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Indian Journal of Novel Drug delivery 8(3), Jul-Sep, 2016, 123-132

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
ARTICLE DETAILS ABSTRACT
Article history: A versatile mode of drug delivery system has been developed to overcome the
Received on 23 August 2016 drawbacks associated in conventional drug delivery system. This review was give
Modified on 20 September 2016 detailed idea about Nanoemulsion system. Nanoemulsion is promising delivery of
Accepted on 23 September 2016
various drugs. It is nanosized submicron sized emulsions, which are manufactured
Keywords: for improving the delivery of active pharmaceutical ingredients. Nanoemulsion was
Nanoemulsion, thermodynamically as well as kinetically stable isotropic system in which two
Microemulsion, immiscible liquids are mixed to form a single phase by means of an emulsifying
Submicron Sized agent (Smix). The droplet size was falls typically in the range of 50-200 nm. The
Emulsions, main difference between emulsion, microemulsion and nanoemulsion lies in the
Drug delivery, size and shape of particles dispersed in the continuous Phase. Nanoemulsion offers
Emulgents, a promising vehicle for increasing the aqueous solubility of poorly water soluble
Novel drug delivery,
drugs and enhances the Pharmacological as well as Therapeutic action of drugs.
Versatile drug delivery.
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

INTRODUCTION The dispersed phase droplet size is about 50-200


Nanoemulsion is a Novel drug delivery system. It nm, having very low oil and water (o/w)
is one of the novel approaches of drug delivery interfacial tension [4]. Nanoemulsion system was
system to enhance the Bioavailability of poorly composed by the appropriate concentration of
water soluble drugs [1]. It is an Isotropic mixture Oil and surfactant phase having droplet size 50-
of Oil, Surfactant: Cosurfactant (Smix), water and 200 nm and Structure of NE droplet was shown
drug. It is a one of the Colloidal Particulate in Figure 1. [5]
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 Figure 1: Structure of Nanoemulsion droplet
surfactant molecules. 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
*Author for Correspondence: continuous water aqueous phase, water in oil
Email: hsmahajan@rediffmail.com (w/o) in which water is dispersed in continuous
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oil phase and bicontinuous Nanoemulsions in Disadvantages of Nanoemulsion System


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

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2. Specific composition is required to avoid response to alternating electric voltage. The tip
Oswald ripening the dispersed phase should of Sonicator contacts the liquid medium, it can
be highly insoluble in the dispersed medium produces mechanical vibration and cavitation
[35]. occurs. Formation of cavitation and collapse
3. Optimum concentration of surfactant is vapour cavities in liquid. Thus, ultrasound can
required to stabilize the Nanoemulsion [36]. directly produces emulsion. In this method is
mainly used for laboratories purpose, where
Mechanism of Nanoemulsion System emulsion droplet size is low as 0.2 mm can be
The Entropy was changes that favours the obtained [44, 45].
dispersion is greater than the energy is required
to increases the surface of dispersion hence the 3. Microfluidization
free energy of conventional emulsion is direct Microfluidization is a one of the patented mixing
function of energy is required to create new technology, which makes use of a device called as
surface between oil and water phase and microfluidizer. This device was used in high
addition of emulsifying agent to reduce the pressure positive displacement pump (500-
interfacial tension subsequently emulsion was 20000psi), which forces the product through the
stabilized [37-39]. interaction chamber, resulting very fine particles
in submicron range. This process is repeated
Formulation Aspects and Method of several times to obtain a desired size to
Preparation for Nanoemulsion System produced uniform or homogeneous
Formulation of Nanoemulsion system includes nanoemulsion system [46, 47].
active drug molecule, additives, polymers and
emulsifier. Various methods for the preparation Low Energy Emulsification
of nanoemulsion system but, mainly divided by 1. Phase inversion emulsification method
two methods: High Energy Emulsification and This method involves phase transitions by
Low Energy Emulsification. The high energy applying higher temperature to emulsification
emulsification method includes high pressure pathway [48-50].
homogenization (HPH), Ultrasonication and
Microfluidization. The low energy method 2. Spontaneous emulsification
includes Phase inversion, Spontaneous In this method nanoemulsion is spontaneously
emulsification. Using combination of both formed. In which, preparation of homogeneous
methods, which includes high energy and uniform organic solution consisting oil and
emulsification and low energy emulsification, for lipophilic surfactant in water miscible surfactant
prepared reverse Naemulsion system are highly and hydrophilic surfactant phase. The organic
viscous system [40-42]. phase was injected in aqueous phase under
continuous magnetic stirring, stable o/w is
High Energy Emulsification Method formed. The aqueous phase was removed by
1. High pressure homogenization (HPH) evaporation under reduced pressure [51-53].
The preparation of nanoemulsion system is
required high pressure homogenization. This Evaluation Parameters of Nanoemulsion
method mainly used high-pressure System
homogenizer/ piston homogenizer to produce 1. Droplet size analysis
nanoemulsions of extremely low particle size (up Droplet size analysis of nanoemulsion was
to 1 nm). The dispersion of two phases (oil and measured by a diffusion method utilizing the
aqueous phase) is achieved forcing there mixture light-scattering particle size analyser (Nano
through a small inlet orifice at very high pressure ZS90, Malvern Pvt. Ltd. USA). It is also measured
(500 to 5000 psi), which subjects the product to by correlation spectroscopy that analyses the
intense turbulence and hydraulic shear resulting fluctuation in scattering of light due to Brownian
in extremely fine particles of emulsion [43]. motion. Droplet size analysis of NE was also
performed by Transmission electron microscopy
2. Ultrasonication (TEM) and Photon correlation spectroscopy
Ultrasonic emulsification is very efficient method (PCS) [54, 55].
for reducing a droplet size. In this method, the
energy is provided through sonotrodes called as 2. Viscosity determination
Sonicator probe. It can contain piezoelectric Theoptimum viscosity is essential for
quartz crystal which can expand and contract in nanoemulsion system. The viscosity of
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nanoemulsion was measured by using 10. Dye test


Brookfield-type rotary viscometer at different Dye test was measured colour uniformity of NE.
shear rates at different temperature [56, 57]. in o/w NE water soluble dye was added taken up
the colour uniformity. If the NE is w/o type the
3. Drug content dye being soluble in water, taken colour only in
Drug content of formulation was determined by the dispersed phase and emulsion was not
using UV spectrophotometric and HPLC method. uniformly coloured. This can be revealed
In case UV, the 10 mg equivalent of drug loaded immediately by microscopic examination of the
nanoemulsion was dissolved in 100 ml of Solvent emulsion [67].
(Drug having optimum solubility of that solvent).
From this stock solution, take 1 ml and dilute it 11. Polydispersity
in 10 ml of solvent (This solvent was not contain It indicates the uniformity of droplet size in
drug loaded nanoemulsion). And Drug content nanoemulsion. The higher the value of
was estimated at reported Lamda max of that polydispersity, lower will be uniformity of
drug molecule [58, 59]. droplet size of nanoemulsion. It is measured by
the Spectrophotometer [68, 69].
4. pH
The pH of nanoemulsion System was measured 12. Filter paper test
by using pH meter. (Systronic 362 pH system, This test is based on the fact that an o/w
India)[60]. nanoemulsion was spread out rapidly when
dropped onto filter paper. In contrast, w/o
5. Refractive index nanoemulsion was migrating only slowly. This
Refractive index of nanoemulsion was measured method was not be used for highly viscous
by Abbes Refractometer. (Ningbo Biocotek creams [70].
Scientific Instrument, Ltd, Tokyo, China) [61].
13. Thermodynamic Stability Studies
6. Zeta Potential The formulated or Optimized NE was centrifuged
Zeta potential was measured the charge on the at the 1000 RCF for 30 min. and observed for
surface of droplet of Nanoemulsion. The phase separation, creaming or cracking. NE was
formulation (0.1 ml) was diluted 100 times using subjected heating and cooling cycle. Six cycle
double distilled water and analysed using between the refrigerator temperatures 4C and
Zetasizer. (Nano ZS90, Malvern Pvt. Ltd. USA)[62, 45C temperature were performed with storage
63]. at each temperature for not <48 hrs. The
optimized formulation was exposed for three
7. Percentage transmittance freeze thaw cycles between -21C and +25C
Percentage transmittance of the optimised with storage at each temperature for not <48 hrs
nanoemulsion formulations was determined to check the thermodynamic stability of
spectrophotometrically using UV nanoemulsion [71, 72].
spectrophotometer (Shimadzu 1700 and 2450,
Japan) at the particular Lamda max of drug 14. In Vitro Skin Permeation Studies
molecule [64, 65]. In vitro drug release of optimized NE was
determined by dialysis bag method.1.0 ml of NE
8. Conductivity Test was placed in dialysis bag (HIMEDIA dialysis
The conductivity of the NE was measured with membrane-150, Delhi, India) was subjected to
conductometer model (Systronics,Pvt. Ltd, release in 900 ml of diffusion media (pH 6.4
India)[66]. phosphate buffer or pH 6.8 phosphate buffer)
stirred at a speed of 100 rpm and temperature
9. Dilution test 37 0.5C. Aliquots of 5 mL samples were
Dilution of NE either with oil or water phase. The withdrawn at regular time intervals from the
test based on fact that dilution of continuous dialyzing medium and volume withdrawn was
phase of nanoemulsion without causing the replaced with the fresh medium each time to
problem of its stability. Thus, o/w NE is diluted maintain sink condition. The sample were
with water and w/o NE is diluted with oil [67]. 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 It is an isotropic mixture of It is an isotropic mixture of
of medicament in which one can Oil, surfactant and Drug. Oil, surfactant, Cosurfactant
dispersed finite globules in (Smix) and Drug.
another liquid phase.
Appearance Cloudy Transparent More Transparent
Droplet Size 0.1-10 200-500 nm 50- 200 nm
Surface area Less More More
Formation Require vigorous shaking Phase titration and Phase Spontaneous Formation
inversion
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 More Less Very Less
concentration
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 was diluted with water (1/100). A drop of the
In vivo studies were conducted in four groups diluted nanoemulsions was directly deposited on
such as control, test, standard and normal group, the holey film grid and observed after drying [80]
each group was containing six male albino rats [81].

having 150-200 gm weight. The rats were fasted


overnight and injection containing optimum dose 17. Phase Behaviour Study
of drug molecule. The control group of rats were Nanoemulsion System was determined by using
given in vehicle and standard groups were given Pseudo ternary phase diagram. It is also
plain sample or optimized NE formulation and determine NE existence area. Pseudo-ternary
normal group of rat were given with normal diet. phase diagrams of oil, water, and surfactant:
The oral dosing was performed by intubation Cosurfactant (Smix) mixture was constructed.
using an 18-gauge feeding needle (the volume to Then prepared Smix by mixing a specific ratio of
be fed was 1.0 mL in all cases). Blood samples surfactants: Cosurfactant (1:1, 2:1, 3:1, 4:1, 1:2
were drawn at 0 hrs, 24 hrs and 48 hrs. Serum and 1:3) after that transparent and homogenous
was separated by centrifugation at 10000 rpm mixture of oil and Smix was formed by using
and used for biochemical analysis. Serum vertex. Each mixture was titrated with water and
cholesterol, triglycerides and high density visually observed for phase clarity and flow
lipoprotein cholesterol (HDL-CH) were estimated ability. Equal quantity of drug in all formulation
in each group. Statistical analysis of the collected batches and Depending on each phase diagram,
data was performed using one way analysis of the nanoemulsion region was identified and
variance [77-79]. different formulations were selected at desired
component ratios, In order to form the stable
16. Transmission Electron Microscopy (TEM) Nanoemulsion (NE) [82-84].
The morphological and structural examination of
nanoemulsion system was studied by using TEM. Applications of Nanoemulsion System
A combination of bright field imaging at Nanoemulsion is Target specific or site specific
increasing magnification and diffraction modes approach for Intranasal, Parenteral, Ocular,
was used, to reveal the form and size of the Intravenous and Transdermal drug delivery
Nanoemulsions. To perform TEM analysis, NE system [85]. It is important approach to improve
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