major phases, of which one is the polymer
drawbacks of this method include harsh chitosan, a di-block co-polymer ethylene
processing conditions (e.g., the use of oxide or propylene oxide (PEO-PPO) and
organic solvents) and the high shear forces the other is a poly anion sodium
used during nanoparticle preparation. tripolyphosphate. In this method, positively
charged amino group of chitosan interacts
14
B) POLYMERIZATION OF MONOMER with negative charged tripolyphosphate to
In this method, monomers are polymerized form coacervates with a size in the range of
to form nanoparticles in an aqueous nanometer. Coacervates are formed as a
solution in which drug may be dissolved. result of electrostatic interaction between
Drug may also be incorporated by two aqueous phases, whereas, ionic
adsorption onto the nanoparticles after gelation involves the material undergoing
polymerization completed. The nanoparticle transition from liquid to gel due to ionic
suspension is then purified to remove interaction conditions at room temperature.
various stabilizers and surfactants

16
Fig. 3: Schematic representation of the emulsification/solvent diffusion technique

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Fig. 4: Schematic representation of ionic gelation method

D) SUPERCRITICAL FLUID as supercritical fluid which is most widely

TECHNOLOGY used in pharmaceutical industries and have
Nanoparticle can be prepared by the use of advantages of low price, nontoxic in nature,
supercritical fluid. This is the alternative and non-inflammable. For the formation of
option for the biodegradable polymers and supercritical fluids many processes are
safe for the environment. Conventional involved like supercritical anti-solvent and
method like solvent evaporation, solvent rapid expansion of critical solution. The
diffusion and organic phase separation, process of supercritical anti-solvent
these create the hazardous to the methanol is used and it is completely
environment due to the organic solvents. miscible with the supercritical fluid to
Supercritical fluid is defined as a solvent at dissolve the solute at the process condition.
temperature above its critical temperature Solutes are insoluble in supercritical liquid
which is remain in a single phase and extract with supercritical fluid after that
regardless of pressure are called precipitation occurs and nanoparticle are
3
supercritical fluid. CO2 (SC CO2) is used formed .

CHARACTERIZATION OF NANOPARTCLES
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Table 2: Physical characterization of Nanoparticles

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 Particle size analysis:  Determination of drug content and

19
20
The particle size analysis was done for entrapment efficiency:
drug loaded nanoparticles in order to find Freeze-dried nanoparticles were dissolved
the diameter of the particles. The mean in suitable solvent and the amount of drug
particle size of the drug loaded was measured by UV spectroscopy at
nanoparticles was found to be 267 nm. 245nm (Shimadzu UV 1800).

 Determination of zeta potential

21
interaction chromatography, two-phase
The zeta potential is commonly used to partition, adsorption of hydrophobic
characterize the surface charge property of fluorescent or radiolabeled probes and
nanoparticles. It reflects the electrical contact angle measurements have been
potential of the particles and is influenced adopted to evaluate surface hydrophobicity.
by the composition of the particle and the Recently several sophisticated methods of
medium in which it is dispersed. surface chemistry analysis have been
Nanoparticles with a zeta potential above used. For example X-ray photoelectron
(+/-) 30 mV have been shown to be stable spectroscopy permits the identification of
in suspension, as the surface charge specific groups on the surface of
prevents particle aggregation. nanoparticles.

 Loading efficiency
22
 Density
11

The density of nanoparticles is determined The Nanosuspension with known amount

with helium or air using a gas pycometer. of drug (10mg/20ml) incorporated was
The value obtained with air and with helium centrifuged at 5000 rpm for 15 minutes.
may differ noticeably from each other. The The supernatant solution was separated.
difference is much more pronounced due to 5ml of supernatant was distributed with 100
specific surface area and porosity of the ml of 2% w/v tween 80 solutions and the
structure. absorbance was measured using UV
spectrophotometer at 306 nm using 2% w/v
 Surface hydrophobisity tween 80 as blank. The amount of drug
The hydrophobicity of nanoparticles has an unentrapped in the supernatant was
important influence on the interaction of calculated. The amount of drug entrapped
colloidal particles with the biological and percentage entrapment was
environment. The hydrophobicity and determined from drug unentrapped.
hydrophilicity collectively determines the Standard deviation was determined for 3
bio-fate of nanoparticles and their contents. trials.
Several methods including hydrophobic

Loading efficiency =Total amount of drug - Amount of unbound drug ×100

Nanoparticles weight

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 Fourier transform infrared (ftir) Polynucleotide vaccines work by delivering

23
spectroscopy genes encoding relevant antigens to host
The chemical structure of nanoparticles, cells where they are expressed, producing
pure Diclofenac sodium, and polymer was the antigenic protein within the vicinity of
analyzed by FTIR (Schimadzu FTIR-8400) professional antigen presenting cells to
in transmission mode. The sample was initiate immune response. Such vaccines
prepared in KBr disks (2 mg sample in 200 produce both humoral and cell mediated
mg KBr). The scanning range was used immunity because intracellular production
-1
from 4000 to 400 cm . of protein, as opposed to extracellular
deposition, stimulates both arms of the
 x-ray diffraction immune system.
In order to confirm the crystalline or
amorphous nature of pure drug, polymer  Ultrasonic drug and gene delivery25
and nanoparticles were subjected to X-ray Ultrasonic drug and gene delivery by
diffractometer (Bruker, D-8 advance). The nanocarriers has tremendous potential
data collection was performed using Cu because of the wide variety of drugs and
anode and a voltage of the monochromator genes could be delivered to targeted
at 40 kV. The diffraction pattern was tissues by fairly non-invasive means. Liquid
determined in the area 30< 2Ө <800 using emulsions and solid nanoparticles are used
continuous scan. with ultrasound to deliver genes in vitro and
in vivo.
 in-vitro release studies
12

In-vitro release of drug from MTX  Parasitic diseases

nanoparticle formulation is determined by Solid liquid nanoparticle and nanostuctured
dialysis bag method in phosphate buffer lipid carriers (NLC) are particulate in nature
saline pH 7.4. The freeze dried MTX and inherent structure exhibit good
nanoparticles (equivalent to 5.0 mg of drug) potential in the treatment of parasitic
was taken in a dialysis bag (molecular cut infections. With respect to encapsulation
off 12,000, pore size 0.2 μm) and placed in ability and target ability, it requires
100 ml of dissolution medium which was extensive investigations on these systems
continuously stirred at 100 rpm at 37°C to arrive at a versatile, effective and
using shaker incubator. Definite aliquots of economical approach for the delivery of
the dissolution medium were withdrawn at anti-parasitic drugs.
specific time intervals and the same volume
of fresh dissolution medium was added to  Nanoparticles for drug delivery into
the flask to maintain a sink condition. The 26
the brain
samples withdrawn were analyzed for drug The blood-brain barrier (BBB) is the most
content spectrophotometrically at 303 nm. important factor limiting the development of
new drugs for the central nervous system.
APPLICATION OF NANOPARTICULATE The BBB is characterized by relatively
DELIVERY SYSTEM impermeable endothelial cells with tight
 Tumor targeting using junctions, enzymatic activity and active
24
nanoparticulate delivery system efflux transport systems. It effectively
The rationale of using prevents the passage of water-soluble
nanoparticles for tumor targeting is molecules from the blood circulation into
based on: the CNS, and can also reduce the brain
1. Nanoparticles will be able to concentration of lipid-soluble molecules by
deliver a concentrate dose of the function of enzymes or efflux pumps.
drug in the vicinity of the tumor Consequently, the BBB only permits
targets via the enhanced selective transport of molecules that are
permeability and retention effect essential for brain function.
or active targeting by ligands on
the surface of nanoparticles.  Nanoparticles for oral delivery of
2. Nanoparticles will reduce the drug peptides and proteins
exposure of health tissues by The surface area of human mucosa
limiting drug distribution to target extends to 200 times that of skin. The
organ. gastrointestinal tract provides a variety of
 Nanoparticles for gene delivery5 physiological and morphological barriers
against protein or peptide delivery, e.g., (a)

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proteolytic enzymes in the gut lumen like an overview. International Journal of

pepsin, trypsin and chymotrypsin; (b) Research and Development in
proteolytic enzymes at the brush border Pharmacy and Life Science.
membrane (endopeptidases); (c) bacterial 2014;3(5):1121-1127.
gut flora; and (d) mucus layer and epithelial 6. Jaimin D Patel, Sachin P Chauhan and
cell lining itself. The histological Seth AK. Formulation and evaluation of
architecture of the mucosa is designed to methotrexate loaded nanoparticle.
efficiently prevent uptake of particulate International Journal of Drug Discovery
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In conclusion nanoparticles are one of the application. Internation Research
promising drug delivery systems, which can Journal of Pharmacy. 2013;4(4):47-57.
control the delivery and target the drug to 9. Mohd Athar and Amar Jyoti Das.
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