Advances in

n Environmental Biology, 10(10) October 2016, Pages: 120-130

AENSI Journals

Advances
ces in Environmental Biology
ISSN-1995-0756

EISSN-1998-1066

Journal home page: http://www.aensiweb.com/AEB/

Nanoemulsionas a novel carrier for drug delivery

system: an overview
Sarfaraz Ahmad, Md. Sajid Ali, Md. Sarfaraz Alam,Md. Intakhab Alam, Nawazish Alam
College of Pharmacy, Jazan University,
ersity, Jazan, Saudi Arabia.
Address For Correspondence:
Sarfaraz Ahmad, College of Pharmacy, Jazan University, Jazan, Saudi Arabia. Pin code-45142
code
E-mail: sarfaraz3030@gmail.com, Mobile No: +966-551286443
+966
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/

Received 28 August 2016; Accepted 18 October 2016; Available online 22 October 2016

ABSTRACT
Nanoemulsions (NE) are submicron sized emulsions that are under research as drug carriers to improve the delivery of therapeutic agents.
These arethermodynamically stable transparent or translucent nano-sized
nano
dispersions having the droplet size 10100 nm.These are stabilized
by an interfacial film of surfactant and cosurfactant
urfactant molecule. Several techniques are to be used for preparation of nanoemulsions including
microfluidization, high pressure homogenization, low energy emulsification and solvent evaporation methods and the parameters
paramete that are
to be used for its characterization
haracterization includes droplet size analysis,viscosity determination, drug content, refractive index, pH, zeta potential,
Electron microscopy (TEM & SEM), thermal stability, release and in-vitro
in
& in-vivo
vivo studies. This review focusesin brief on current status
of nanoemulsions in the delivery of drugs and cosmetics, formulation aspects, advantage and disadvantage of nanoemulsion.

KEYWORDS: Nanoemulsion, Physicochemical properties, Drug delivery system, Surfactant, Co-surfactant,

Co surfactant, Applications
INTRODUCTION
Nanoemulsion (NE)is
is one of the most proficient dispersed nanosystems of droplet size ranging to
submicron size[1]. Nanoemulsions are thermodynamically stable transparent or translucent nano-sized
nano
dispersions of oil-in-water
water (o/w) or water-in-oil
oil (w/o) stabilized by an interfacial film of surfactant and
cosurfactant molecule having the droplet size 10100
10
nm [2].. One of the unique characteristics of the NE
technology is the relatively high percentage of total particle
particle volume occupied by the internal
hydrophobic oil core of the droplets. Nanoemulsions are also referred to as mini-emulsions
emulsions and ultrafine
emulsions. Phase behaviour
haviour studies have shown that
th the size of the droplets is governed by the surfactant phase
p
structure (bicontinuousmicroemulsion or lamellar) at the inversion point induced by either temperature or
composition. This provides high solubilization oflipophilic
of
compound as compared toother lipoidal vehicle such
as liposomes[3].The
The capacity of nanoemulsions
nanoemulsions to dissolve large quantities of hydrophobics, along with their
mutual compatibility and ability to protect the drugs from hydrolysis and enzymatic degradation make them
ideal vehicles for the purpose of parenteral transport[4,
transport 5]. Further, the frequency and dosage of injections can
be reduced throughout the drug therapy period as these emulsions guarantee the release of drugs in a sustained
and controlled manner over long periods of time. Additionally, the lack of flocculation, sedimentation and
creaming, combined with a large surface area and free energy, offer certain advantages over emulsions of larger
particle size.Their
Their very large interfacial area positively influences the drug transport and their delivery, along
with targeting them to specific
fic sites [6]. Reducing droplet sizes to the nanoscale leads to some very interesting
physical properties,
perties, such as optical transparency
trans
and unusual elastic behavior[7].. In the world of nanomaterials,
nanoemulsions hold great promise as useful dispersions of deformable nanoscale droplets that can have flow
properties ranging from liquid to highly solid and optical properties ranging from opaque to nearly transparent.

Copyright 2016 by authors and Copyright,

Copyrigh American-Eurasian Network for Scientific Information (AENSI Publication).

121

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

Moreover, it is very likely that nanoemulsions will play an increasingly important role commercially, since they
can typically be formulated by using significantly less surfactant than is required for nanostructured
lyotropicmicroemulsion phases [8, 9]. Nanoemulsions are part of a broad class of multiphase colloidal
dispersions. Although some lyotropic liquid crystalline phases, also known as micellar phases, mesophases,
and microemulsions, may appear to be similar to nanoemulsions in composition and nanoscale structure, such
phases are actually quite different.
Now-a-days nanoemulsions are frequently used for various purpose like delivery of vaccine, DNA encoded
drug,antibiotics, cosmetic and topical preparations and can be administrated via various routes like oral,
pulmonary, ocular and transdermal etc. [10]. Research works proves that nanoemulsion is far more efficient
drug delivery system than other drug delivery system[11,12]. Nanoemulsions are made from surfactants
approved for human consumption and common food substances that are Generally Recognized as Safe
(GRAS) by the FDA. These emulsions are easily produced in large quantities by mixing a water-immiscible oil
phase with an aqueous phase under high shear stress, or mechanical extrusion process that is available
worldwide [8,13].
Classification Of Nanoemulsions [14]:
Table 1: Depending on the composition there are three types of Nano emulsions:
S.No.
Class
Descriptions
Oil in Water Nanoemulsion
1.
Oil droplets are dispersed in the continuous aqueous phase.
(O/W)
Water in oil Nanoemulsion
2.
Water droplets are dispersed in the continuous oil phase.
(W/O)
3.
Bi-Continuous Nanoemulsion
Micro domains of oil and water are inter-dispersed within the system.

In all three types of nanoemulsions, the interface is stabilized by an appropriate combinationof surfactants
and/or co-surfactants.
The major difference between emulsion and nanoemulsion are, Nanoemulsions are thermodynamically and
kinetically stable, while emulsions are unstable. Emulsions are cloudy require the large energy input while
nanoemulsions are formed either with (sometime spontaneously) or without high energy input. Emulsions
have smaller surface area to volume, less free energy than nanoemulsion. Emulsions require high amount
ofsurfactant as compared to nanoemulsion e.g., 20-25% surfactant is added in the preparation of emulsion but 510 % surfactant is suitable for nanoemulsion[15].

Fig. 1: N. Nanoemulsion: Droplet diameter less than 100 nm; M. Microemulsion: Droplet diameter more than
1000 nm
Table 2: Advantages and disadvantages of nanoemulsion[16-19]
Advantages of nanoemulsion over other dosage forms
1.
Increase the rate of absorption.
2.
Eliminates variability in absorption.
3.
Helps in solublizing lipophilic drug.
4.
Provides aqueous dosage form for water insoluble
drugs.
5.
Increases bioavailability.
6.
Various routes like tropical, oral and intravenous can
be used to deliver the product.
7.
Rapid and efficient penetration of the drug moiety.
8.
Helpful in taste masking.
9.
Provides protection from hydrolysis and oxidation
as drug in oil phase in o/wnanoemulsion is not exposed to
attack by water and air.
10.
Liquid dosage form increases patient compliance.
11.
Less amount of energy requirement.
12.
Nanoemulsions are thermodynamically stable system

Disadvantages of nanoemulsion based systems

1.
Use of a large concentration of surfactant and cosurfactant necessary for stabilizing the nanodroplets.
2.
Limited solubilizing capacity for high-melting
substances.
3.
The surfactant must be nontoxic for using
pharmaceutical applications.
4.
Nanoemulsion stability is influenced by environmental
parameters such as temperature and pH. These parameters change
upon nanoemulsion delivery to patients.
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.
6.
Homogenizer
(instrument
required
for
the nanoemulsions formulation) arrangement is an expensive
process.
Moreover
microfluidization and ultrasonication (manufacturing
process)

122

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

and the stability allows self-emulsification of the system whose

properties are not dependent on the process followed.
13.
Same nanoemulsions can carry both lipophilic and
hydrophilic drugs.
14.
The use of nanoemulsion as delivery systems can
improve the efficacy of a drug, allowing the total dose to be
reduced and thus minimizing side effects.

require large amount of financial support.

7.
The stability of nanoemulsions is quite unacceptable
and produces a big problem during the storage of formulation for
the longer time.
8.
Ostwald ripening is the main problem associated with
unacceptability of nanoemulsions formulations. Ostwald ripening
is due to the high rate of curvature of small droplet show greater
solubility as compared to large drop with a low radius of
curvature.
9.
There is a perception in the personal care and
cosmetic industry that nanoemulsions are expensive to produce.
Expensive equipments are required as well as the use of high
concentrations of emulsifiers.
10.
Lack of understanding of the mechanism of
production of submicron droplets and the role ofsurfactants
and cosurfactants.
11.
Lack of understanding of the interfacial chemistry that
is involved in production of nanoemulsions.

Formulationof Nanoemulsion:
Nanoemulsions are multiphase colloidal dispersion which is generally characterized by its stability and
clarity. There is an application of high shear obtained by micro fluid or ultrasonic approach used to reduce the
droplet size to nanoscale. There is a marginal difference between the terms nanoemulsion and microemulsion.
The microemulsion generally forms through thermodynamic self-assembly whereas nanoemulsion requires
external shear for rupturing the droplets. In retrospect, the historical choice of the word microemulsion to
describe the nanoscale is unfortunate since they are structurally between 1 to 100 nm as for nanoemulsion.
Microemulsions are not the emulsions of micro scale droplets. They are formed by self-assembled equation
phase in which the surface tension dose not play a significant role. The nanoemulsions underline the
basic principle in its formulation. They generally comprises of two immiscible phase with an interfacial
tension between them reduced by addition of surfactant[20].
Components of Nanoemulsion[21]:
Following are the three main components of nanoemulsions:
1. Oil
2. Surfactant/Cosurfactant
3. Aqueous phase
Oil:
Solubility of the drug in the oil phase is an important factor for the selection of oils. Specially this
is very important in the case of oral formulation development, since the ability of nanoemulsionto maintain
the drug in solubilized form is greatly influenced by the solubility of the drug in the oil phase. If the surfactant
or cosurfactant is contributing to drug solubilization, there could be a risk of precipitation, as dilution of
nanoemulsion in the gastrointestinal tract will lead to lowering of the solvent capacity of the surfactant or
cosurfactant (Table 3).
Surfactant:
There arethree typesof surfactantsused for stabilizing the systems. These are anionic, cationic, and nonionic.
Nonionic surfactants are relatively less toxic than their ionic counterparts and typically have lower
CMCs. Also, o/w nanoemulsion dosage forms for oral or parenteral use based on nonionic surfactants
are likely to offer in vivo stability. Therefore, proper selection of surfactants becomes a crucial criterion.
Another important criterion is the selection of surfactant with proper HLB value. Hydrophilic surfactant
and cosurfactant are considered to prefer the interface and to lower the necessary energy to form the
nanoemulsions, consequently improving the stability. For example, the required HLB value to form o/w
nanoemulsions should be greater than 10. The right blend of low and high HLB surfactants leads to the
formation of a stable nanoemulsion upon dilution with water[22] (Table 3 & 4).
Cosurfactant:
Cosurfactants are added to obtain nanoemulsion systems at low surfactant concentration. Short- to
medium-chain length alcohols (C3C8) are commonly added ascosurfactants, which further reduce the
interfacial tension and increase the fluidity of the interface. They also increase the mobility of the
hydrocarbon tail and allow greater penetration of the oil into this region. Alcohols may also increase the
miscibility of the aqueous and oily phases due to its partitioning between these phases. Therefore, ethanol,
isopropyl alcohol, 1-butanol, and propylene glycol were selected as cosurfactants. PEG 400 and Carbitol were

123

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

also selected, as they also show increased permeation when incorporated into formulations and are
relatively bearable.
Table 3: Commonly used oils, surfactants and cosurfactants for the preparation of nanoemulsion [23].
S. No.
Oil
Surfactant
1.
Captex 355 (Glyceryl Tricaorylate/Caprate)
Capryol 90
Captex 200 (Propylene
Tween 80
2.
Dicaprylate/Dicaprate Glycol)
3.
Captex 8000 (Glyceryl Tricaprylate) (Tricaprylin)
Lauroglycol 90
Witepsol (90:10 % w/w c12 Glyceride
PEG MW > 4000
4.
tri: diesters)
Myritol 318 (c8/c10 triglycerides)
Labrafil M 1944 CS, M
5.
2125 CS
Isopropyl myristate (Myristic acid isopropyl ester)
Poloxamer 124
6.
and 188

Cosurfactant
Transcutol p
Glycerin, Ethylene glycol
Propylene glycol
Softigen 701, 767
Ethanol
Propanol

Table 4: Types of Surfactant [24-26]

Sr.
Types
of Comments
No:
Surfactant
1
Non-ionic
Non-ionic surfactants includepolyoxyethylene surfactants such as Brij 35 (C12E35) or sugar esters such as
sorbitanmonooleate (Span 80), Tween.
2

Cationic

Anionic

Ampholytic

Cationic surfactants include lecithinpreparations from a variety of sources including soybean and egg are
available commercially and contain diacylphosphatidylcholine as its major constituent. Quaternary
ammonium alkyl salts form one of the best known classes of cationic surfactants.
Anionic surfactant include sodium bis-2-ethylhexylsulphosuccinate (AOT) which is twin-tailed and is a
particularly effective stabiliser of w/o microemulsions. Anionic surfactant is in common use consist of soap
of Alkali, Amines, Metals,Sulphated alcohal and Sulphonates
Alkali Soap:Potassium and sodium stearate
Amines Soap:Ethanolamine,Di ethanolamine, Isopropanolamine, oleic acid
Metals Soap: Calcium and aluminum stearate
Substances whose ionic characteristics depend upon pH of the system.Phospholipidsare a notable example
and exhibit excellent biocompatibility. At intermediate pH behave as Zwitterionic. Eg: Lecithin, Ndodycylalanine

Factors affecting the Formulation of Nanoemulsion[27]:

The formation of stable transparent nanoemulsions poses two challenges: the ability to initially create an
emulsion where the entire droplet size distribution is below 80 nm, and the subsequent stabilization of this
emulsion against Ostwald ripening. Appropriate composition is required to avoid Oswald ripening. The
dispersed phase should be highly insoluble in the dispersed medium.
I.
The surfactant is an essential part of the nanoemulsion. They should not form lyotropic liquid
crystalline microemulsion phases.
II.
The presence of excess surfactants enables new surface area of nanoscale to be rapidly coated
during emulsification there by inhibiting induced coalescence.
III.
Extreme share must be applied to rupture microscale droplets to nanoscale by providing the stress
level to reach above the Laplace pressure of the droplets with a pressure of 10- 100 atm. Out of various
methods ultrasonication is widely used in laboratory.
Preparation Methods Of Nanoemulsions:[28]:
For the preparation of nanoemulsion drug is dissolved in lipophilic part (oil). Aqueous phase (water) can be
mixed with surfactant and cosurfactant is then added at slow rate with gradual stirring until the system is
transparent. The amount of surfactant and cosurfactant to be added and the percent of oil phase that can be
incorporated shall be determined with the help of pseudo-ternary phase diagram. Ultrasonicator can finally be
used so to achieve the desired size range for dispersed globules. It is then being allowed to equilibrate.
Factors required for nanoemulsion preparation[29]:
Three important conditions:
i. Surfactants must be critically evaluated so that an ultra-low interfacial tension (< 10-3 mN/m) can be
attained at the oil / water interface which is a prime requirement to produce nanoemulsions.
ii. Surfactant concentration must be high enough to provide the number of surfactant molecules needed to
stabilize the microdroplets to be produced by an ultra-low interfacial tension.
iii. The interface must be flexible or fluid enough to promote the formation of nanoemulsions.

124

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

Construction of Phase Diagram:

Pseudo-ternary phase diagrams of oil, water, and cosurfactant/surfactants mixtures are constructed at fixed
cosurfactant/surfactant weight ratios. Phase diagrams are obtained by mixing of the ingredients, which shall be
pre-weighed into glass vials and titrated with water and stirred well at room temperature[30]. Formation
of monophasic/biphasic system is confirmed by visual inspection. In case turbidity appears followed by a phase
separation, the samples shall be considered as biphasic. In case monophasic, clear and transparent mixtures are
visualized after stirring; the samples shall be marked as points in the phase diagram. The area covered by these
points is considered as the nanoemulsion region of existence[31]Several methods have been suggested for the
preparation of nanoemulsion. Here some methods are discussed which are freely used for the nanoemulsion
preparation.

Fig. 2: Ternary phase diagram

Phase Inversion Method:
In this method, fine dispersion is obtained by chemical energy resulting of phase transitions occur through
emulsification method. The adequate phase transitions are produced by changing the composition at constant
temperature or by changing the temperature at constant composition. Phase inversion temperature (PIT) method
was introduced by Shinoda et al. based on principle of the changes of solubility of polyoxyethylene-type
surfactant with temperature. This surfactant becomes lipophilic as increase in temperature because of
dehydration of polymer chain. At low temperature, the surfactant monolayer has a great positive spontaneous
curvature forming oil swollen micellar solution phase[32].
Sonication Method:
Sonication method is best way to prepare nanoemulsions. In sonication method the droplet size of
conventional emulsion or microemulsions are reduced with the help of sonication mechanism. This method is not
applicable for large batches, but only small batches of nanoemulsions can be prepared by this method.
Ultrasonic System[33]:
In ultrasonic emulsification, the energy input is provided through so called sonotrodes (sonicator probe)
containing piezoelectric quartz crystals that can be expand and contract in response to alternating electrical
voltage. As the tip of sonicator probe contacts the liquid, it generates mechanical vibration and therefore
cavitations occurs, which is the main phenomenon responsible for ultrasonically induced effects. Cavitation is the
formation and collapse of vapour cavities in a flowing liquid. Such a vapour cavity forms when the local pressure
is reduced to that of at the temperature of the flowing liquid because of local velocity changes. The collapse of
these cavities causes powerful shock waves to radiate throughout the solution in proximity to the radiating face of
the tip, thereby breaking the dispersed droplets. Within the ultrasound range, the power available varies inversely
with the frequency and only powerful ultrasound (0-200kHz) is able to produce physical and chemical changes
such as emulsification.
Ultrasound can be used directly to produce emulsion, but since breaking an interface requires a large amount
of energy, it is better to prepare coarse emulsion before applying acoustic power. Due to small product throughput
the ultrasound emulsification process mainly applied in laboratories where emulsion droplet size as low as 0.2
micrometer can be obtained.
Microfluidizer:
It is possible to produce emulsion at much higher pressures up to approximately 700 Mpa, in the nozzle
of microfludizer that is the heart of this device (the interaction chamber) two jets of crude emulsion from two
opposite channels collide with one another. The process stream is delivered by a pneumatically powered pump
that is capable of pressurizing the in-house compressed air (150-650 Mpa) up to about 150Mpa. Forcing the
flow stream by high pressure through microchannels toward an impingement area creates a tremendous shearing
action, which can provide an exceptionally fine emulsion[34]

125

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

Jet Disperser:
Forcing the flow stream by high pressure through microchannels towards an impregnated area creates a
tremendous shearing action, which can provide an exceptionally fine emulsion. In general, initial forces in
turbulent flow along with cavitations are predominantly responsible for droplet disruption in microfludizer.
Disruption in laminar elongation flow is also possible, especially when emulsion has high viscosity.
In the jet disperser two or more jets of crude emulsion each from opposing bores collide with one another but
at a different design than microfludizer, the diameter of the bores in jet dispersers are typically 0.3-0.5mm.
Finally an orifice plate is the simplest construction form for a homogenizing nozzle. The diameter of orifice
bore is of same order of magnitude as the jet dispersers and inlet head diameter of orifice plate is typically 1060nm, in jet dispersers & orifice plates, droplets are disrupted predominantly due to laminar elongation flow
ahead of the bores. Unlike radial diffusers, the nozzle is microfludizer; jet dispersers and orifice plate contain no
moving parts, so they can be used at high pressures up to 300-400 Mpa [35].
Physicochemical Characterization Of Nanoemulsions[36-42]:
Table 5: Physicochemical Characterization of Nanoemulsions
S. No
Test
Descriptions
1
Dye Solubilization
A water soluble dye is solubilized within the aqueous phase of the w/o globule but is
dispersible in the o/w globule. An oil soluble dye is solubilized within the oil phase of the
o/w globule but is dispersible in the w/o globule.
2
Dilutability
o/w nanoemulsions are dilutable with water whereas w/o are not and undergo phase
inversion into o/w nanoemulsion.
3
Fluorescence
Many oils exhibit fluorescence when exposed to UVlight. When a w/o nanoemulsion is exposed to a
fluorescence light under a microscope, the entire field fluoresces. If the fluorescence is spotty, the
nanoemulsion will be o/w type.
4
Filter paper
This test is based on the fact that an o/w nanoemulsion willspread out rapidly when dropped onto
filter paper. Incontrast, a w/o nanoemulsion will migrate only slowly.This method should not be
used for highly viscous creams
5
Conductance
o/w nanoemulsion where the external phase is water are highly conducting whereas w/o are not,
Measurement
since water is the internal or dispersal phase.
To determine the temperature of the continuous phase and to detect phase inversion phenomena, the
electrical conductivity measurements are highly useful.
A sharp increase in conductivity in certain w/o nanoemulsion systems was observed at low
volume fractions and
such
behaviour
was interpreted
as an indication of a
percolativebehaviour or exchange of ions between droplets before the formation of
bicontinuous structures.
Dielectric measurements are a powerful means of probing both structural and dynamic
features of Nanoemulsion systems.
6
Dynamic
light- The DLS measurements are taken at 90 in a dynamic light scattering spectrophotometer which uses
scattering
a neon laser of wavelength 632 nm. The data processing is done in the built-in computer with the
measurements
instrument.
7
Drug content
Preweighednanoemulsion is extracted by dissolving in asuitable solvent, extract is analyzed by
spectrophotometeror HPLC against standard solution of drug
8
Polydispersity
The average diameters and Polydispersity index of samples were measured by Photon
Correlation Spectroscopy. The measurements were performed at 25C using a He-Ne laser.
9
Phase analysis
It is used to determine the type of nanoemulsion (o/w or w/o) by measuring the electrical
conductivity using aconductometer.
10
Particle size analysis A Photon Correlation Spectrometer is used to monitor the particle size of nanoemulsions. Light
scattering are monitor at 90 angle and 25C of temperature.
11
Rheological
Rheological measurements are performed at 250.1C using a Bohlin rheometer equipped with a
measurements
cone/plate apparatus 40 mm per 4. For each sample, continuous variation of shear rate is applied
and the resulting shear stress is measured. Viscosity of dispersions with Newtonian flow
properties is calculated according to the relation: =/.
12
Refractive Index
Refractive index is determined at 25C using refractometer.
13
Surface Tension
A surface tension measurement is carried out at 20C using a thermostatically controlled
processor tensiometer K100.
14
pH
and
osmotic pH of the formulation ismeasured at 25C using digital pH meter and the osmotic pressure
pressure
is measured using micro osmometer.
15
Transmission
To observe the morphology of the oil droplets in the nanoemulsion, each batch also characterized by
electron
TEM using a negative staining technique.
microscopy
16
Viscosity
The viscosity of the formulations is determined as such without dilution using a Brookfield DV III
determination
ultra V6.0 RV cone and plate rheometer at 250C 0.3.
17

18

Electrical
conductivity
measurement
Percentage
transmittance
studies

Electrical conductivity of the samples ismeasured using a conductivity meter having acell
constant of 0.11 cm-1 at the frequency of 94Hz. The measurements were performed intriplicate at
25 1 C.
Percentage transmittance of the prepared nanoemulsion formulation is determined
spectrophotometrically. The formulation has the highest percentage transmittance or close to
100% indicated that formulation is clear and transparent. One ml of the formulation is diluted
100 times using solvent and analyzed at max against solvent as blank.

126

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

19

Thermodynamic
stability studies

20

In
vitro
drug
release / in vitro
skin
permeation
studies
Pharmacokinetic
studies/In
vivo
studies

21

Heating cooling cycle:Six cycles between refrigerator temperature 4C and 45C with storage
at each temperature of not less than 48 h is studied. Those formulation which are stable at these
temperature, is subjected tocentrifugation test.
Centrifugation:Passed formulation is centrifuged at 3500 rpm for 30 min. Those formulations that
do not show any phase separation are taken for freeze thaw stress test.
Freeze thaw cycle:Three freeze thaw cycle between -21C & 25C with storage at each
temperature for not less than 48 h is done for the formulation. Those formulation which passed
thermodynamic stress test, are further taken for dispersibility test forassessing the efficiency
of emulsification
Dissolution studies or skin permeation studies is performed on the basis of delivery system.

Performed animal studies on basis of delivery system by using specific animal models.

Applications Of Nanoemulsion:
Nanoemulsion show great promise for the future of cosmetics, diagnostics, drug therapies and
biotechnologies. Nanoemulsions containing pharmaceutically active agents can be utilized for the production of
pharmaceutical preparations[43].
Ocular Delivery:
Oil in water emulsions are being explored for improved topical lipophilic drug delivery to the eye.
Lipophilic drug loaded o/w ocular emulsions provide equivocally a better balance between ocular bioavailability
improvement and patient comfort following topical instillation into the eye e.g. Piroxicam, pilocarpine,
indomethacin, cyclosporine A. For the treatment of eye diseases, drugs are essentially delivered topically.
O/Wnanoemulsions have been investigated for ocular administration, to dissolve poorly soluble drugs, to
increase absorption and to attain prolong release profile. The nanoemulsions containing pilocarpine were
formulated using lecithin, propylene glycol and PEG 200 as co- surfactant and IPM as the oil phase.[44].
Percutaneous Route:
Many drugs exhibit low skin penetration, which results in poor efficacy. As opposed to common chemical
skin penetration enhancers, organic solvents are generally associated with some degree of skin irritation, toxicity
and sensitization. A solvent free topical vehicle based on drug entrapment in the o/w emulsion with droplets of
submicron size is more efficacious in terms of percutaneous absorption along with possibly devoid of adverse
effects. In addition, the uniqueness of the large internal hydrophobic core of o/w submicronized emulsion
droplets allows high solubilization capacity for water insoluble topically active medicaments.It also aids in
carrying water, an excellent softener, to the skin e.g. NSAIDs, diazepam, -tocopherol, antifungal drugs
(econazole or miconazole nitrate) [45], EMLA (Eutectic mixtures of local anaesthetic) has proven to be a useful
medication for children. It is an emulsion containing a mixture of lidocaine and prilocaine [46].
Nasal Route:
The nasal route has received great attention due to number of advantages over parenteral and oral
administration especially by-passing the liver. Nanoemulsions increase absorption by solubilizing the drug in
the inner phase of an emulsion and prolonging contact time between emulsion droplets and nasal mucosa e.g. a
lipid soluble rennin-inhibitor was incorporated into an o/w emulsion. Enhanced and prolonged in vivo nasal
absorption was observed in emulsion compared to aqueous suspension. Other drugs which have been formulated
for nasal delivery are insulin and testosterone[47].
Pulmonary Delivery:
A novel pressurized aerosol system has been devised for the pulmonary delivery of salbutamol using
lecithin stabilized microemulsions formulated in trichlorotrifluoroethane[48].
In Biotechnology:
Many enzymes including lipases, esterases, hydrogenases, and oxidases often function in cells in
microenvironments that are hydrophobic in nature. In biological systems many enzymes operate at interface
between hydrophobic and hydrophilic domains and these usually interfaces are stabilize by polar lipids and other
natural ampiphiles. Enzymatic catalysis in nanoemulsions has been used for a variety of reactions, such as
synthesis of esters, peptides and sugar acetals trans-esterification, various hydrolysis reactions and steroid
transformation. The most widely used class of enzymes in microemulsion based reactions is of lipases.

127

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

Prophylactic in Bio-Terrorism Attack:

Nanoemulsions are used as a prophylactic medication and are used against bio-attack pathogens such as
anthrax and ebola.
Nanoemulsion as Mucosal Vaccines:
Nanoemulsionscan be used forneedle free immunization bydelivering recombinant protein and
inactivatedorganism to a mucosal surface as nanoemulsioncause the protein surface to be adjuvanted andthus
facilitates uptake by antigen-presenting cells.
Nanoemulsion formulation of cyclosporine:
A nanoemulsion formulation of cyclosporine has been introduced to replace Sandimmune, a crude oil-inwater emulsion of cyclosporine formulation. Neoral is formulated with a finer dispersion, giving it a more rapid
and predictable absorption and less inter and intra patient variability.
Nanoemulsion in Cell Culture Technology:
Nanoemulsions are used in cell culture technologybecause they increase uptake of oil solublecomponent
in cell culture and improve growth ofculture cell.
Oral Drug Delivery System:
Formulations were developed to enhance oral bioavailability of hydrophobic drugs like paclitaxel, ramipril,
celecoxib and ubiquinone. It can be used to improve oral bioavailability of poorlyto soluble drug because
it has a very small particle size[49].
Transdermal Drug Delivery System (TDDS):
Nanoemulsion canbe used for transdermal drug delivery due to increased permeation through the skin.
Indomethacin a potent NSAID, the anti-inflammatory effects of true optimized nanoemulsion formulation
were compared with marketed gel in carragenan induced paw edema in rats. The % inhibition value was
significant for developed Nanoemulsion,so great potential for transdermal application of indomethacin
[50].Transdermal route by means of nanoemulsion technique has been considered to eliminate oral GI
adverse effects, maintains the plasma drug level for longer period of time, improve patient compliance and
suitable for long treatment of arthritis.
Cosmetics:
Nanoemulsions have been widely increasing as potential vehicles for the controlled delivery of cosmetics
and for the optimized dispersion of active ingredients in particular skin layers. It is increasingly used in the
cosmetic because the active constituents are easily absorbed to give effective action due to small size of droplets
and reduce the water loss from the skin.This may reduce the trans-epidermal water loss (TEWL), indicating that
the barrier function of the skin is enhanced[51].Due to their lipohilic inner property, nanoemulsions are more
suitable for the transport of lipophilic compounds than liposomes. Similar to liposomes, they support the skin
penetration of active ingredients and thus increase their concentration in the skin. Another advantage is the
small-sized droplet with its high surface area allowing effective transport of the active to the skin.
Furthermore, nanoemulsions gain increasing interest due to their own bioactive effects. Nanoemulsions are
suitable in cosmetics because there is no inherent creaming, sedimentation, flocculation or coalescence
observed[52].
Antimicrobial Nanoemulsions:
Antimicrobialnanoemulsions areo/w droplet which has a broad-spectrum activity against bacteria (e.g., E.
coli, Salmonella, S.aureus),
enveloped
viruses
(e.g., HIV, Herpes simplex),
fungi
(e.g., Candida, Dermatophytes), and spores (e.g., Anthrax) [53].Nanoemulsions are droplets attached with lipid
containing organisms and release part of the energy trapped within the emulsion. Pathogenlipid membrane is
destabilized by active ingredient andthe energy released by the emulsion, leading to microbial cell lysis[54].
Nanoemulsions in Cancer Therapy:
Nanoemulsions are used as vehicle in cancer chemotherapy for extendingthe rate of drug release after
intramuscular andintratumoral injection (w/o systems). It also improves the transport of anti-cancer drugs via
lymphatic system [55, 56, 57].
Conclusion:
Overall we can conclude nanoemulsion formulation may be considered as effective, safe and patient
compliance drug delivery of pharmaceutical products. One of the distinctive characteristics of the

128

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

nanoemulsion technology is the relatively high percentage of total particle volume occupied by the internal
hydrophobic oil core of the droplets. In future further research work and development will be carried out for
clinical application of nanoemulsion formulation.
REFERENCES
[1] Mishra, R.K., G.C. Soni, R. Mishra, 2014. Nanoemulsion: A Novel Drug Delivery Tool. International
Journal of Pharma Research & Review, 3(7): 32-43.
[2] Shah, P., and D. Bhalodia, 2011. Nanoemulsion a pharmaceutical review. Systematic Reviews in Pharmacy,
1(1): 24-31.
[3] Mehrnia, M.A., S.M. Jafari, B.S. Makhmal-Zadeh, Y. Maghsoudlou, 2016. Crocin loaded nano-emulsions:
Factors affecting emulsion properties in spontaneous emulsification. International Journal of Biological
Macromolecules, 84: 261-267.
[4] Huang, B., W.J. Dong, G.Y. Yang, W. Wang, Ji CH, F.N. Zhou, 2015. Dendrimer-coupled sonophoresismediated transdermal drug-delivery system for diclofenac. Drug Design Development and Therapies, 9:
3867-3876.
[5] Liu, P., M. Cettina, J.J. Wong, 2009. Effects of isopropanol-isopropyl myristate binary enhancers on in
vitro transport of estradiol in human epidermis: a mechanistic evaluation. Pharmaceutical Sciences, 98(2):
565-572.
[6] Amarji, B., N.K. Garg, B. Singh, O.P. Katare, 2016. Microemulsions mediated effective delivery of
methotrexate hydrogel: more than a tour de force in psoriasis therapeutics, Journal of Drug Targeting,
24(2): 147-160.
[7] Villegas, V., B. Naveros, M.L. Lpez, A.C. Campmany, P. Zagal, M.L. Ramrez, 2014. Development and
characterization of two nano-structured systems for topical application of flavanones isolated from
Eysenhardtia platycarpa. Colloids and Surfaces B: Biointerfaces, 116: 183-192.
[8] Liu, W., X.L. Yang, W.S. Ho, 2011. Preparation of uniform-sized multiple emulsions and micro/nano
particulates for drug delivery by membrane emulsification. Journal of Pharmaceutical Sciences, 100(1): 7593.
[9] Fryd, M.M., T.G. Mason, 2012. Advanced nanoemulsions, Annual Review of Physical Chemistry, 63: 493518.
[10] Anton, N., A. Crevoisier, S.Schmitt, T. Vandamme, 2012. A new application of lipid nanoemulsions as
coating agent, providing zero-order hydrophilic drug release from tablets.Journal of Drug Delivery, 271319.
[11] Prakash, R.T.U. and P. Thiagaraja, 2011. Nanoemulsions for drug delivery through different routes.
Research in Biotechnology, 2(3): 01-13.
[12] Ravi, T.P.U. and T. Padma, 2011. Nanoemulsions for Drug Delivery through Different Routes, Research
in Biotechnology, 2(3): 1-13.
[13] Kotta, S., A.W. Khan, K. Pramod, S.H. Ansari, R.K. Sharma, J. Ali, 2012. Exploring oral nanoemulsions
for bioavailability enhancement of poorly water-soluble drugs. Expert Opinion Drug Delivery, 9(5):
585-598.
[14] Gupta, P.K., J.K. Pandit, A. Kumar, S. Pallavi, S. Gupta, 2010. Pharmaceutical Nanotechnology Novel
Nanoemulsions - high energy emulsification, preparation, evaluation, and application. The Pharma
Research, 3: 117-138.
[15] Anthony, A. Attama and L. Charles, 2011. Current state of nanoemulsion in drug delivery. Scientific
Research, 2: 1-14.
[16] Aboofazeli, R., 2010. Nanometric scaled emulsions (Nanoemulsions). Iranian Journal of Pharmaceutical
Research, 9(4): 325-326.
[17] Kotta, S., A.W. Khan, S.H. Ansari, R.K. Sharma, J. Ali, 2015. Formulation of nanoemulsion: a comparison
between phase inversion composition method and high-pressure homogenization method.Drug Delivery,
22(4): 455-466.
[18] Bansal, T., G. Mustafa, Z.I. Khan, F.J. Ahmad, R.K. Khar, S. Talegaonkar, 2008. Solid selfnanoemulsifying delivery systems as a platform technology for formulation of poorly soluble drugs,
Crit Rev Ther Drug Carrier Syst, 25: 63-116.
[19] Goindi, S., P. Arora, N. Kumar, A. Puri, 2014. Development of novel ionic liquid-based microemulsion
formulation for dermal delivery of 5-Fluorouracil.AAPS PharmSciTech, 15(4): 810-21.
[20] Ahuja, A., J. Ali, S. Baboota, M.S. Faisal, F. Shakeell, S. Shafiq, 2008. Stability evaluation of Celecoxib
nanoemulsion containing Tween 80. Thai Journal of Pharmaceutical Science, 32: 4-9.
[21] Pandey, Y.R., S. Kumar, B.K. Gupta, J. Ali, S. Baboota, 2016. Intranasal delivery of
paroxetine nanoemulsion via the olfactory region for the management of depression: formulation,
behavioural and biochemical estimation.Nanotechnology, 27(2): 025102.

129

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

[22] Dolgachev, V.A., S.M. Ciotti, R. Eisma, S. Gracon, J.E. Wilkinson, J.R. Baker, M.R. Hemmila, 2016.
Nanoemulsion Therapy for Burn Wounds Is Effective as a Topical Antimicrobial Against Gram-Negative
and Gram-Positive Bacteria. Journal of Burn Care & Research, 37(2): e104-14.
[23] Engelskirchen, S., R.Maurer, T. Levy, R. Berghaus, H. Auweter, O. Glatter, 2012. Highly concentrated
emulsified microemulsions as solvent-free plant protection formulations.Journal of Colloid and Interface
Science, 388(1):151-61.
[24] BECHER, P., 1977. "Emulsions: Theory and Practice", Reprint, Krieger Publication.
[25] Proceedings, 1978. World Conference on Soaps and Detergents, Journal of the American Oil Chemists
Society, 55(1).
[26] Raza, M.Q., N. Kumar, R. Raj, 2016. Surfactants for Bubble Removal against Buoyancy. Scientific
Reports, 6:19113.Sharma, S.N., N.K. Jain, 1985. A text book of professional pharmacy. Vallabh Prakashan,
1st edn, 201.
[27] Zainol, N.A., T.S. Ming, Y. Darwis, 2015. Development and Characterization of Cinnamon Leaf Oil
Nanocream for Topical Application, Indian Journal of Pharmaceutical Science, 77(4): 422-433.
[28] Ahuja, A., S. Baboota, F. Shakeel, S. Shafiq, 2007. Design development and evaluation of novel
nanoemulsion formulations fortransdermal potential of Celecoxib. Acta Pharmaceutica, 57: 315-332.
[29] Rizwan, M., M. Aqil, S.Talegaonkar, A. Azeem Y. Sultana, A. Ali, 2009. Enhanced transdermal drug
delivery techniques: an extensive review of patents -Review .Recent patents on drug delivery and
formulation, (2):105-24.
[30] Okamoto, T., S. Tomomasa, H. Nakajima, 2016. Preparation and Thermal Properties of Fatty
Alcohol/Surfactant/Oil/Water Nanoemulsions and Their Cosmetic Applications. Journal of Oleo Science,
65(1): 27-36.
[31] Alkilani, A.Z., M.T. Crudden, R.F. Donnelly, 2015. Transdermal Drug Delivery: Innovative Pharmaceutical
Developments Based on Disruption of the Barrier Properties of the stratum corneum. Pharmaceutics, 7(4):
438-70.
[32] Jaiswal, M., R. Dudhe, and P.K. Sharma, 2015. Nanoemulsion: an advanced mode of drug delivery system.
Biotechnology, 5(2): 123-127.
[33] Singh, K.K., S.K. Vingkar, 2008. Formulation, antimalarial activity andbiodistribution of oral lipid
nanoemulsion of primaquine. International Journal of Pharmaceutics, 347: 138.
[34] Trotta, M., 1999. Influence of phase transformation on indomethacin release from microemulsions.
Journal of Control Release, 60: 399-405.
[35] Shen, L.N., Y.T. Zhang, Q. Wang , L. Xu , N.P. Feng, 2014. Preparation and evaluation of microemulsionbased transdermal delivery of total flavone of rhizoma arisaematis. International Journal of Nanomedicine,
9: 3453-64.
[36] Ali, M.S., N. Alam, Alam and M. Siddiqui, 2014. Preparation, Characterization and Stability Study of
Dutasteride Loaded Nanoemulsion for Treatment of Benign Prostatic Hypertrophy. Iranian journal of
Pharmaceutical Research, 13(4): 1125-1140.
[37] Ahmad, S., K. Nitesh, 2014. Stability testing of Betamethasone Dipropionate Nanoemulsion (O/W) having
salmon fish oil as a vehicle. Internationale Pharmaceutica Sciencia, 4(1): 21-27.
[38] Shafiq, S., S. Faiyaz, T. Sushma, F.J. Ahmad, R.K. Khar, M. Ali, 2007. Design and development of oral oil
in water Ramipril nanoemulsion formulation: in vitro and in vivo evaluation. Journal of Biomedicine and
Nanotechnology, 3: 28Y44.
[39] Ahmad, S., K. Nitesh, 2014. Omega 3-Fatty Acid (Epa and Dha) Rich Salmon Fish Oil Enhance AntiPsoriatic activity of Glucocorticoid (Betamethasone Dipropionate) in Nano Formulation. International
Journal of Drug Development & Research, 6(2): 61-76.
[40] Farhan, A.J., A. Mushir, S. Faiyaz, T. Cushman, K.K. Roop, S. Sheikh, 2008. Investigation of
nanoemulsion system for transdermal delivery of domperidone: ex-vivo and in vivo studies. Current
Nanoscience, 4(4): 381-390.
[41] Nirmal, S., A. Seth, S. Chauhan, C. Aundhia, A. Javia, G. Sailor, 2013. Formulation, design and
characterization of microemulsion based system for topical delivery of antipsoriatic drug. World Journal of
Pharmacy and Pharmaceutical Sciences, 3: 1464-1480.
[42]
Sajid, M.A., M.S. Alam, N. Alam, M.I. Alam, F. Imam, M.D. Ali, 2012. Formulation, Characterization
and In-vivo study of nanoemulsion topical gel of beclomethasone dipropionate for psoriasis. World
Journal of Pharmacy and Pharmaceutical Sciences, 1: 839-857.
[43] Balazs, B., G. Vizseralek, S. Berko, M. Szucs, A. Kelemen, B. Sinko, K. Novak, P. Revesz, E. Csanyi,
2016. Investigation of the Efficacy of Transdermal Penetration Enhancers Through the Use of Human Skin
and a Skin Mimic Artificial Membrane.Journal Pharmaceutical Science. pii: S0022-3549(15)00172-0. doi:
10.1016/S0022-3549(15)00172-0. [Epub ahead of print]
[44] Devarajan, V., and V. Ravichandran, 2011. Nanoemulsions: As Modified Drug Delivery Tool. Pharmacie
Globale International Journal of Comprehensive Pharmacy, 4(2): 1-6.

130

Sarfaraz Ahmad et al, 2016

Advances in Environmental Biology, 10(10) October 2016, Pages: 120-130

[45] Burapapadh, K., M. Kumpugdee Vollrath, D. Chantasart and P. Sriamornsak, 2010. Fabrication of pectinbased nanoemulsions loaded with itraconazole for pharmaceutical application. Carbohydrate Polymers,
82(2): 384-393.
[46] Chantasart, D., S. Chootanasoontorn, J. Suksiriworapong, S.K. Li, 2015. Investigation of pH Influence on
Skin Permeation Behavior of Weak Acids Using Nonsteroidal Anti-Inflammatory Drugs.Journal of
Pharmaceutical Sciences, 104(10): 3459-70.
[47] Kumar, M., A. Misra, A.K. Babbar, A.K. Mishra, P. Mishra, K. Pathak, 2008. Intranasal nanoemulsion
based brain targeting drug delivery system of risperidone. International Journal of Pharmaceutics, 358: 285291.
[48] Arunkumar, N., M. Deecaraman, C. Rani, 2007. Nanosuspension Technology and its applications in drug
delivery. Indian Pharmacopeia, 124.124. 110.202.
[49] Casadei, M.A., F. Cerreto, S. Cesa, M. Giannuzzo, M. Feeney, C. Marianecci, 2006. Solid lipid
nanoparticles incorporated in dextran hydrogels: A new drug delivery system for oral formulations.
International Journal of Pharmaceutics, 325(1-2): 140-146.
[50] Sajid, M.A., et al. 2012. Topical nanoemulsion of turmeric oil for psoriasis: characterization, ex vivo and in
vivo assessment. International Journal of Drug Delivery, 4: 184-197.
[51] Patel, P.D., G.J. Patel, P.D. Bharadia, V.M. Pandya and D.A. Modi, 2011. Nanoemulsion: An advanced
concept of dosage form. Journal and Cosmetology, 5(1): 122-133.
[52] Charles, L., A. Anthony, Attama, 2011. Current State of Nanoemulsions in Drug Delivery. Journal of
Biomaterials and Nanobiotechnology, pp: 2626-639.
[53] Landry, K.S., Y. Chang, D.J.Clements, L. sborough, 2014. Effectiveness of a novel spontaneous carvacrol
nanoemulsion against Salmonella enterica Enteritidis and Escherichia coli O157:H7 on contaminated mung
bean and alfalfa seeds.International Journal of Food Microbiology, 18(187):15-21.
[54] Ziani, K., Y. Chang, L. Mc, L.S. borough and J. McClements David, 2011. Physicochemical
Properties and Antimicrobial Efficacy of Electrostatic
Complexes
Based
on Cationic
Polylysine and Anionic Pectin. Journal of Agriculture and Food Chemistry, 59(11): 6247-6255.
[55] Mushir, A., A. Javed and B. Vikas, 2010. Study of surfactant combinations and development of a novel
nanoemulsion for minimising variations in bioavailability of ezetimibe. Colloids and Surfaces B:
Biointerfaces, 76: 412.
[56] Khatri, S., P. Lohani, G. Shweta, 2013. Nanoemulsions in Cancer Therapy, Indo Global Journal of
Pharmaceutical Sciences, 3(2): 124-133.
[57] Liu, X., H.S.S.Qhattal, S. Wang, T. Salihima and S.K. Srivastava, 2011. Nanoemulsions of Cancer
Chemopreventive Agent Benzyl Isothiocyanate Display Enhanced Solubility Dissolution and Permeability.
Journal of Agriculture and Food Chemistry, 59(23): 12396-12404.
[58] Souto, E.B., A.P. Nayak and R.S. Murthy, 2011. Lipid nanoemulsions for anti-cancer drug therapy.
Pharmazie, 66(7): 473-8.