Adv Pharm Bull, 2021, 11(1), 56-67

doi: 10.34172/apb.2021.006
TUOMS
https://apb.tbzmed.ac.ir PRESS

Mini Review

Formulation and Applications of Lipid-Based Nanovehicles: Spotlight

on Self-emulsifying Systems
ID
Mohammed M. Mehanna* , Amina Tarek Mneimneh
Department of Pharmaceutical Technology, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon.

Article info Abstract

Article History: The drug delivery investigation field is continuously widened and adapted to overcome many
Received: 25 Nov. 2019 factors such as poor drug solubility, absorption, rapid metabolism, the variability of drug plasma
Revised: 31 Mar. 2020 levels, cellular efflux and many others. Due to resemblance to body constituents and their
Accepted: 19 Apr. 2020 biocompatibility, lipids offer a promising scheme for poorly water-soluble and lipophilic drugs.
epublished: 7 Nov. 2020 Various nanoparticles including vesicular systems, lipid particulate systems, and emulsion
systems provide some unique benefits as pharmaceutical carriers in drug and biomolecules
Keywords: delivery systems. Nowadays synthesis is directed toward simple, costless techniques, therefore,
• Drug delivery self-emulsifying systems have gained superiority over the other carriers. Self nano-emulsifying
• Lipids systems composed of oil, surfactant, and co-surfactant emulsified upon contact with an
• Solubility
aqueous medium, has been widely exploited. This review attempts to provide a comprehensive
• Self-nanoemulsifying system
interpretation of different types of lipid-based carriers emphasizing on the self-nanoemulsifying
system, why it is gaining interest, formulation, composition, and applications.

Introduction distributions. High-pressure homogenization technique is

Synthesizing new drugs alone is not sufficient to establish most commonly used and it might cause drug degradation
advancement in drug therapy. The conventional drug in high molecular weight compounds.
delivery systems are destined to failure, due to many Lipid-based carriers are recognized as safe and efficient
factors, mainly low drug solubility, poor absorption, hence they have been used as alluring candidates for
enzymatic degradation, rapid metabolism, cellular efflux pharmaceutical, as well as vaccines, diagnostics, and
and variability in plasma concentration.1 nutraceutical formulations. Therefore, lipid-based drug
Incorporation of lipids in drug delivery has been a trend delivery (LBDD) systems have gained much importance
in the past decades. Lipid-based carriers are composed in recent years due to their ability to improve the solubility
of phospholipids, cholesterol, cholesterol esters and and bioavailability of drugs with poor water solubility.
triglycerides among others.2 The physiochemical diversity Self-emulsifying drug delivery systems which belongs
of lipids, their biocompatibility and their resemblance to LBFs are efficient, sophisticated, and more patient
to body tissue constituents offer a promising system for compliant formulation method for poorly water soluble
poorly water-soluble and lipophilic drugs.3 Lipid carriers drugs. It may enhance drug solubility, dissolution behavior
(LCs) provide several advantages that enable it to be an ideal in the GIT, gut permeability and thus may increase the
vehicle for drug delivery. Namely; it can be manipulated absorption of the poorly water soluble model drug. This
according to product requirements whether its disease paper illustrates different types of LBFs to be precise,
conditions, route of administration, stability, toxicity emulsions, vesicular systems, and lipid particulate systems
or efficacy. Besides, lipid-based formulations (LBFs) and their subcategories, focusing on self-nanoemulsifying
can provide a controlled release delivery based on their systems and their applications in the pharmaceutical field.
biocompatibility with body tissue after administration, it’s
not susceptible to erosion phenomena, the feasibility of Materials and Methods
scaling up,4 moreover, it provides enhanced drug loading, In this review, related articles and research papers from
ability to carry both lipophilic and hydrophilic drugs and different reliable researchers and database such as Elsevier,
stability. Springer and MDPI were collected and discussed. The
However, LCs face certain limitations such as, lipid search was constructed based on the following keywords:
crystallization that leads to polymorphism with different lipid-based drug delivery, self-nanoemulsifying system,
drug loading capacity, different shapes, and various kinetic lipid vesicular systems.

*Corresponding Author: Mohammed M. Mehanna, Tel: 0961/70718661, Email: mmhanna@bau.edu.lb

© 2021 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits
unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required
from the authors or the publishers.
 Highlights on self-nanoemulsifying systems

Type of LBDD system incorporate both hydrophilic and lipophilic drugs, with
LBDD systems are classified into vesicular systems, lipid high entrapment efficiency, target delivery to the site of
particulate systems, and emulsion systems. action, increase bioavailability of poorly soluble drugs,
reduce cost, adverse effects and toxicity.12 Semalty et al
Vesicular systems developed pharmacosomes of aceclofenac with higher
Liposomes drug content 91.88% (w/w). The prepared pharmacosome
Liposomes are microscopic, colloidal, concentric showed higher solubility than aceclofenac alone, with
bilayered vesicles (Figure 1A) with diameter that ranges increased drug release over 4 hours during dissolution
from 0.02 to 10 μm,5 constituted mainly of amphiphilic study.13
phospholipids.6 Upon contact with an aqueous medium,
they assemble as a complex to shield their hydrophobic Phytosomes/Herbosomes
parts. Stealth porphyrin-phospholipid liposomes with Phytosomes are cell-like design; amphiphilic and that
balanced lipid ratios, has been established to prolong the what helps in increasing the bioavailability of active
blood circulation time of doxorubicin (Dox). The half-life phytochemical constituents as they can easily permeate
of Dox in mice was 21.9h and stable for months. Following and cross the lipid membrane. These systems have gained
intravenous injection, Dox deposition increased by a lot of interest lately. Boswellic acid uses have been limited
7-folds subcutaneously.7 This type of liposome was able to for its low bioavailability and high first pass hepatic
accomplish both rapid light induced release rate and high metabolism. Sahu et al formulated boswellic acid loaded
storage and serum stability with long blood circulation. phytosomes. The preparation showed a high sustained
Many liposomal preparations are in phase Ⅰ or Ⅱ clinical release (80%) for 8hrs, indicating rapid penetration
trials such as annamycin-loaded liposomes for treating through the skin may be because of nanosized vesicular
breast cancer and acute lymphocytic leukemia.8 Liposomal size The entrapment efficiency increased to 74% with the
drug formulations are also available for intravenous and increase in concentration of cholesterol and ethanol.14
intramuscular applications. For example, Exparel® (2011)
is a bupivacaine intravenous used for pain management, Transfersomes/Penetrosomes
and Marqibo® (2012) is a vincristine used for acute Transfersomes or elastic liposomes (Figure 1B); these
lymphoblastic leukaemia.9 On September 2018, the FDA vesicular systems are a type of manipulated liposomes
approved a new drug, Arikayce (amikacin liposome that are ultra-deformable due to the presence of edge
inhalation suspension), for the treatment of lung disease activator or surfactants, thus able to deliver the drug into
caused by Mycobacterium avium complex in patients who or through the skin to reach systemic circulation with
do not respond to conventional treatment.10 high entrapment efficiency. Mehanna et al developed
penetrosomes for the transdermal delivery of tadalafil.
Niosomes The deformability of penetrosomes provided a potential
In the structure and function, niosomes resemble delivery of tadalafil to avoid its oral administration side
liposomes. They are minute multi-lamellar formulated effects.15
by the addition of non-ionic surfactant to cholesterol
with successive hydration in aqueous media (Figure 1C). Ethosomes
Niosomes can overcome liposomes drawbacks such as Ethosomes are ethanolic liposomes (Figure 1D) that act as
chemical instability, purity of phospholipids and high a non-invasive carrier system to deliver biologically active
cost, also niosomes provide high penetration ability. Jyouti agents (hydrophilic and lipophilic) to deeper layers of the
et al prepared inhalable curcumin loaded freeze-dried skin and systemic circulation. The presence of ethanol
cationic small unilamellar niosomes by a reverse-phase provides high stability and disrupts the skin lipid bilayer
evaporation method. The cationic niosomes showed to enhance skin penetration. These ethanolic vesicles can
higher release 94%, with long term stability. The freeze- incorporate as well as amphiphilic molecules.16 Bodade
dried cationic niosomes inhibited the A549 lung cancer et al showed that ethosomal system was able to enhance
cells proliferation at the IC50 of 3.1 μM, significantly the entrapment efficacy of repaglinide (75% to 92%). The
lower than 7.5 μM of optimized freeze-dried niosomes ex-vivo skin permeation test revealed higher permeation
and curcumin suspension 32 μM, this formulation (64%–97%) through excised rat skin when compared
succeeded in overcoming the poor physiochemical and to free drug for treatment of diabetes with a sustained
biocompatibility problems of delivering curcumin to release behavior (69% over 24h) and thus reducing dose
cancerous lung cells.11 frequency.17

Pharmacosomes Aquasomes
Pharmacosomes are colloidal vesicles, micelles or Aquasomes are self-assembled ceramic nanostructures;
hexagonal assemblies that are attached covalently they consist of three layers. A solid nanocrystalline core
to phospholipid with a nanometric size. They can made up of polymers (albumin, acrylate or gelatin) or

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ceramic (diamond or calcium phosphate), coated with Lipid particulate systems

carbohydrate film on which active molecules are adhered These nanoparticles are formulated from solid or a
to, in addition to tin oxide layer for structural stability.18 mixture between solid and liquid lipids and emulsifiers.
The main application for aquasomes is delivering vaccines, Lipid nanoparticulate systems have advantages over other
insulin, red blood cells substitute for hemoglobin, enzymes systems specifically; ease of scaling up, the biodegradable
and gene therapy.19 materials used, low toxicity, drug solubility enhancement
and the possibility of combining hydrophilic and lipophilic
Novasomes drug.25 All of those explain the increased interest in
Novasomes are modified types of liposomes with a diameter the field of lipid nanoparticles in the different routes of
ranging from 0.1 to 1 μm. It is a mixture of polyoxyethylene administration including peroral, dermal, parenteral,
fatty acids, free fatty acids, and cholesterol, forming 2-7 pulmonary, in addition to nasal, ocular and cerebral
bilayers surrounding an amphipathic core. Novasome applications.26–29
surface charge can be neutral, negative or positive.20 Abd-
Elal et al prepared intranasal zolmitriptan novasome that Lipospheres
showed a significant increase in brain targeting (99%) Lipospheres or lipid microspheres are encapsulating
compared to the intravenous administration for migraine systems with a diameter range between 0.1-100 μm. They
attacks.21 consist of hydrophobic solid triglyceride fat core stabilized
by phospholipids on its surface, and an innermost core
Vesosomes holding the therapeutic agent and dispersed in a lipid
Vesosomes are a multi-compartment framework with matrix. Lipospheres are widely used for parenteral delivery
separate inner compartments withdrawn from the external as they possess stability over a while at room temperature
membrane. Each can incorporate varied materials and with no particular undesirable effects, even at high dose
have a different composition. Due to their multi-structure, levels. These are employed for the controlled delivery of
they protect the encapsulated contents and demonstrates several types of drugs including local anesthetics, anti-
extended-release of drug.6 inflammatory compounds, anticancer, vaccines, and
antibiotics agents.30 Lipospheres can be prepared by a
Colloidosomes solvent evaporation method, melt dispersion technique,
Colloidosomes are microcapsules whose shells are sonication technique and evaporation method.31 Nasr
composed of colloidal particles.22 Microencapsulation et al proved that lipospheres can be a promising tool
enables the controlled release of active ingredients, thus for topical delivery of aceclofenac possessing superior
colloidosomes are the choice of systems for encapsulation anti-inflammatory effects compared with the marketed
and controlled drug release.23 Nan et al prepared chitosan- product along with high stability and drug entrapment.32
coated alginate monodisperse colloidosomes for oral
delivery of insulin with high drug encapsulation efficiency Solid lipid nanoparticles
(up to 96.7%) and an obvious pH-sensitive release profile.24 Solid lipid nanoparticles (SLNs) are the first type of lipid

Figure 1. Schematic representation of the different types of lipid-based vesicular delivery systems. (A) Conventional liposomes generally consist of a lipid bilayer
composed of phospholipids and cholesterol, which encloses an aqueous core. Liposome characteristics can be modified by the addition of surfactants to form
(B) Transfersomes® and (C) niosomes (depending on the ratio of phospholipid to surfactant), or relatively high concentrations of ethanol to form (D) ethosomes.
Modified from Hua.33

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 Highlights on self-nanoemulsifying systems

nanoparticles reported for drug delivery. SLNs were

developed in the middle of the 1990s as an alternative for
liposomes, emulsions, and polymeric nanoparticles. This
colloidal delivery system is composed of biocompatible
lipid nucleus and an amphiphilic surfactant outer shell
with a size of 50 to 1000 nm (Figure 2). Depending on
drug thermal stability, it is incorporated in the solid lipid
colloidal system either by cold or hot homogenization
techniques.34 The advantages of SLN systems over
others are compromised by their nano-size range which
offers a narrow window of distribution required for
targeted site delivery, protection for the incorporated
drug from chemical degradation, organic solvents free
and thus ease of industrial scaling up.35 Commonly used
methods for the preparation of SLNs are high-pressure
homogenization, solvent emulsification, evaporation or
diffusion, supercritical fluid, ultrasonication or high-
speed homogenization and spray drying.36 Kelidari
et al formulated voriconazole-loaded SLNs by probe Figure 2. Schematic illustration of SLN structure versus NLC structure, where
ultrasonication technique. His study showed for the first NLC advantages over SLNs are highlighted. Reproduced from Ref.39

time that this system can be employed as an effective

delivery system for voriconazole against azole-resistant improved and prolonged reduction in the total cholesterol
Aspergillosis fumigatus isolates, as SLNs increased its and non-high density lipoprotein compared to drug
dissolution and bioavailability.37 SLNs drug release is suspension with 4-folds increase in its bioavailability.42
characterized by three patterns; homogeneous release During storage, SLN and NLC act differently (Figure 3).
when the melting points of drug and lipid are in steady- SLN is formulated completely from solid lipids; therefore,
state; lipid-enriched core when lipids melt at higher after crystallization, it forms a rigid core restricting
temperature than drug and drug encapsulated core the movement of drugs within the core, leading to the
when lipid liquefies at point earlier than drug. Some expulsion of the drug into dispersion media. Due to this
disadvantages face SLNs include particle size growing and phenomenon, entrapment efficiency is lowered. However,
imperfection in solid core upon drug loading, variable the composition of NLCs is the mixture of solid and
gelation tendency, drug escape during storage and low liquid lipids, thus an imperfect core is formed. Such core
incorporation due to crystalline SLNs core.38 provides higher drug loading and enough space for the
incorporation of the drug. Hence during storage, the drug
Nanostructure lipid carriers is not expelled out of the core.43
The second generation of lipid carriers is nanostructured
lipid carriers (NLCs), which are unstructured solid lipid Lipid-drug conjugates
matrix prepared by blending solid and liquid lipids Lipid-drug conjugates are drug molecules that have been
with an aqueous phase along with surfactant or mixture covalently modified with lipids. According to the type of
of surfactants (Figure 2). Among many preparation drug and the lipid used different conjugation strategies are
techniques, a high-pressure homogenization process is the utilized including; conjugation with lipids and chemical
preferred one as no solvent is needed. The hot surfactant bonding. Lipid-drug conjugates offer several advantages,
solution is added to the hot blended and melted lipids with including specific site targeting, low toxicity, and better
the drug, the resulted microemulsion is homogenized drug loading into delivery systems, enhanced oral
under high pressure to yield hot nanoemulsion. The bioavailability, and tumor targeting. Pharmacokinetics
nanoemulsion is cooled and NLC is formed. This process study showed that linking paclitaxel to docosahexaenoic
can be easily scaled up.40 NLCs have three types, imperfect acid provides a sustained high drug concentration in
type, amorphous type, and multiple types. The use of plasma for a longer time compared with paclitaxel alone,
generally recognized as safe (GRAS) materials, the large- thus increasing dose by 4.4-folds with no increase in
scalable production, and improved drug safety allow toxicity.44
NLCs to be an attractive delivery system candidate for the
pharmaceutical market. Meloxicam NLC gel was prepared Emulsions
by Khurana et al and showed sustained release pattern, Emulsions are liquid-liquid heterogeneous colloidal
enhanced skin permeation and a better deposition into systems composed of at least two immiscible liquids,
the dermis in comparison with control meloxicam gel.41 water, and oil that are uniformly dispersed as fine
Fathi et al prepared oral simvastatin NLCs that showed droplets by mechanical agitation. Emulsions are usually

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Mehanna and Mneimneh

small size, they appear transparent or slightly turbid and

have good stability against flocculation, coalescence or
phase separation.50 There are many structural similarities
between nanoemulsion and microemulsion, however,
there are also some vital differences represented in Table
1 and there has been great misperception about the exact
nature and classifications of these different systems.51
The advantages of NE have appealed scientists to explore
them in various fields especially the pharmaceutical drug-
delivering area. Whether O/W or W/O, nanoemulsions
can solubilize both hydrophilic and hydrophobic drugs
and thus enhance their oral bioavailability such as
Figure 3. Illustration of stability of SLN and NLC during storage. Reproduced curcumin, ramipril and ezetimibe.53-55 Nanoemulsions
with permission from Salvi and Pawar.43
have long term stability and hence provide long shelf-life
of the formulated agents. Encapsulation in nanoemulsion
classified as oil-in-water (O/W) or water-in-oil (W/O) protects therapeutic agents against enzymatic and chemical
depending on the nature of the continuous phase. They factors. They are biodegradable, biocompatible and easy to
are thermodynamically unstable, yet they can be stabilized prepare. The rapid skin penetration, low viscosity and the
by an emulsifying agent mainly surfactants.45 almost translucent nature of the nanoemulsion provide
a visual appeal and patient compliance especially with
Microemulsions dermal, ‘roll-on’-type formulations, sprays, and gels.56
Microemulsions are clear, thermodynamically stable Fabricating methods used for nanoemulsion preparation
isotropic mixture of oil, water, surfactant, and co- is divided into high energy and low energy emulsification
surfactant, which were first introduced by Hoar and methods57 as illustrated in Figure 4.
Schulman in 1940s.46 Microemulsions show several
interesting characteristics including enhancing drug High energy methods
solubility, thermodynamic stability, ease of preparation High-pressure homogenization
and scaling up, and high drug loading capacity.47 High-pressure homogenization is the widely used
Microemulsions are widely formulated in the field technique in the preparation of nanoemulsion. This
of cosmetics and cosmeceutical, especially for skin method can be used on a large scale; however, a high
and hair preparations. Clobetasol propionate-loaded amount of energy and the evolved temperature during
microemulsion based gel prepared by Patel et al showed emulsification are not suitable for thermosensitive
that higher drug permeation into the skin microemulsion therapeutic agents. It provides high pressure up to 20000
(60.33 ± 4.67%) compared with the marketed product psi that produces nanoemulsion in very small particle
(37.77 ± 0.77%) with better retention in the skin and size (up to 1 nm), yet the small size of the nanoemulsion
minimal irritation potential thus proved to be a promising depends on the number of cycles, as the number of
formulation for the effective treatment of vitiligo.48 homogenization cycles increases the smaller the droplet
size is produced. The major drawbacks of high-pressure
Pickering emulsions homogenization are poor productivity and product
Pickering emulsions are simple emulsions that depend on deterioration.59
lipid having inner nanostructures stabilized by silica, clays,
calcium carbonate or titanium dioxide. This system can be Microfluidization
any type of emulsions, oil/water (o/w), water in oil (w/o) Microfluidization shares the same principle of high-
or even multiple emulsions stabilized by solid particles pressure homogenizer, yet the difference is utilizing
rather than surfactant.6 The main advantage of this microchannels to produce the droplets. In this technique,
system is its resistance to coalescence due to the stability the cycle is repeated until the desired size is achieved;
provided by solid particles. Shah et al prepared chitosan- sometimes nitrogen atmosphere is used to filter large
tripolyphosphate nanoparticles stabilized Pickering droplets.57 The advantages of this method include smaller
emulsion to deliver curcumin. The stability of curcumin droplet, higher efficiency of droplet disruption and more
in the Pickering emulsion was significantly improved with uniform droplet distribution. However, microfluidization
a sustained release profile over a long period.49 is expensive and not reproducible on a large scale.60

Nanoemulsions Ultrasonication
Nanoemulsions (NE), oil-in-water (o/w) or water-in-oil This method produces kinetically stable nanoemulsions.
(w/o), are heterogeneous dispersion with droplet size in Sound waves more than 20 kHz are applied and a sonicator
the nanometric range between 20-200 nm. Due to this probe is introduced into the dispersion of liquids with

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Table 1. Differences between nanoemulsions and microemulsions51,52

Characteristics Nanoemulsions Microemulsions

Definition Colloidal system of two immiscible liquids Swollen micelle

Only formed when surfactants are first mixed
Order of mixing Order of mixing does not matter
with oils
Thermodynamic stability Non-equilibrium Equilibrium

Kinetic stability Stable Less stable

Size <200 nm 10-100 μm

Droplet size control Depend on surfactant/oil ratio Exhibit different phases with different nanosize morphology

Destabilization Ostwald ripening only Dilution and temperature change

Spontaneous emulsification (depends upon temperature,
Preparation High energy or low energy methods
composition, and pressure)
Characterization methods with dilution
Applicable Invalid as the droplet size increase
step
Dilution and temperature Robust Strongly affected

surfactant and co-surfactant to create mechanical vibration the emulsification path allowing the incorporation of the
and cavitation, providing high energy to produce small- oil in the cubic phase easing its emulsification.64 Phase
sized droplets.61 Ultrasonication is used on a small scale so inversion composition method is simple, low cost and
it’s not suitable for large volume and care must be taken to doesn’t require organic solvent.65
prevent coalescence.
Solvent diffusion or spontaneous emulsification
Low- energy methods The solvent diffusion method depends on spontaneous
Phase inversion temperature emulsification without the need for special equipment. It
Phase inversion temperature (PIT) depends on the ability is achieved by simply mixing oil first into surfactant and
of polyoxyethylene-type surfactant (nonionic) to change injected into the aqueous phase at a fixed temperature.66
their hydrophilic nature into lipophilic ones depending The spontaneity of the emulsification process depends on
on the temperature.61 This method was first introduced optimizing certain parameters namely; the composition
by Shinoda.62 If the emulsion prepared at a temperature and volume of the aqueous and organic phase, temperature,
near phase inversion temperature then rapidly cooled pH, ionic strength, in addition to the mixing conditions
or heated, a small size nanoemulsion with narrow size such as stirring speed, rate and order of addition.67 The
distribution and kinetically stable one will be formed. If main disadvantage of this method is its limitation to small
w/o emulsion is rapidly cooled, it converts to o/w, on the volumes of surfactant and oil and the utilization of organic
opposites if o/w emulsion is rapidly heated, it converts to solvents in some cases.
w/o emulsion.63 The advantage of this method is its low
cost yet it is only limited to non-ionic surfactants. Applications of nanoemulsion
Nanoemulsions have been used in most routes of drug
Phase inversion composition administration, namely, topical, ocular, intranasal,
This method is similar to phase inversion temperature, but intravenous and oral delivery.
the difference is that can be achieved by changing the oil Intranasal based nanoemulsion was prepared by
to water ratio or surfactant properties. Maestro et al used Mahajan et al where the optimized nanoemulsion showed
this method to convert water/oleylammonium chloride– a high percentage of drug targeting efficiency (2919.261 ±
oleylamine–C12E10/hexadecane into o/w nanoemulsion 5.68) and nose-to-brain drug direct transport percentage
by introducing a direct cubic liquid crystal phase along (96.574% ± 0.76) proving that this system is a good carrier

Figure 4. Various methods for nanoemulsion fabrication. Reproduced with permission from Date et al.58

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Mehanna and Mneimneh

for saquinavir mesylate to CNS through intranasal route.68 varying saturation degrees have been used widely for the
Topical nanoemulsion prepared by Oliviera et al for the design of SNEDDS; when used with surfactants these
treatment of dermatoses. The ex-vivo permeation study semisynthetic derivatives form good emulsification
showed that 8.5% of the applied 8-methoxy psoralen systems for oral administration.77 Lipids not only solubilize
dose permeated through the biological membranes, and a large number of lipophilic drugs but also enhance the drug
retention in viable skin induced by the NE was almost transport via the intestinal lymphatic system increasing its
two-fold higher than a compounded cream (5.04 ± 0.30 absorption from the GIT. Thomas et al. formulated two
μg cm−2). These results proposed that the developed SNEDDS with medium-chain (MC) and long-chain (LC)
nanoemulsion is a promising alternate for 8-methoxy lipid, and found that MC-SNEEDs can incorporate more
psoralen topical therapy.69 drug than that of LC-SNEDDS.78 Surfactant is crucial for
Thermosensitive in-situ ocular diclofenac nanogel the emulsification of the SNEDDS, for achieving high
prepared by Chauhan and Batra as a good replacement emulsifying performance, the HLB of the surfactant used,
for conventional eye drops due to higher permeation and their cloud point, viscosity and solubility in the oil phase
prolonged precorneal residence time. The formulated affect formulation of SNEDDS, the nanoemulsion region
nanoemulsion in-situ gel showed drug release for a longer and droplet size.58 The formulation of effective SNEDDS
duration of time (8 h) as compared to the marketed eye requires high concentration of surfactants, and therefore
drops (3 h), thus sustained drug delivery was achieved, the incorporation of the co-emulsifiers, co-surfactants or
and also the developed formulation exhibited higher solubilizers in SNEDDS modulate self-nanoemulsification,
permeation across goat cornea in 4 hours. Hence, expand the self-nanoemulsification region, increase drug
nanoemulsion was found to be.70 loading, and droplet size of nanoemulsion.58
Vehicle in cancer chemotherapy due to their ability
to prolong rate of drug release after intramuscular and Advantages of SNEDDS
intratumoral injection and enhance the transport of SNEDDS provides long term stability due to the absence of
anticancer agents via lymphatic system.71 Piplartine was water, orally SNEDDS suffer from no palatability problems
formulated into nanoemulsion by Fofaria et al and did not as they can be filled into capsules or formulated into
exhibit any toxicity upon administration for 60 days with tablets.58 The success of any drug delivery system depends
1.5-fold increase in oral bioavailability as compared to free on its industrial applicability, ease of manufacture, scale-
piplartine and clear anti-tumor activity at a dose of 10 mg/ up, and transformation from research to the market. Due
kg in melanoma tumor-bearing mice.72 to high surfactant/co-surfactant to oil ratios, SNEDDS
Cosmetics; the active constituents of NE are easily have more drug-loading capacity which is the success of
absorbed due to the small size of the droplet and can this system. Since the rapid onset of action is required in
reduce the water loss from the skin, providing an elegant many pathological cases, such as hypertension, angina,
and stable product that can be formulated as moisturizers and inflammation, SNEDDS enhances the oral absorption
and creams. Opuntia ficus-indica (O/W) nanoemulsion of the drug and thus provides fast onset of action.
presented suitable stability for at least 60 days and was able
to increase the water content of the stratum corneum for Spontaneous emulsification process
5 h after application showing its moisturizing efficacy.73 The mechanism of spontaneous emulsification is not
fully understood, as it can occur through different
Self-nanoemulsifying drug delivery system (SNEDDS) mechanisms. According to what described by Reiss, self-
SNEDDS is an isotropic mixture of oil, surfactant and emulsification takes place when the entropy change that
co-surfactant emulsified with mild agitation with the favors dispersion is greater than the energy required
therapeutic agent. When diluted with aqueous media with to increase the surface area of the dispersion.79 In the
mild stirring, it instantly produces oil-in-water micro or conventional emulsion systems, surfactants decrease the
nanoemulsion.74 Upon mild agitation followed by dilution interfacial energy by creating a layer around the internal
with aqueous media, these systems can spontaneously phase of globules acting as a barrier against coalescence
form fine (oil in water) emulsion with a globule size but still, these emulsions are thermodynamically unstable.
less than 200 nm.61 These small droplets containing the In a spontaneous self-emulsifying system, the free energy
dissolved drug in the oil phase have enhanced surface needed to form the emulsion is either very low or negative.
area and thus faster digestion and absorption in the Groves and Galindez reported that the liquid crystalline
gastrointestinal tract.75 The increase in the surface area phase formed between the oil/surfactant and water phases
provides better drug solubility and permeation. The drug effectively swells allowing spontaneous formation of an
can be formulated in a dose less than 25mg and up to 2 g.76 interface between the oil droplets and water.80

Composition of self-nanoemulsifying drug delivery system Application of self-nanoemulsifying drug delivery system
Lipid is an important ingredient in SNEDDS formulation. The strength of SNEDDS is not limited to augment the
Modified long and medium-chain triglyceride oils with dissolution rate only it is extended to overcome mucus

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gel barrier, delivery of biomolecules, and even drug ordinary gel, permeability coefficient increased from 5.93
targeting.81 to 33.48 cm-2 min-1and drug deposition in the skin from
222.7 to 1287.2 μg.91 Bifonazole-loaded self-emulsifying
Solubility and bioavailability improvement system was formulated by Alhakamy and Hosny utilizing
When the drug is incorporated into SNEDDS, it will be Peceol®, Kolliphore® EL and Plurol Oleique® 497 for the
solubilized at the site of absorption, making it easy to topical delivery of this antifungal agent, the nano size of
pass the biological membrane and reach the site of action, the formula enhanced drug antifungal activity and its
hence the bioavailability problem of the drug is bypassed. permeability by 1.85 and 2.179 folds compared to aqueous
Joshi et al formulated SNEDS of curcumin that showed suspension, due to the tendency of Kolliphore® EL toward
improvement in Cmax and AUC(0-t) by 1632.1% and 7411.1%, the cellular membrane and the formation of micelles by
respectively compared to an aqueous suspension of free Plurol Oleique® 497, thereby, extracting the lipids from the
curcumin, with better results against diabetic neuropathy.82 skin and enabling greater penetration of bifonazole across
Glipizide is an oral antidiabetic drug. Chemically is a skin deeper layer proving that this system is an efficient
weak acid with poor water solubility. Glipizide solid vehicle for transdermal delivery.92
SNEDS has been formulated by Dash et al where the
optimized formula showed an enhancement in solubility Bio-molecules delivery
and dissolution.83 Shakeel et al also formulated self- Bio-molecules (lipids, proteins, genes, and
nanoemulsifying drug delivery system of indomethacin to polysaccharides) have earned great attention as modern
improve its solubility as well as in-vitro dissolution rate, therapeutics due to their high selectivity, specificity, and
the solubility study results showed 4573 folds increase low-toxic effects. Yet they suffer from low bioavailability
in solubility, and drug release was faster with 93% of the due to poor permeation because of their large size and
drug was released in first 15 min of study as compared to hydrophilicity (proteins) and enzymatic degradation.93
48% from commercial capsules.84 Researches have shown Polypeptide-k (PPK) is a peptide extracted from
that SNEDDS can be achieved in different formulations dried ripened seeds of Momordica charantia that has
without compromising bioavailability (Table 2). been reported for its antidiabetic activity by inhibiting
α-glucosidase and α-amylase, yet its oral delivery is still
Mucus permeation enhancer a challenge due to limited dissolution, bioavailability
Mucus barriers are present in buccal, ocular and nasal along with the enzymatic degradation in the GIT.94 Self-
cavities, also in intestine, lung, and vagina. Secretion and emulsifying delivery system of PPK was stable against pH
clearance rates of mucus are fast, so the mucus barrier change, dilution and temperature changes, with enhanced
creates a challenge for drug carriers to reach the epithelial dissolution profile and a potentiated antidiabetic
surface and remains there for the required time. Due to activity.94 Gene therapy requires the availability of
the hydrophobic surface of the nanodroplets of SNEDDS, genetic material at the targeted site. Gene therapy is a
the interaction with the mucus barrier is minimal and promising tool for the progression of many diseases
enables it to pass without being entrapped.90 Current such as cancer, AIDS, Parkinson’s and Alzheimer’s. The
treatments for melanoma and psoriasis are inefficient challenge with delivering non-viral genes is due to their
due to poor transcutaneous permeation, thus creating poor cellular uptake and enzymatic degradation of the
a need for a new colloidal carrier. Pund et al prepared DNA-based drugs especially in the oral route. DNA was
leflunomide nanoemulgel for the localized treatment of incorporated in the lipid phase of the nanoemulsion,
psoriatic as well as melanoma. The ex-vivo permeation creating a protective effect against degradation via DNase
study showed a significant enhancement in the flux of I enzyme. It was also reported that the incorporation
5.65 times with nanoemulgel formulation compared to into the lipid phase and the hydrophobic ion pairing

Table 2. Summary of some research articles describing different SNEDDS formulations

Drug Excipients Formulation Bioavailability (in-vitro/in-vivo results) Reference

Controlled release osmotic
Cyclosporine A Labrafil® Transcutol®, Cremophor® 80% drug release in 12 h 85
pump tablets

Ziprasidone Capmul® Labrasol®, PEG 400* Sustained release pellets 95% drug release within 12 h 86

96.5% drug released within 15 min in-vitro

Embelin Capryol®, Acrosyl®,PEG 400* Tablets 87
compared to 5% pure drug

S-SNEDDS powder-filled
Glimepiride Miglyol®, Tween®, PEG 400* 95% in-vitro drug release within 1 h 88
hard gelatin capsules
3–3.5-Fold increased dissolution rate with
Valsartan Capmul®, Labrasol®, Tween® Tablets 89
almost all drug released within 1 h

*Polyethylene glycol (PEG 400)

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didn’t decrease the uptake or the transfection efficiency characterization of lipid microparticles as a drug carrier
compared with marketed liposomal transfection reagent.93 for somatostatin. Int J Pharm 2001;218(1-2):133-43. doi:
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Conflict of Interest
i-formulation and physicsochemical characterization.
The authors report no conflict of interest in this work
Drug Dev Ind Pharm 2015;41(5):714-21. doi:
10.3109/03639045.2014.900075
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