It is isotropic mixture of oil, surfactant and co-surfactant

1. Indian Journal of Novel Drug delivery 8(3), Jul-Sep, 2016, 123-132
123
Indian Journal of Novel Drug Delivery
IJNDD
An Official Publication of
Karnataka Education and
Scientific Society
Review Article
Nanoemulsions: A Versatile Mode of Drug Delivery System
HITENDRA S MAHAJAN*, SAGAR K SAVALE
Department of Pharmaceutics and Quality Assurance, R. C .Patel Institute of Pharmaceutical Education and Research,
Shirpur 425405, MS, India
A R T I C L E D E T A I L S A B S T R A C T
Article history:
Received on 23 August 2016
Modified on 20 September 2016
Accepted on 23 September 2016
A versatile mode of drug delivery system has been developed to overcome the
drawbacks associated in conventional drug delivery system. This review was give
detailed idea about Nanoemulsion system. Nanoemulsion is promising delivery of
various drugs. It is nanosized submicron sized emulsions, which are manufactured
for improving the delivery of active pharmaceutical ingredients. Nanoemulsion was
thermodynamically as well as kinetically stable isotropic system in which two
immiscible liquids are mixed to form a single phase by means of an emulsifying
agent (Smix). The droplet size was falls typically in the range of 50-200 nm. The
main difference between emulsion, microemulsion and nanoemulsion lies in the
size and shape of particles dispersed in the continuous Phase. Nanoemulsion offers
a promising vehicle for increasing the aqueous solubility of poorly water soluble
drugs and enhances the Pharmacological as well as Therapeutic action of drugs.
The design and development of nanoemulsions aimed at controlling or improving
required bioavailability levels of Pharmaceutical agents. In this review, the
attention is focused to give a basic idea about its Introduction, advantages,
disadvantages, components, factors, mechanism, formulation method, evaluation
and applications of Nanoemulsion system. It also focused in Nanoemulsion system
Comparision between emulsion and microemulsion system.
© KESS All rights reserved
Keywords:
Nanoemulsion,
Microemulsion,
Submicron Sized
Emulsions,
Drug delivery,
Emulgents,
Novel drug delivery,
Versatile drug delivery.
INTRODUCTION
Nanoemulsion is a Novel drug delivery system. It
is one of the novel approaches of drug delivery
system to enhance the Bioavailability of poorly
water soluble drugs [1]. It is an Isotropic mixture
of Oil, Surfactant: Cosurfactant (Smix), water and
drug. It is a one of the Colloidal Particulate
nanosystem having a droplet size ranging to
submicron size range acting as carriers of drug
molecule. Carriers are the solid spheres and
there surface is amorphous as well as lipophilic
with negative charge [2]. Nanoemulsion (NE) as a
novel drug delivery system they enhance the
Pharmacological as well as Therapeutic action of
drug and minimize the adverse effect or toxic
reactions of drugs [3]. Nanoemulsion is a
dispersed modern colloidal system having
isotropically clear or transparent dispersion of
two immiscible liquid phases such as oil and
water, stabilized by the interfacial film of
surfactant molecules.
The dispersed phase droplet size is about 50-200
nm, having very low oil and water (o/w)
interfacial tension [4]. Nanoemulsion system was
composed by the appropriate concentration of
Oil and surfactant phase having droplet size 50-
200 nm and Structure of NE droplet was shown
in Figure 1. [5]
Figure 1: Structure of Nanoemulsion droplet
On the basis of composition of nanoemulsion
system was divided in to three types such as oil
in water (o/w) in which oil is dispersed in
continuous water aqueous phase, water in oil
(w/o) in which water is dispersed in continuous
*Author for Correspondence:
Email: hsmahajan@rediffmail.com

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oil phase and bicontinuous Nanoemulsions in
which micro domains of oil and water are inter
dispersed within the system [6].The major
application of nanoemulsion is to induces
treatment of the reticuloendothelial system
(RES)[7], enzyme replacement therapy in liver [8],
tyrosine kinase inhibitor (TK) [8], epidermal
growth factor inhibitor in lungs (EGFR) [9],
Treatment of various cancers such has brain
(intranasal nose to brain approach) [10], lungs,
colon, ovarian, breast, blood cancer and
Vaccination [11].
Advantages of Nanoemulsion System
1. Nanoemulsion is the approach to improve
water solubility of poorly water soluble
drugs (it was applicable in BCS class II, IV
drugs) and ultimate bioavailability of
lipophilic drugs [12].
2. The nanosized droplet leading to enormous
interfacial areas associated with NE would
influences the transport properties of drug
molecules as an important factor for
sustained as well as targeted drug delivery
system [13].
3. NE have been reported to make the plasma
concentration of drug profiles and
bioavailability of drugs are more
reproducible [14].
4. NE was Provides protection from hydrolysis
and oxidation as drug in oil phase in O/W
Nanoemulsion is not exposed to attack by
water and air [15].
5. It may be used as substitute for liposomes
and vesicles [16].
6. NE is deliver a various route like Intranasal
(nose to brain), Intravenous, topical and oral
administration having a rapid and efficient
penetration of drug moiety [17].
7. It is having a maximum solubilization
capacity than micellar solution and their
thermodynamic stability offers advantages
over unstable dispersion such as emulsion
and suspension. NE can be manufactured
with little energy input (heat or mixing)
having a long shelf life [18].
8. NE having a smaller nano sized droplet sized
having a higher surface area and higher free
energy than macro emulsion that make them
an effective transport system [19].
9. NE is not damage healthy human and animal
cells, so nanoemulsions are suitable for
human and veterinary therapeutic purposes
[20].
Disadvantages of Nanoemulsion System
1. NE having a Limited solubilizing capacity for
high-melting substances [21].
2. The large concentration of surfactant and co-
surfactant necessary for stabilizing the
Nanodroplets [22].
3. NE stability is influenced by environmental
parameters such as temperature and pH [23].
4. The surfactant should be nontoxic for using
pharmaceutical applications [24].
5. The formulation of nanoemulsions is an
expensive process due to size reduction of
droplets is very difficult as it required a
special kind of instruments and process
methods [25].
Components of Nanoemulsion System
The main components of NE are oil, emulsifying
agent (Smix) and aqueous phase. Oil like oleic acid,
ethyl oleate, castor oil, olive oil, clove oil and
Triglycerides (LCT, MCT, SCT) [26]. Maximum
solubility of drug in oil phase is important for
selection of oil for preparation of nanoemulsion.
The mixture of oil and water may yield a crude
temporary emulsion which upon standing, will
separate two distinct phases due to coalescence
of the dispersed globules [27]. Emulsifying agent
was added to maintain the stability of such
system. Emulgents are mainly classified as
surfactants like Tweens (20, 80), Spans (60, 80).
Another emulsifying agent such has Cosurfactant
are like polyethylene glycol 400, polyethylene
glycol 200, Polypropylene glycol 400, Ethanol,
Propanol and ethylene glycol is impart the
stability of NE and reduced interfacial tension or
interfacial fluidity of formulation [28, 29]. Maximum
solubility of drug and oil in Emulgents
(surfactant and Cosurfactant system) phase is
important for selection of emulsifying agent [30].
The HLB is low (3-6) emulsifying system is
formed w/o NE and HLB is high emulsifying
system is formed w/o NE and HLB is high
emulsifying system (8-18) to formed o/w NE [31].
Emulsifying agent was adsorbed rapidly around
dispersed phase of globules to from a coherent
film to prevent coalescence, Emulgents form
monomolecular, multimolecular or particulate
films around the dispersed globule [32, 33].
Factors to be Consider for Preparation of
Nanoemulsion System
1. Selection of appropriate emulsifying system
(surfactant) such that an ultra-low interfacial
tension may achieved which is primary need
to produced stable Nanoemulsion System [34].

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2. Specific composition is required to avoid
Oswald ripening the dispersed phase should
be highly insoluble in the dispersed medium
[35].
3. Optimum concentration of surfactant is
required to stabilize the Nanoemulsion [36].
Mechanism of Nanoemulsion System
The Entropy was changes that favours the
dispersion is greater than the energy is required
to increases the surface of dispersion hence the
free energy of conventional emulsion is direct
function of energy is required to create new
surface between oil and water phase and
addition of emulsifying agent to reduce the
interfacial tension subsequently emulsion was
stabilized [37-39].
Formulation Aspects and Method of
Preparation for Nanoemulsion System
Formulation of Nanoemulsion system includes
active drug molecule, additives, polymers and
emulsifier. Various methods for the preparation
of nanoemulsion system but, mainly divided by
two methods: High Energy Emulsification and
Low Energy Emulsification. The high energy
emulsification method includes high pressure
homogenization (HPH), Ultrasonication and
Microfluidization. The low energy method
includes Phase inversion, Spontaneous
emulsification. Using combination of both
methods, which includes high energy
emulsification and low energy emulsification, for
prepared reverse Naemulsion system are highly
viscous system [40-42].
High Energy Emulsification Method
1. High pressure homogenization (HPH)
The preparation of nanoemulsion system is
required high pressure homogenization. This
method mainly used high-pressure
homogenizer/ piston homogenizer to produce
nanoemulsions of extremely low particle size (up
to 1 nm). The dispersion of two phases (oil and
aqueous phase) is achieved forcing there mixture
through a small inlet orifice at very high pressure
(500 to 5000 psi), which subjects the product to
intense turbulence and hydraulic shear resulting
in extremely fine particles of emulsion [43].
2. Ultrasonication
Ultrasonic emulsification is very efficient method
for reducing a droplet size. In this method, the
energy is provided through sonotrodes called as
Sonicator probe. It can contain piezoelectric
quartz crystal which can expand and contract in
response to alternating electric voltage. The tip
of Sonicator contacts the liquid medium, it can
produces mechanical vibration and cavitation
occurs. Formation of cavitation and collapse
vapour cavities in liquid. Thus, ultrasound can
directly produces emulsion. In this method is
mainly used for laboratories purpose, where
emulsion droplet size is low as 0.2 mm can be
obtained [44, 45].
3. Microfluidization
Microfluidization is a one of the patented mixing
technology, which makes use of a device called as
microfluidizer. This device was used in high
pressure positive displacement pump (500-
20000psi), which forces the product through the
interaction chamber, resulting very fine particles
in submicron range. This process is repeated
several times to obtain a desired size to
produced uniform or homogeneous
nanoemulsion system [46, 47].
Low Energy Emulsification
1. Phase inversion emulsification method
This method involves phase transitions by
applying higher temperature to emulsification
pathway [48-50].
2. Spontaneous emulsification
In this method nanoemulsion is spontaneously
formed. In which, preparation of homogeneous
and uniform organic solution consisting oil and
lipophilic surfactant in water miscible surfactant
and hydrophilic surfactant phase. The organic
phase was injected in aqueous phase under
continuous magnetic stirring, stable o/w is
formed. The aqueous phase was removed by
evaporation under reduced pressure [51-53].
Evaluation Parameters of Nanoemulsion
System
1. Droplet size analysis
Droplet size analysis of nanoemulsion was
measured by a diffusion method utilizing the
light-scattering particle size analyser (Nano
ZS90, Malvern Pvt. Ltd. USA). It is also measured
by correlation spectroscopy that analyses the
fluctuation in scattering of light due to Brownian
motion. Droplet size analysis of NE was also
performed by Transmission electron microscopy
(TEM) and Photon correlation spectroscopy
(PCS) [54, 55].
2. Viscosity determination
Theoptimum viscosity is essential for
nanoemulsion system. The viscosity of

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126
nanoemulsion was measured by using
Brookfield-type rotary viscometer at different
shear rates at different temperature [56, 57].
3. Drug content
Drug content of formulation was determined by
using UV spectrophotometric and HPLC method.
In case UV, the 10 mg equivalent of drug loaded
nanoemulsion was dissolved in 100 ml of Solvent
(Drug having optimum solubility of that solvent).
From this stock solution, take 1 ml and dilute it
in 10 ml of solvent (This solvent was not contain
drug loaded nanoemulsion). And Drug content
was estimated at reported Lamda max of that
drug molecule [58, 59].
4. pH
The pH of nanoemulsion System was measured
by using pH meter. (Systronic 362 μ pH system,
India)[60].
5. Refractive index
Refractive index of nanoemulsion was measured
by Abbes Refractometer. (Ningbo Biocotek
Scientific Instrument, Ltd, Tokyo, China) [61].
6. Zeta Potential
Zeta potential was measured the charge on the
surface of droplet of Nanoemulsion. The
formulation (0.1 ml) was diluted 100 times using
double distilled water and analysed using
Zetasizer. (Nano ZS90, Malvern Pvt. Ltd. USA)[62,
63].
7. Percentage transmittance
Percentage transmittance of the optimised
nanoemulsion formulations was determined
spectrophotometrically using UV
spectrophotometer (Shimadzu 1700 and 2450,
Japan) at the particular Lamda max of drug
molecule [64, 65].
8. Conductivity Test
The conductivity of the NE was measured with
conductometer model (Systronics,Pvt. Ltd,
India)[66].
9. Dilution test
Dilution of NE either with oil or water phase. The
test based on fact that dilution of continuous
phase of nanoemulsion without causing the
problem of its stability. Thus, o/w NE is diluted
with water and w/o NE is diluted with oil [67].
10. Dye test
Dye test was measured colour uniformity of NE.
in o/w NE water soluble dye was added taken up
the colour uniformity. If the NE is w/o type the
dye being soluble in water, taken colour only in
the dispersed phase and emulsion was not
uniformly coloured. This can be revealed
immediately by microscopic examination of the
emulsion [67].
11. Polydispersity
It indicates the uniformity of droplet size in
nanoemulsion. The higher the value of
polydispersity, lower will be uniformity of
droplet size of nanoemulsion. It is measured by
the Spectrophotometer [68, 69].
12. Filter paper test
This test is based on the fact that an o/w
nanoemulsion was spread out rapidly when
dropped onto filter paper. In contrast, w/o
nanoemulsion was migrating only slowly. This
method was not be used for highly viscous
creams [70].
13. Thermodynamic Stability Studies
The formulated or Optimized NE was centrifuged
at the 1000 RCF for 30 min. and observed for
phase separation, creaming or cracking. NE was
subjected heating and cooling cycle. Six cycle
between the refrigerator temperatures 4°C and
45°C temperature were performed with storage
at each temperature for not <48 hrs. The
optimized formulation was exposed for three
freeze thaw cycles between -21°C and +25°C
with storage at each temperature for not <48 hrs
to check the thermodynamic stability of
nanoemulsion [71, 72].
14. In Vitro Skin Permeation Studies
In vitro drug release of optimized NE was
determined by dialysis bag method.1.0 ml of NE
was placed in dialysis bag (HIMEDIA dialysis
membrane-150, Delhi, India) was subjected to
release in 900 ml of diffusion media (pH 6.4
phosphate buffer or pH 6.8 phosphate buffer)
stirred at a speed of 100 rpm and temperature
37 ± 0.5°C. Aliquots of 5 mL samples were
withdrawn at regular time intervals from the
dialyzing medium and volume withdrawn was
replaced with the fresh medium each time to
maintain sink condition. The sample were
analysed in particular Lamda max of drug
molecule by using UV analysis and the samples
were percentage Cumulative drug release was
calculated [73-76].

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Table 1: Nanoemulsions comparison between Emulsion and Microemulsion System
Parameter Emulsion Microemulsion Nanoemulsion
Definition It is a Biphasic liquid dosage form
of medicament in which one can
dispersed finite globules in
another liquid phase.
It is an isotropic mixture of
Oil, surfactant and Drug.
It is an isotropic mixture of
Oil, surfactant, Cosurfactant
(Smix) and Drug.
Appearance Cloudy Transparent More Transparent
Droplet Size 0.1-10 µ 200-500 nm 50- 200 nm
Surface area Less More More
Formation Require vigorous shaking Phase titration and Phase
inversion
Spontaneous Formation
Energy High Low Very Low
Type o/w, w/o, w/o/w, o/w/o o/w, w/o, cylinder o/w, w/o, Bicontinuous
Stability Thermo dynamically unstable Thermo dynamically stable Thermodynamically and
kinetically stable
Viscosity More Less Very less
Surfactant
concentration
More Less Very Less
Optimization wet gum and Dry gum method Ternary Phase diagrams Psedoternary Phase
Diagrams
Interfacial tension High Low Ultra-low
Abs. rate Slow Fast Very Fast
Permeation Minimum Intermediate Maximum
Bioavailability Minimum Intermediate Maximum
15. In Vivo Pharmacodynamics Studies
In vivo studies were conducted in four groups
such as control, test, standard and normal group,
each group was containing six male albino rats
having 150-200 gm weight. The rats were fasted
overnight and injection containing optimum dose
of drug molecule. The control group of rats were
given in vehicle and standard groups were given
plain sample or optimized NE formulation and
normal group of rat were given with normal diet.
The oral dosing was performed by intubation
using an 18-gauge feeding needle (the volume to
be fed was 1.0 mL in all cases). Blood samples
were drawn at 0 hrs, 24 hrs and 48 hrs. Serum
was separated by centrifugation at 10000 rpm
and used for biochemical analysis. Serum
cholesterol, triglycerides and high density
lipoprotein cholesterol (HDL-CH) were estimated
in each group. Statistical analysis of the collected
data was performed using one way analysis of
variance [77-79].
16. Transmission Electron Microscopy (TEM)
The morphological and structural examination of
nanoemulsion system was studied by using TEM.
A combination of bright field imaging at
increasing magnification and diffraction modes
was used, to reveal the form and size of the
Nanoemulsions. To perform TEM analysis, NE
was diluted with water (1/100). A drop of the
diluted nanoemulsions was directly deposited on
the holey film grid and observed after drying [80]
[81].
17. Phase Behaviour Study
Nanoemulsion System was determined by using
Pseudo ternary phase diagram. It is also
determine NE existence area. Pseudo-ternary
phase diagrams of oil, water, and surfactant:
Cosurfactant (Smix) mixture was constructed.
Then prepared Smix by mixing a specific ratio of
surfactants: Cosurfactant (1:1, 2:1, 3:1, 4:1, 1:2
and 1:3) after that transparent and homogenous
mixture of oil and Smix was formed by using
vertex. Each mixture was titrated with water and
visually observed for phase clarity and flow
ability. Equal quantity of drug in all formulation
batches and Depending on each phase diagram,
the nanoemulsion region was identified and
different formulations were selected at desired
component ratios, In order to form the stable
Nanoemulsion (NE) [82-84].
Applications of Nanoemulsion System
Nanoemulsion is Target specific or site specific
approach for Intranasal, Parenteral, Ocular,
Intravenous and Transdermal drug delivery
system [85]. It is important approach to improve

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the water solubility of poorly water soluble
drugs [86]. It is novel approach for prevent the
problem of first pass metabolism or Presystemic
metabolism and it can directly absorbed in
systemic circulation for giving a 100 %
bioavailability [87]. Nanoemulsion system is
applicable for treatment of various disorders
such has Cancer (brain, lugs, breast, ovarian and
blood cancer), Asthma, diabetes and Skin
infections (hypersensitivity reactions, skin
irritation) [88, 89]. Another application of NE
system in cosmetics industries, it is act as
antimicrobial NE system [90]. It is important for
prevention of Biodegradations and enzymatic
degradations of drugs [91]. It is also useful in
biotechnological field [92].
Nanoemulsions Comparison, Between
Emulsion and Microemulsion System
Nanoemulsion is a system is more effective,
convenient and stable as compared to emulsion
and microemulsion system.
The Nanoemulsion Comparision between
Emulsion and Microemulsion System was
reported in Table 1. [93-100]
CONCLUSION
Nanoemulsion was widely used in
pharmaceutical system. Nanoemulsion was
offers several advantaged for the delivery of
drugs, biological and diagnostic agents.
Nanoemulsion was applicable in all routes and
therefore hold promise for different fields. This
novel technology was overcome the problem of
less aqueous soluble drug and it is a vehicle for
aqueous insoluble drugs. Now a days,
nanoemulsion was used in targeted drug delivery
of various anticancer drugs, photosensitizers or
therapeutic agents. It provides prolonged action
of the medicaments.
Overall all nanoemulsion formulation considered
as effective, safe and patient compliance
formulation for the delivery of pharmaceuticals.
It is expected that further research and
development was carried out in the future
regarding nanoemulsion.
ACKNOWLEDGEMENTS
The authors are grateful to Hon. Principal, SES’s,
R. C. Patel Institute of Pharmaceutical Education
and Research, Dr. S. J. Surana sir and wish to
acknowledge all those who are involved directly
or indirectly for compilation of this article. It has
been a great honour to work with such a
professional.
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