Journal of Biomaterials and Nanobiotechnology, 2011, 2, 626-639
doi:10.4236/jbnb.2011.225075 Published Online December 2011 (http://www.scirp.org/journal/jbnb)
Current State of Nanoemulsions in Drug Delivery
Charles Lovelyn, Anthony A. Attama*
Department of Pharmaceutics, University of Nigeria, Nsukka, Nigeria.
Received September 20th, 2011; revised October 27th, 2011; accepted November 14th, 2011.
ABSTRACT
Nanoemulsions have attracted great attention in research, dosage form design and pharmacotherapy. This is as a result
of a number of attributes peculiar to nanoemulsions such as optical clarity, ease of preparation, thermodynamic stabil-
ity and increased surface area. Nanoemulsions also known as submicron emulsions serve as vehicles for the delivery of
active pharmaceutical ingredients as well as other bioactives. They are designed to address some of the problems asso-
ciated with conventional drug delivery systems such as low bioavailability and noncompliance. The importance of de-
sign and development of emulsion nanocarrier systems aimed at controlling and/or improving required bioavailability
levels of therapeutic agents cannot be overemphasized. Reducing droplet sizes to the nanoscale leads to some very in-
teresting physical properties, such as optical transparency and unusual elastic behaviour. This review sheds light on
the current state of nanoemulsions in the delivery of drugs and other bioactives. The morphology, formulation, charac-
teristics and characterization of nanoemulsions were also addressed.
Keywords: Nanoemulsion, Preparation, Characterization, Application in Drug Delivery, Patents
1. Introduction
Nanoemulsions are oil-in-water (o/w) emulsions with
mean droplet diameters ranging from 50 to 1000 nm.
Usually, the average droplet size is between 100 and 500
nm. The particles can exist as oil-in-water and water-
in-oil forms, where the core of the particle is either oil or
water, respectively. Nanoemulsions are made from sur-
factants approved for human consumption and common
food substances that are “Generally Recognized as Safe”
(GRAS) by the FDA. These emulsions are easily pro-
duced 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 world-
wide [1].
Nanoemulsions are also referred to as miniemulsions,
ultrafine emulsions and submicron emulsions. Phase be-
haviour studies have shown that the size of the droplets is
governed by the surfactant phase structure (bicontinuous
microemulsion or lamellar) at the inversion point induced
by either temperature or composition.
The capacity of nanoemulsions to dissolve large quan-
tities of hydrophobics, along with their mutual compati-
bility and ability to protect the drugs from hydrolysis and
enzymatic degradation make them ideal vehicles for the
purpose of parenteral transport. 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 mode over
long periods of time. Additionally, the lack of floccula-
tion, sedimentation and creaming, combined with a large
surface area and free energy, offer obvious advantages
over emulsions of larger particle size, for this route of
administration. Their very large interfacial area posi-
tively influences the drug transport and their delivery,
along with targeting them to specific sites [2,3].
Reducing droplet sizes to the nanoscale leads to some
very interesting physical properties, such as optical trans-
parency and unusual elastic behaviour. 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. Moreover, it is very likely that nanoe-
mulsions will play an increasingly important role com-
mercially, since they can typically be formulated using
significantly less surfactant than is required for nanos-
tructured lyotropic microemulsion phases. Nanoemul-
sions 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,

Current State of Nanoemulsions in Drug Delivery 627
such phases are actually quite different [4]. Lyotropic
liquid crystals are equilibrium structures comprised of
liquids and surfactant, such as lamellar sheets, hexagon-
ally packed columns, and wormlike micellar phases, that
form spontaneously through thermodynamic self assem-
bly. By contrast, nanoemulsions do not form spontane-
ously; an external shear must be applied to rupture larger
droplets into smaller ones. Compared to microemulsion
phases, relatively little is known about creating and con-
trolling nanoemulsions. This is primarily because ex-
treme shear, well beyond the reach of ordinary mixing
devices, must be applied to overcome the effects of sur-
face tension to rupture the droplets into the nanoscale
regime [4].
2. Preparation of Nanoemulsions
Nanoemulsions are non-equilibrium systems of struc-
tured liquids [2-4], and so their preparation involves the
input of a large amount of either energy or surfactants
and in some cases a combination of both. As a result,
high energy or low energy methods can be used in their
formulation [3]. The high-energy method utilizes me-
chanical devices to create intensely disruptive forces
which break up the oil and water phases to form nano-
sized droplets. This can be achieved with ultrasonicators,
microfluidiser and high pressure homogenisers [4-6].
Particle size here will depend on the type of instruments
employed and their operating conditions like time and
temperature along with sample properties and composi-
tion [7]. This method allows for a greater control of par-
ticle size and a large choice of composition, which in
turn controls the stability, rheology and colour of the
emulsion. Although high-energy emulsification methods
yield nanoemulsions with desired properties and have
industrial scalability, they may not be suitable for ther-
molabile drugs such as retinoids and macromolecules,
including proteins, enzymes and nucleic acids.
Nanoemulsion can be prepared by a low-energy emul-
sification method, which has been recently developed
according to the phase behavior and properties of the
constituents, to promote the formation of ultra-small
droplets [8,9]. These low-energy techniques include self-
emulsification, phase transition and phase inversion
temperature methods [10]. The low energy method is
interesting because it utilizes the stored energy of the
system to form small droplets. This emulsification can be
brought about by changing the parameters which would
affect the hydrophilic lipophilic balance (HLB) of the
system like temperature, composition, etc. [11,12].
Energy is usually required in emulsion formulation
because the process may be non-spontaneous. The pro-
duction of nanoemulsions costs more energy than that
required to produce macroemulsions. Presence of surfac-
tants help lower the surface tensions between oil and
water. Small molecules such as non-ionic surfactants
lower surface tension more than polymeric surfactants
such as poly(vinyl alcohol). Another important role of
the surfactant is its effect on the interfacial dilatational
modulus [13]. During emulsification an increase in the
interfacial area takes place and this causes a reduction in
surface excess. The equilibrium is restored by adsorption
of surfactant from the bulk, but this takes time (shorter
times occur at higher surfactant activity). Because of the
lack or slowness of equilibrium with polymeric surfac-
tants, dilatational modulus will not be the same for ex-
pansion and compression of the interface [13]. In practice,
surfactant mixtures are used and these have pronounced
effects on surface tension and dilatational modulus.
Some specific surfactant mixtures give lower surface
tension values than either of the two individual compo-
nents. Polymer-surfactant mixtures may show some syn-
ergistic surface activity.
Another important role of the emulsifier is to prevent
shear-induced coalescence during emulsification. The
requirement is that the continuous phase has a significant
excess of surfactant. This excess enables new surface
area of the nanoscale droplets to be rapidly coated during
emulsification, thereby inhibiting shear-induced coales-
cence. This excess is generally in the form of surfactant
micelles in the continuous phase. These micelles dissoci-
ate into monomers that rapidly adsorb onto the surfaces
of newly created droplets [4].
2.1. Methods of Preparation of Nanoemulsions
2.1.1. High Pressure Homogenization
This technique makes use of high-pressure homogenizer/
piston homogenizer to produce nanoemulsions of ex-
tremely low particle size (up to 1 nm). During this proc-
ess, several forces, such as hydraulic shear, intense tur-
bulence and cavitation, act together to yield nanoemul-
sions with extremely small droplet size. The resultant
product can be re-subjected to high-pressure homogeni-
zation until nanoemulsion with desired droplet size and
polydispersity index is obtained. The production of small
droplets (submicron) requires application of high energy.
Several procedures may be applied to enhance the effi-
ciency of emulsification when producing nanoemulsions.
The emulsion is preferably prepared at high volume fac-
tion of the disperse phase and diluted afterwards. How-
ever, very high phase volume ratios may result in coa-
lescence during emulsification, but more surfactant could
be added to create a smaller reduction in effective surface
tension and possibly diminishing recoalescence. Surfac-
tant mixtures that show more reduction in surface tension
than the individual components could also be used. If
possible the surfactant is dissolved in the disperse phase

Current State of Nanoemulsions in Drug Delivery 628
rather than the continuous phase; this often leads to
smaller droplets. It may be useful to emulsify in steps of
increasing intensity, particularly with emulsions having
highly viscous disperse phase.
2.1.2. Microfluidization
Microfluidization is a patented mixing technology, which
makes use of a device called microfluidizer. This device
uses a high-pressure positive displacement pump (500 -
20,000 psi), which forces the product through the interac-
tion chamber, consisting of small channels called “mi-
crochannels”. The product flows through the micro-
channels on to an impingement area resulting in very fine
particles of submicron range. The two solutions (aqueous
phase and oily phase) are combined together and proc-
essed in an inline homogenizer to yield a coarse emulsion
[1]. The coarse emulsion is introduced into a microfluid-
izer where it is further processed to obtain a stable na-
noemulsion. The coarse emulsion is passed through the
interaction chamber of the microfluidizer repeatedly until
the desired particle size is obtained. The bulk emulsion is
then filtered through a filter under nitrogen to remove
large droplets resulting in a uniform nanoemulsion. High-
pressure homogenization and microfluidization can be
used for fabrication of nanoemulsions at laboratory and
industrial scale, whereas ultrasonic emulsification is main-
ly used at laboratory scale.
2.1.3. Ph ase I nve rsion Temperature Technique
Studies on nanoemulsion formulation by the phase inver-
sion temperature method have shown a relationship be-
tween minimum droplet size and complete solubilization
of the oil in a microemulsion bicontinuous phase inde-
pendently of whether the initial phase equilibrium is sin-
gle or multiphase. Due to their small droplet size nanoe-
mulsions possess stability against sedimentation or crea-
ming with Ostwald ripening forming the main mecha-
nism of nanoemulsion breakdown [9]. Phase inversion in
emulsions can be one of two types: transitional inversion
induced by changing factors which affect the HLB of the
system, e.g. temperature and/or electrolyte concentration,
and catastrophic inversion, which can also be induced by
changing the HLB number of the surfactant at constant
temperature using surfactant mixtures [13].
Phase inversion temperature (PIT) method employs
temperature-dependent solubility of nonionic surfactants,
such as polyethoxylated surfactants, to modify their af-
finities for water and oil as a function of the temperature.
It has been observed that polyethoxylated surfactants
tend to become lipophilic on heating owing to dehydra-
tion of polyoxyethylene groups. This phenomenon forms
a basis of nanoemulsion fabrication using the PIT
method. In the PIT method, oil, water and nonionic sur-
factants are mixed together at room temperature. This
mixture typically comprises o/w microemulsions coex-
isting with excess oil, and the surfactant monolayer ex-
hibits positive curvature. When this macroemulsion is
heated gradually, the polyethoxylated surfactant becomes
lipophilic and at higher temperatures, the surfactant gets
completely solubilized in the oily phase and the initial
o/w emulsion undergoes phase inversion to w/o emulsion.
The surfactant monolayer has negative curvature at this
stage. This method involves heating of the components
and it may be difficult to incorporate thermolabile drugs,
such as tretinoin and peptides, without affecting their
stability. Although it may be possible to reduce the PIT
of the dispersion using a mixture of components (surfac-
tants) with suitable characteristics, in order to minimize
degradation of thermolabile drugs.
2.1.4. Solvent Displacement Method
The solvent displacement method for spontaneous fabri-
cation of nanoemulsion has been adopted from the nano-
precipitation method used for polymeric nanoparticles. In
this method, oily phase is dissolved in water-miscible
organic solvents, such as acetone, ethanol and ethyl
methyl ketone. The organic phase is poured into an
aqueous phase containing surfactant to yield spontaneous
nanoemulsion by rapid diffusion of organic solvent. The
organic solvent is removed from the nanoemulsion by a
suitable means, such as vacuum evaporation. Spontane-
ous nanoemulsification has also been reported when so-
lution of organic solvents containing a small percentage
of oil is poured into aqueous phase without any surfac-
tant.
Solvent displacement methods can yield nanoemul-
sions at room temperature and require simple stirring for
the fabrication. Hence, researchers in pharmaceutical
sciences are employing this technique for fabricating
nanoemulsions mainly for parenteral use. However, the
major drawback of this method is the use of organic sol-
vents, such as acetone, which require additional inputs
for their removal from nanoemulsion. Furthermore, a
high ratio of solvent to oil is required to obtain a nanoe-
mulsion with a desirable droplet size. This may be a lim-
iting factor in certain cases. In addition, the process of
solvent removal may appear simple at laboratory scale
but can pose several difficulties during scale-up.
2.1.5. Phase Inv ersion Compositi on Method
(Self-Nanoemulsification M et hod)
This method has drawn a great deal of attention from
scientists in various fields (including pharmaceutical
sciences) as it generates nanoemulsions at room tem-
perature without use of any organic solvent and heat.
Kinetically stable nanoemulsions with small droplet size
(~50 nm) can be generated by the stepwise addition of
water into solution of surfactant in oil, with gentle stir-

Current State of Nanoemulsions in Drug Delivery 629
ring and at constant temperature. The spontaneous na-
noemulsification has been related to the phase transitions
during the emulsification process and involves lamellar
liquid crystalline phases or D-type bicontinuous micro-
emulsion during the process. Nanoemulsions obtained
from the spontaneous nanoemulsification process are not
thermodynamically stable, although they might have high
kinetic energy and long-term colloidal stability.
2.2. Advantages of Nanoemulsions as Drug
Delivery Systems
The attraction of nanoemulsions for application in per-
sonal care and cosmetics as well as in health care is due
to the following advantages [13,14]:
1) The very small droplet size causes a large reduction
in the gravity force and the Brownian motion may be
sufficient for overcoming gravity. This means that no
creaming or sedimentation occurs on storage.
2) The small droplet size also prevents any floccula-
tion of the droplets. Weak flocculation is prevented and
this enables the system to remain dispersed with no
separation.
3) The small droplets also prevent their coalescence,
since these droplets are elastic, surface fluctuations are
prevented.
4) Nanoemulsions are suitable for efficient delivery of
active ingredients through the skin. The large surface
area of the emulsion system allows rapid penetration of
actives.
5) The transparent nature of the system, their fluidity
(at reasonable oil concentrations) as well as the absence
of any thickeners may give them a pleasant aesthetic
character and skin feel.
6) Unlike microemulsions (which require a high sur-
factant concentration, usually in the region of 20% and
higher), nanoemulsions can be prepared using reasonable
surfactant concentration. For a 20% o/w nanoemulsion, a
surfactant concentration in the region of 5% - 10% may
be sufficient. Nanoemulsions are usually formulated with
surfactants, which are approved for human consumption
(GRAS), they can be taken by enteric route.
7) The small size of the droplets allows them to de-
posit uniformly on substrates. Wetting, spreading and
penetration may be also enhanced as a result of the low
surface tension of the whole system and the low interfa-
cial tension of the o/w droplets.
8) Nanoemulsions can be applied for delivery of fra-
grants, which may be incorporated in many personal care
products. This could also be applied in perfumes, which
are desirable to be formulated alcohol free.
9) Nanoemulsions may be applied as a substitute for
liposomes and vesicles (which are much less stable) and
it is possible in some cases to build lamellar liquid crys-
talline phases around the nanoemulsion droplets.
2.3. Disadvantages of Nanoemulsion Drug
Delivery Systems
Inspite of the above advantages, nanoemulsions have
only attracted interest in recent years for the following
reasons [13,14]:
1) Preparation of nanoemulsions requires in many
cases special application techniques, such as the use of
high pressure homogenisers as well as ultrasonics. Such
equipment (such as the Microfluidiser) became available
only in recent years.
2) There is a perception in the personal care and cos-
metic industry that nanoemulsions are expensive to pro-
duce. Expensive equipment are required as well as the
use of high concentrations of emulsifiers.
3) Lack of understanding of the mechanism of produc-
tion of submicron droplets and the role of surfactants and
cosurfactants.
4) Lack of demonstration of the benefits that can be
obtained from using nanoemulsions when compared with
the classical macroemulsion systems.
5) Lack of understanding of the interfacial chemistry
that is involved in production of nanoemulsions.
3. Applications of Nanoemulsions in Drug
Delivery
3.1. Nanoemulsions and Intranasal Drug
Delivery
Intranasal drug delivery system has now been recognized
as a reliable route for the administration of drugs next to
parenteral and oral routes. Nasal mucosa has emerged as
a therapeutically viable channel for the administration of
systemic drugs and also appears to be a favourable way
to overcome the obstacles for the direct entry of drugs to
the target site [15]. This route is also painless, non-inva-
sive and well tolerated. The nasal cavity is one of the
most efficient sites because of its reduced enzymatic ac-
tivity, high availability of immunoactive sites and its
moderately permeable epithelium [16]. There are several
problems associated with targeting drugs to brain, espe-
cially the hydrophilic ones and those of high molecular
weight. This is because of the impervious nature of the
endothelium, which divides the systemic circulation and
barrier between the blood and brain [17]. The olfactory
region of the nasal mucosa provides a direct connection
between the nose and brain, and by the use of nanoemul-
sions loaded with drugs, conditions such as Alzheimer’s
disease, migraine, depression, schizophrenia, Parkinson’s
diseases, meningitis, etc. can be treated [18,19].
Preparation of nanoemulsions containing risperidone
for its delivery to the brain via nose has been reported
[19]. It is inferred that this emulsion is more effective

Current State of Nanoemulsions in Drug Delivery 630
through the nasal rather than intravenous route. Another
application of intranasal drug delivery system in thera-
peutics is their use in development of vaccines. Immunity
is achieved by the administration of mucosal antigen.
Currently, the first intranasal vaccine has been marketed
[20]. Among the possible delivery systems, the use of
nano based carriers hold a great promise to protect the
biomolecules, promote nanocarrier interaction with mu-
cosae and to direct antigen to the lymphoid tissues.
Therefore the use of nanoemulsions in intranasal drug
delivery system is set to bring about significant results in
targeting drugs to the brain in treatment of diseases re-
lated to the central nervous system [21].
3.2. Nanoemulsions and Transdermal Delivery
Drug delivery through the skin to the systemic circula-
tion is convenient for a number of clinical conditions due
to which there has been a considerable interest in this
area [22,23]. It offers the advantage of steady state con-
trolled drug delivery over extended period of time, with
self administration also being possible, which may not be
the case with parenteral route. The drug input can be
eliminated at any time by the patient just by removing
the transdermal patch. Their transparent nature and fluid-
ity, confers on nanoemulsions a pleasant skin feel. An
extra advantage is the total absence of gastrointestinal
side effects like irritation and bowel ulcers which are
invariably associated with oral delivery. Transdermal
drug products have been developed for a number of dis-
eases and disorders including cardiovascular conditions,
Parkinsons’ and Alzheimer diseases, anxiety, depression,
etc. However, the fundamental disadvantage which limits
the use of this mode of administration is the barrier im-
posed by the skin for effective penetration of the bioac-
tives. The three routes by which drugs can primarily
penetrate the skin are through the hair follicles, sweat
ducts or directly across stratum corneum, which restricts
their absorption to a large extent and limits their bioa-
vailability. For improved drug pharmacokinetics and
targeting, the primary skin barriers need to be overcome.
Also the locally applied drug redistribution through cu-
taneous blood and lymph vessel system needs to be con-
trolled. Nano sized emulsions are able to easily penetrate
the pores of the skin and reach the systemic circulation
thus getting channelized for effective delivery [2]. Caf-
feine has been used for treatment of different types of
cancer by oral delivery. Water-in-oil nanoemulsion for-
mulations of caffeine have been developed for transder-
mal drug delivery. Comparison of in vitro skin permea-
tion profile between these and aqueous caffeine solutions
showed significant increase in permeability parameters
for the nanoemulsion loaded drugs [24].
Use of nanoemulsions in transdermal drug delivery
represents an important area of research in drug delivery,
which enhances the therapeutic efficacy and also the
bioavailability of the drugs without any adverse effects.
It is also regarded as a promising technique with many
advantages including, high storage stability, low prepara-
tion cost, thermodynamic stability, absence of organic
solvents, and good production feasibility. They have also
made the plasma concentration profiles and bioavailabil-
ity of drugs reproducible. These systems are being used
currently to provide dermal and surface effects, and for
deeper skin penetration [2]. Many studies have shown
that nanoemulsion formulations possess improved trans-
dermal and dermal delivery properties in vitro [25-33], as
well as in vivo [34-36]. Nanoemulsions have improved
transdermal permeation of many drugs over the conven-
tional topical formulations such as emulsions [37,38] and
gels [39,40].
3.3. Nanoemulsions and Parenteral Drug
Delivery
This is one of the most common and effective routes of
drug administration usually adopted for actives with low
bioavailability and narrow therapeutic index. Their ca-
pacity to dissolve large quantities of hydrophobics, to-
gether with their mutual compatibility and ability to pro-
tect the drugs from hydrolysis and enzymatic degradation
make nanoemulsions ideal vehicles for the purpose of
parenteral transport. 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 mode over long periods of
time. Additionally, the lack of flocculation, sedimenta-
tion and creaming, combined with a large surface area
and free energy, offer obvious advantages over emul-
sions of larger particle size, for this route of administra-
tion [2]. Their very large interfacial area positively in-
fluences the drug transport and their delivery, along with
targeting them to specific sites. Major clinical and pre-
clinical trials have hence been carried out with parenteral
nanoemulsion based carriers. The advances in these
novel drug delivery systems have been reviewed by Patel
and Patel [41]. Nanoemulsions loaded with thalidomide
have been synthesized where a dose as low as 25 mg
leads to plasma concentrations which can be therapeutic
[42]. However, a significant decrease in the drug content
of the nanoemulsion was observed at 0.01% drug formu-
lation after two months storage which could be overcome
by the addition of polysorbate 80. Chlorambucil, a lipo-
philic anticancer agent has been used against breast and
ovarian cancer. Its pharmacokinetics and anticancer ac-
tivity has been studied by loading it in parenteral emul-
sions prepared by high energy ultrasonication method.
Treatment of colon adenocarcinoma in the mouse with

Current State of Nanoemulsions in Drug Delivery 631
this nanoemulsion leads to higher tumor suppression rate
compared to plain drug solution treatment concluding
that the drug loaded emulsion could be an effective car-
rier for its delivery in cancer treatment [43]. Carbama-
zepine, a widely used anticonvulsant drug had no par-
enteral treatment available for patients due to its poor
water solubility. Kelmann et al. [44] have developed a
nanoemulsion for its intravenous delivery, which showed
favorable in vitro release kinetics.
3.4. Nanoemulsions and Drug Targeting
Another interesting application, which is experiencing an
active development, is the use of nanoemulsion formula-
tions, for controlled drug delivery and targeting [9]. Be-
cause of their submicron size, they can easily be targeted
to the tumor area. Although nanoemulsions are chiefly
seen as vehicles for administering aqueous insoluble
drugs, they have more recently received increasing atten-
tion as colloidal carriers for targeted delivery of various
anticancer drugs, photosensitizers, neutron capture ther-
apy agents, or diagnostic agents. The development of
magnetic nanoemulsions is an innovative approach for
cancer therapy. These can deliver photosensitizers like
Foscan® to deep tissue layers across the skin thereby in-
ducing hyperthermia for subsequent free radical genera-
tion. This methodology can be used for the treatment of
cancer in the form of photodynamic therapy [45].
3.5. Nanoemulsions and Vaccine Delivery
A vaccine carrier system using nanoemulsions is currently
being researched. This medication delivery system uses
nanotechnology to vaccinate against human immunode-
ficiency virus (HIV). There is recent evidence that HIV
can infect the mucosal immune system. Therefore, de-
veloping mucosal immunity through the use of nanoe-
mulsions may become very important in the future fight
against HIV [46]. The oil-based emulsion is administered
in the nose, as opposed to traditional vaccine routes. Re-
search is demonstrating that genital mucosa immunity
may be attained with vaccines that are administered into
the nasal mucosa [47].
3.6. Nanoemulsions and Pulmonary Drug
Delivery
Until now, the submicron emulsion system has not yet
been fully exploited for pulmonary drug delivery and very
little has been published in this area [48]. Emulsion sys-
tems have been introduced as alternative gene transfer
vectors to liposomes [49]. Other emulsion studies for gene
delivery (non-pulmonary route) have shown that binding
of the emulsion/DNA complex was stronger than lipo-
somal carriers [50]. This stable emulsion system delivered
genes more efficiently than liposomes [51]. Bivas-Benita
et al. [52] reported that cationic submicron emulsions are
promising carriers for DNA vaccines to the lung since
they are able to transfect pulmonary epithelial cells, which
possibly induce cross priming of antigen-presenting cells
and directly activate dendritic cells, resulting in stimula-
tion of antigen-specific T-cells. Therefore the nebuliza-
tion of submicron emulsions will be a new and upcoming
research area. However, extensive studies are required for
the successful formulation of inhalable submicron emul-
sions due to possible adverse effects of surfactants and
oils on lung alveoli function (adverse interactions with
lung surfactant).
3.7. Prophylactic in Bio-Terrorism Attack
Based on their antimicrobial activity, research has begun
on use of nanoemulsion as a prophylactic medication, a
human protective treatment, to treat people exposed to
bio-attack pathogens such as anthrax and ebola. A broad
spectrum nanoemulsion was tested on surfaces by the
USA army in Dec 1999 for decontamination of Anthrax
spore surrogates. It was tested again by RestOps in March
2001 as a chemical decontamination agent. All tests were
successful. The technology has been tested on gangrene
and Clostridium botulism spores and can even be used on
contaminated wounds to salvage limbs. The nanoemul-
sion technology can be formulated into a foam, liquid,
cream, or spray to decontaminate a variety of materials as
has been done by NanoBio Corporation [53].
4. Characterization of Nanoemulsion
Optical microscopy, even using differential interference
contrast or other phase contrast methods, is generally not
a viable method for examining nanoemulsions. As dis-
cussed below, more sophisticated techniques, such as
dynamic light scattering, x-ray or neutron scattering,
atomic force microscopy, or cryo-electron microscopy
are typically required to explore the structure and behav-
iour of nanoemulsions [4].
Nanoemulsions have some interesting physical proper-
ties that distinguish them from ordinary microscale emul-
sions. For instance, microscale emulsions typically ex-
hibit strong multiple scattering of visible light, and, as a
result, have a white appearance. The multiple scattering
occurs as the light is refracted many times through drop-
lets, films, and plateau borders, provided there is a sig-
nificant refractive index contrast between the dispersed
and continuous phases. In the absence of optical absorp-
tion, photons that enter the emulsion are scattered many
times by microscale structures before they leave the
emulsion [4]. By contrast, the structures in nanoemul-
sions are much smaller than visible wavelengths, so most

Current State of Nanoemulsions in Drug Delivery 632
nanoemulsions appear optically transparent, even at large
phase volume ratio and for large difference in refractive
index. Nanoemulsions may loose their transparency with
time as a result of increase in droplet size. Nanoemul-
sions have a much larger surface area to volume ratio
than ordinary emulsions, so phenomena related to de-
formation of the droplets, such as the elastic modulus, are
typically larger for nanoemulsions than ordinary emul-
sions. Due to the large surface to volume ratio of droplet
interfaces in nanoemulsions, the concentration of sur-
face- tant required to stabilize them is larger than for
microscale emulsions, yet it is generally smaller than for
lyotropic microemulsion phases. Different characteriza-
tion parameters for nanoemulsions are discussed in the
following sections:
4.1. Morphology of Nanoemulsions
The morphology of nanoemulsions can be determined by
transmission electron microscopy (TEM) and scanning
electron microscopy (SEM). SEM gives a three-dimen-
sional image of the globules [54]. The samples are ex-
amined at suitable accelerating voltage, usually 20 kV, at
different magnifications. A good analysis of surface mor-
phology of disperse phase in the formulation is obtained
through SEM. Image analysis software, (e.g., Leica Im-
aging systems, Cambridge, UK), may be employed to
obtain an automatic analysis result of the shape and sur-
face morphology [55].
In TEM, higher resolution images of the disperse
phase are obtained. The sample is negatively stained with
1% aqueous solution of phosphotungstic acid or by drop-
ping 2% uranyl acetate solution onto a 200 µm mesh size
Pioloform™-coated copper grid or a microscopic car-
bon-coated grid using a micropipette and the sample
examined under the transmission electron microscope
(for e.g., Joel 1230, Tokyo, Japan) at 80 kV [56]. Quali-
tative measurements of sizes and size distribution of
TEM micrographs can be performed using a digital im-
age processing programme [56].
4.2. Nanoemulsion Droplet Size, Polydispersity
and Zeta Potential
Dynamic light scattering which is referred to as Photon
Correlation Spectroscopy (PCS) is used to analyze the
fluctuations in the intensity of scattering by droplets/
particles due to Brownian motion [57]. Nanoemulsion
droplet size, polydispersity and zeta potential can be as-
sessed by PCS using a particle size analyzer. This in-
strument also measures polydispersity index, which is a
measure of the broadness of the size distribution derived
from the cumulative analysis of dynamic light scattering.
The polydispersity index indicates the quality or homo-
geneity of the dispersion [58]. PCS gives z-average par-
ticle diameter. Laser diffraction is another technique for
measuring particle size. The fundamental particle size
distribution derived by this technique is volume based
and is expressed in terms of the volume of equivalent
spheres (DN%) and weighted mean of the volume distri-
bution (mass mean diameter). Since the laser diffraction
system is used for this analysis, a rough equivalent of
particle polydispersity could be given by two factors/
values namely, uniformity (how symmetrical the distri-
bution is around the median point) and span (the width of
the distribution). The span value is defined by the ex-
pression:
Span = (D90% − D10%)/D50% (1)
where DN% (N = 10%, 50%, 90%), means that the vo-
lume percentage of particles with diameters up to DN%
equals to N%. The smaller the span value the narrower
the particle size distribution.
4.3. Viscosity Determination
This is carried out using a viscometer. The viscosity of
nanoemulsions is a function of the surfactant, water and
oil components and their concentrations. Increasing the
water content lowers the viscosity, while decreasing the
amount of surfactant and cosurfactant increases interfa-
cial tension between water and oil resulting in increased
viscosity. Viscosity is very important for stability and
efficient drug release. Nanoemulsion carrier formulations
are basically oil-in-water and so in addition to being less
greasy than water-in-oil formulations, often possess
lower apparent viscosities. They are therefore expected
to exhibit faster release of active ingredients and wash
out easily after application on the skin surface. Various
equipment and methods are available for assessment of
rheological properties of nanoemulsion carriers. Moni-
toring of viscosity change is a method of assessing sta-
bility of liquid and semi-solid preparations including
nanoemulsion formulations.
4.4. In Vitro Skin Permeation Studies
Franz diffusion cell is used to obtain the drug release
profile of the nanoemulsion formulation in the case of
formulations for transdermal application. The extent or
depth of skin penetration by the released content can be
visualized by confocal scanning laser microscopy. In
vitro drug release can be determined by dispersing an
amount of the preparation in the donor compartment of a
Franz cell having a membrane as barrier and monitoring
the appearance of the encapsulated drug in the reception
medium, usually PBS (pH 7.4) and stirring on a magnetic
stirrer at 100 rpm at 37˚C ± 1˚C. Samples (1 ml) of the
dispersion are withdrawn from the medium and replaced
with an equivalent amount of the medium at definite in-

Current State of Nanoemulsions in Drug Delivery 633
tervals. The withdrawn sample is then filtered using a
0.22 - 50 µm filter (e.g., Millipore, USA) and the drug
released then analyzed using UV-visible spectroscopy at
wavelength of peak absorption of the drug [59]. An al-
ternative and popular method of ex-vivo release study is
performed using diffusion cell. The skin is cut from the
ear or abdomen and underlying cartilage and fats care-
fully removed. Appropriate size of skin is cut and placed
on the diffusion cell which had earlier been filled with
receptor solution. Samples of the vesicular preparation
are then applied on the dorsal surface of the skin and the
instrument started. At intervals, up to 24 h, samples are
withdrawn from the receptor medium and replaced with
equal amounts of the medium and the withdrawn samples
analyzed for the drug permeated using HPLC [60,61] or
UV spectroscopy. Semi-permeable membrane such as
regenerated cellulose could be used in place of skin for in
vitro release studies [62,63]. The flux J, of the drug
across the skin or membrane is calculated from the for-
mula:
J = D dc/dx (2)
where D is the diffusion coefficient and is a function of
the size, shape and flexibility of the diffusing molecule
as well as the membrane resistance, c is the concentration
of the diffusing species, x is the spatial coordinate [63].
In vivo release study otherwise referred to as derma-
topharmacokinetics, is carried out by applying or admin-
istering the preparation to whole live animal. Blood sam-
ples are then withdrawn at intervals, centrifuged and the
plasma analyzed for the drug content using HPLC. Re-
sults obtained from in vitro and in vivo studies are ex-
trapolated to reflect bioavailability of the drug formu-
lation.
5. Thermodynamic Stability and
Surface Characteristics
Although the physical appearance of a nanoemulsion
may resemble that of a microemulsion, in that both sys-
tems may be transparent and of low viscosity, there is an
essential difference between the two systems. A nanoe-
mulsion is at best, kinetically stable, while microemul-
sion is thermodynamically stable [64]. Nanoemulsions
because of their small droplet size, possess higher stabil-
ity against sedimentation or creaming than microemul-
sions [65]. The two systems are very different since
nanoemulsions are formed by mechanical shear and mi-
croemulsion phases are formed by self-assembly.
6. Formulation of Nanoemulsions
6.1. Screening for Excipients Solubility
The solubility of the drug in various oils, surfactants and
cosurfactants is determined by dissolving an excess
amount of the drug in small quantities of the selected oils,
surfactants and cosurfactants and mixed using a mixer. A
combination of oils can also be used for the determina-
tion of solubility.
The mixtures are allowed to equilibrate at ambient
temperature in an isothermal shaker [66]. Samples are
removed from the shaker and centrifuged. The super-
natant is filtered through a 0.45 µm membrane filter. The
concentration of the drug is determined in each oil, sur-
factant, cosurfactant and combination of oils by HPLC or
UV Spectrophotometer at their respective λmax.
6.2. Construction of Pseudoternary Phase
Diagram
In order to find out the concentration range of compo-
nents for the nanoemulsions, pseudo-ternary phase dia-
grams are constructed using water titration method at
ambient temperature [67]. Different phase diagrams are
prepared with varying weight ratios of surfactant to co-
surfactant. These ratios are chosen in increasing concen-
tration of surfactant with respect to cosurfactant and in-
creasing concentration of cosurfactant with respect to
surfactant for a detailed study of the phase diagrams. For
each phase diagram at a specific surfactant: cosurfactant
weight ratio, the ratios of oil to the mixture of surfactant
and cosurfactant are varied. The mixtures of oil, surfac-
tant and co-surfactant at certain weight ratios are diluted
with water drop-wise, under moderate magnetic stirring.
Visual observations are made for transparent and easily
flowable nanoemulsions. The physical state of the nanoe-
mulsions are marked on a pseudoternary phase diagram
with one axis representing the aqueous phase, the second
one representing oil and the third representing a mixture
of surfactant and cosurfactant at a fixed weight ratio [66].
6.3. Stability of Nanoemulsions
Stability of a dosage form refers to the chemical and
physical integrity of the dosage unit and when appropri-
ate, the ability of the dosage unit to maintain protection
against microbiological contamination [68,69]. Stability
of drug product is one of the problems associated with
the development of emulsions, microemulsions and na-
noemulsions. Nanoemulsions have been known to en-
hance the physical as well as chemical stability of drugs
[64,70,71].
Stability studies are performed on nanoemulsions by
storing them at refrigerator and room temperatures over a
number of months. The viscosity, refractive index and
droplet size are determined during this period of storage.
Insignificant changes in these parameters indicate for-
mulation stability.
Accelerated stability studies can also performed. In

Current State of Nanoemulsions in Drug Delivery 634
this instance, nanoemulsion formulation are kept at ac-
celerated temperatures and samples withdrawn at regular
intervals and analyzed for drug content by stability indi-
cating HPLC methods [69]. The amount of drug de-
graded and remaining in nanoemulsion formulation is
determined at each time interval.
7. Patents on Nanoemulsions
Though many of them have not reached the market yet, a
good number of patents have been received on nanoe-
mulsion formulations. Probably due to the challenges of
industrial scale production of nanoemulsions, few patents
have been transferred into commercial products. Some
patents related to nanoemulsions are presented in Table
1 [72-74].
8. Commercial Nanoemulsions
In spite of some difficulties, certain nanoemulsion for-
mulations have been translated into commercial products,
available in the market for use. Some commercial nanoe-
mulsion formulations are listed in Table 2 [1].
9. Nanoemulsion Formulation of
Phytopharmaceuticals
Phytopharmaceuticals have been formulated into microe-
mulsions. The same cannot be said of nanoemulsions.
Literature search showed few documented phytophar-
maceutical microemulsions with different degrees of ac-
tivity. A new self-microemulsifying drug delivery system
has been successfully developed to improve the solubility
Table 1. Patents on nanoemulsion for mulations.
Patent Claim Assignee Patent Number
Transparent nanoemulsion less than 100 nm based on fluid
non-ionic amphiphilic lipids and use in cosmetics or in
dermopharmaceuticals
L’Oreal (Paris, FR) US Patent number: 5,753,241
Nanoemulsions based on sugar fatty ethers and its uses in
the cosmetics, dermatological and/ophthalmological fields L’Oreal (Paris, FR) US Patent number: 6,689,371
Non-toxic antimicrobial compositions and methods of use NanoBio Corporation US Patent Number:
6,559.189 and 6,635,676
Method of preventing and treating microbial infections NanoBio Corporation US Patent Number: 6,506,803
Nanoemulsion of 5-aminolevulinic acid ASAT AG Applied Science and Technology
(Zug, CH) PCT/EP99/08711
Nanoemulsion of poorly soluble pharmaceutical active
ingredients and methods of making the same WO/2007/103294
Nanoemulsion based on ethylene oxide & propylene oxide
block copolymers and its use in the cosmetics, derma-
tological & ophthalmological fields
L’Oreal (Paris, FR) Patent Number: 6,464,990
Nanoemulsion based on glycerol fatty esters and its uses in
cosmetics, dermatological & ophthalmological fields L’Oreal (Paris, FR) Patent Number: 6,541,018
Nanoemulsions based on oxyethylenated or non-oxyethy-
lenated sorbitan fatty esters and its uses in cosmetics, der-
matological and ophthalmological fields
L’Oreal (Paris, FR) Patent Number: 6,335,022
Nanoemulsions based on phosphoric acid fatty acid esters
and its uses in cosmetics, dermatological and/ ophthalmo-
logical fields
L’Oreal (Paris, FR) Patent Number: 6,274,150
Table 2. Commercial nanoemulsion formulations.
Drug/Bioactive Brand Name Manufacturer Indication
Palmitate alprostadil Liple Mitsubishi Pharmaceutical, Japan Vasodilator, platelet inhibitor
Dexamethason Limethason Mitsubishi Pharmaceutical, Japan Steroid
Propofol Diprivan Astra Zaneca Anaesthetic
Flurbiprofenaxtil Ropion Kaken Pharmaceutical, Japan NSAID
Vitamins A, D, E and K Vitalipid Fresenius Kabi Europe Parenteral nutrition

Current State of Nanoemulsions in Drug Delivery 635
and oral absorption of curcumin [75]. Hesperetin, a fla-
vonoid with anti-inflammatory, UV-protecting and anti-
oxidant effect formulated into a microemulsion showed
enhanced in vitro permeation compared to the aqueous
and isopropyl myristate (IPM) suspension of hesperetin
[76]. Neem oil microemulsion has also been formulated
and its acaricidal activity investigated [77]. Since it is a
function of globule size, these microemulsions could also
be transformed to nanoemulsions through appropriate
technologies that could cause breakdown of the globules
to nano range.
10. Major Challenges of Nanoemulsion Drug
Delivery Systems
Production of nanoemulsions requires significant energy
input and although low-energy methods exist, they are not
for industrial scale manufacture, low energy methods
usually require high concentrations of surfactants and
generally do not yield stable nanoemulsions.
Nanoemulsions are produced on industrial scale via the
high-energy method which utilizes mechanical devices
such as high pressure homogenizers which are very costly,
extremely energy intensive and difficult to service. This
challenge clearly accounts for the low translation of
patented nanoemulsion formulations into commercial
products.
There is also the lack of understanding of the me-
chanism of production of submicron droplets and the role
of surfactants and cosurfactants as well as a lack of
understanding of the interfacial chemistry that is involved
in production of nanoemulsions [13]. For example, few
formulation chemists are aware of the phase inversion
temperature (PIT) concept and how this can be usefully
applied for the production of small emulsion droplets.
Finally, there is the fear of introduction of new systems
without full evaluation of the cost and benefits [13].
11. Future Industrial Perspectives
Nanoemulsion since its emergence has proved to be ver-
satile and useful novel drug delivery system. Nano-
emulsions are proposed for numerous applications in
pharmacy as drug delivery systems because of their ca-
pacity of solubilizing non-polar active compounds. Fu-
ture perspectives of nanoemulsion are very promising in
different fields of therapeutics or application in devel-
opment of cosmetics for hair or skin. One of the versatile
applications of nanoemulsions is in the area of drug de-
livery where they act as efficient carriers for bioactives,
facilitating administration by various routes. Their par-
enteral delivery has been adopted for supplying nutria-
tional requirements, controlled drug release, vaccine de-
livery and for drug targeting to specific sites. The advan-
tages and applications of oral drug delivery through these
vehicles are numerous where the droplet size is related to
their absorption in the gastrointestinal tract. Nanoemul-
sions have also been studied for their use in ocular deliv-
ery where pharmacological drugs are more sustained
compared to their respective solutions. Pulmonary and
transdermal routes are other successful ways of adminis-
tering nanoemulsified delivery system. Although there
have not been many reports of nanoemulsion applications
in other fields, there is a great potential for nanoemulsion
applications in other areas, such as in chemical and
physical sciences, agriculture and engineering.
In the production of nanoemulsions there are some
limitations, but pharmaceutical and food industries have
to adjust their technologies to accommodate nanoemul-
sion production. Considering the versatile platforms na-
noemulsions offer to formulation scientists in many fields,
retooling of production facilities or outright change in
technology of industries originally involved in produc-
tion of parenteral and macro emulsions will lead to a lot
economic windfall on the long run. This is because the
effect of difficulty in preparation and the high energy
input that may be involved in the production of nanoe-
mulsion may just be felt on the short run. In as much as
the cost of acquiring the technology for nanoemulsion
production may be high, the production of nanoemul-
sions involves only a few steps, compensating the many
steps involved in the production of some other products
of lower versatility. Due to the renewed interest in herbal
drug formulation, nanoemulsion may be the ideal deliv-
ery platform for these difficult-to-formulate phytophar-
maceuticals. Novel nanoemulsion dosage forms of herbal
drugs will lead to higher remuneration for the pharma-
ceutical industries.
With the advent of new instruments for high pressure
homogenization and the competition between various
manufacturers, the cost of production of nanoemulsions
will decrease. Fundamental research in investigation of
the role of surfactants in nanoemulsion production proc-
ess will lead to optimized emulsifier systems and more
economic use of surfactants will emerge. Nanoemulsions
can be manipulated for targeted delivery and this hold
significant promise in the area of oncology for the treat-
ment of tumors and drug delivery to the brain.
12. Conclusions
The importance of design and development of emulsion
nanocarrier systems aimed at controlling and/or improv-
ing required bioavailability levels of therapeutic agents
cannot be overemphasized. Reducing droplet sizes to the
nanoscale leads to some very interesting physical proper-
ties, such as optical transparency and unusual elastic be-
haviour. In the world of nanomaterials, nanoemulsions
hold great promise as useful dispersions of deformable

Current State of Nanoemulsions in Drug Delivery 636
nanoscale droplets that can have different flow properties
and optical properties ranging from opaque to nearly
transparent. Moreover, it is very likely that nanoemul-
sions will play an increasingly important role comer-
cially, since they can typically be formulated using sig-
nificantly less surfactant than is required for nanostruc-
tured lyotropic microemulsion phases. The article has
highlighted developments in this area. The various na-
noemulsion carrier formulations developed so far have
been identified. Nanoemulsions offer several advantages
for the delivery of drugs and are thus receiving increasing
attention as drug carriers for improving the delivery of
active pharmaceutical ingredients. They are applicable for
almost all routes of delivery and therefore hold promise
for different fields, be it cosmetics, therapeutics or biote-
chnology.
13. Expert Opinion
Nanoemulsion drug delivery systems can be prepared by
simple technology. They offer efficient targeting and
controlled drug delivery. They also offer efficient protec-
tion of the encapsulated bioactive materials and enhanced
delivery relative to most conventional dosage forms. The
prospects lie in the ingenuity of formulation experts to
utilize the advantages of nanoemulsion carriers in over-
coming peculiar problems of drug delivery such as per-
meation and in vivo stability. We recommend more re-
search efforts to exploit the potentials of emulsion
nanotechnology in drug delivery of small molecule drugs
and novel phytopharmaceuticals. This new technology
could be developed to overcome the poor absorption of
flavonoid nutrients and poor miscibility of these com-
pounds with the lipid contents of cell membrane linings.
The poor lipophilic affinity severely limits their ability to
cross the lipid-rich enterocyte membrane.
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