Expert Opinion On Drug Delivery From Nan

Expert Opinion on Drug Delivery
ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: http://www.tandfonline.com/loi/iedd20
From nanoemulsions to self-nanoemulsions, with

recent advances in self-nanoemulsifying drug
delivery systems (SNEDDS)
Fiza Ur Rehman, Kifayat Ullah Shah, Shefaat Ullah Shah, Ikram Ullah Khan &
Gul Majid Khan
To cite this article: Fiza Ur Rehman, Kifayat Ullah Shah, Shefaat Ullah Shah, Ikram Ullah Khan
& Gul Majid Khan (2016): From nanoemulsions to self-nanoemulsions, with recent advances in
self-nanoemulsifying drug delivery systems (SNEDDS), Expert Opinion on Drug Delivery, DOI:
10.1080/17425247.2016.1218462
To link to this article: http://dx.doi.org/10.1080/17425247.2016.1218462
Accepted author version posted online: 02

Aug 2016.
Published online: 02 Aug 2016.
Submit your article to this journal
Article views: 6
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=iedd20
Download by: [Kifayat Ullah Shah] Date: 07 August 2016, At: 08:56
Publisher: Taylor & Francis
Journal: Expert Opinion on Drug Delivery
DOI: 10.1080/17425247.2016.1218462
REVIEW
From nanoemulsions to self-nanoemulsions, with recent advances in self-nanoemulsifying

drug delivery systems (SNEDDS)
Fiza Ur Rehman1, Kifayat Ullah Shah1, Shefaat Ullah Shah2*, Ikram Ullah Khan3*, Gul
Majid Khan1
Downloaded by [Kifayat Ullah Shah] at 08:56 07 August 2016
1
Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
2
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, D.I.Khan, KPK,
Pakistan
3
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College
University Faisalabad, Pakistan
*
Corresponding Authors:
Shefaat Ullah Shah
2
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, D.I.Khan, KPK,
Pakistan
Tel: 00923365140682, 00923482818735
Emails: shefaat-ullah.shah@univ-lorraine.fr
shefaatbu@gmail.com
Ikram Ullah Khan

3
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College
University Faisalabad, Pakistan
Email: ikramglt@gmail.com
Tel: 00923215014820
ABSTRACT
Introduction: Lipid-based drug delivery systems (LBDDS) are the most promising technique to
formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic
performance of hydrophobic drugs and has become an essential approach in drug delivery
research. Self-nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that
combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the
formulation of drugs with poor aqueous solubility.
Areas covered: The review in its first part shortly describes the LBDDS, nanoemulsions and
clarifies the ambiguity between nanoemulsions and microemulsions. In the second part, the
review discusses SNEDDS and elaborates on the current developments and modifications in this
area without discussing their associated preparation techniques and excipient properties.
Expert opinion: SNEDDS have exhibit the potential to increase the bioavailability of poorly
water soluble drugs. The stability of SNEDDS is further increased by solidification. Controlled
release and supersaturation can be achieved, and are associated with increased patient
compliance and improved drug loads, respectively. Presence of biodegradable ingredients and
ease of large-scale manufacturing combined with a lot of “drug-targeting opportunities” give
SNEDDS a clear distinction and prominence over other solubility enhancement techniques.
Keywords: Colloidal dispersions, Drug targeting, Lipid based drug delivery system (LBDDS),
Nanoemulsions, Self nanoemulsifying drug delivery system (SNEDDS), Solubilization.
Article highlights box:
• Nanoemulsions provide the benefits of both “lipid formulations” and “nanotechnology”.

• Nanoemulsions and microemulsions are fundamentally different colloidal dispersions and
correct distinction between them is vital as it influences the selection of fabrication and
characterization methods.
• These colloidal dispersions have many structural similarities but in contrast to
microemulsions, nanoemulsions are thermodynamically unstable and kinetically stable
systems.
• Self nanoemulsifying drug delivery system (SNEDDS) has reinstalled the prominence of
nanoemulsions by coping up the issues with nanoemulsions and lifting up the drug
bioavailability profile.
• Recently researchers have revealed novel applications and types of SNEDDS like
supersaturated SNEDDS, solid SNEDDS, controlled release SNEDDS, mucus
permeating SNEDDS, delivery of biomolecules, double emulsions and targeted
SNEDDS.
• Modern in-vitro dispersion and lipolysis tests for lipid formulations are more predictive
and provide reasonable in-vitro/in-vivo correlation. HLB-RSM is a novel formulation
strategy for SNEDDS and carries the potential to overcome the problems associated with
old conventional formulation techniques.
1. Introduction
In the last two decades, lipid based drug delivery system (LBDDS) has earned great
repute as the most promising approach to improve solubility, absorption and consequently
bioavailability of drugs showing poor aqueous solubility. The low water solubility of almost half
of the new chemical entities discovered is the most arduous challenge to the development of new
and improved pharmaceutical products [1-3]. This problem leads to dose variation, uncertain
absorption profile, low oral bioavailability, wide intra and inter subject variability and hence
poor therapeutic efficacy [4]. Various conventional techniques such as salt formation, pH
adjustment, permeation enhancers, use of surfactants, solid dispersions, cyclodextrin inclusion
complexes, use of co-solvents, particle size reduction and prodrug formation have been
employed to improve solubility [5-11]. However, ‘lipid formulations’ have emerged as the most
successful mode of enhancing solubility of poorly soluble drugs, belonging to BCS class II and
IV [12].
Lipid based formulations for oral delivery show a lot of diversity ranging from ‘simple oil
solutions’ at lower side to complex ‘surfactant, co-surfactant or co-solubilizer and oil mixtures’
at the upper extreme [13]. LBDDS can be modified greatly according to the need by changing
their components as well as concentration of these excipients making them feasible for both
hydrophilic and hydrophobic drugs [14]. Their mechanism of enhancing bioavailability include
extended retention time in stomach, changes in physical barrier [15, 16], changes in biochemical
barrier [17, 18], improved solubilization [19] , decreased drug metabolism [18, 20] and
stimulation of lymphatic transport [21]. With time, these systems have been geared up to micro
and nano scales resulting in their improved therapeutic potential for BCS class II, and IV drugs
[22-25]. Among the various multifunctional nanocarriers which have been engineered these days
as pharmaceutical nanocarriers, lipid based nanocarriers enjoy the esteem of being least toxic in-
vivo [26-28]. Lipid nanocarriers include liposomes, solid lipid nanoparticles (SLNs), lipid-
polymer hybrid nanoparticles, microemulsions, nanoemulsions, lipid containing micells, nano
structured lipid carriers (NLC), self-micro emulsifying and nanoemulsifying drug delivery
systems (SMEDDS and SNEDDS) [28-32].
2. From nanoemulsions to self nanoemulsions
2.1 Nanoemulsions
Nanoemulsions are the emulsions which comprise nano sized droplets with
diameter below 300 nm, typically ranging from 20-200 nm [33-35]. These transparent,
heterogeneous dispersions of two immiscible liquids are thermodynamically at non equilibrium
state [36, 37]. As their destabilization kinetics is very slow reaching almost several months they
are kinetically stable systems [38]. Their bioavailability enhancing potential was explored almost
4 decades ago. Nanoemulsions are sometimes also referred to as “Approaching thermodynamic

stability” due to very fine droplets which prevent creaming or sedimentation, flocculation, and
coalescence as a result of Brownian motion, decreased gravity force, and non-deformity of the
droplets [35, 39, 40]. Also these nano- vehicles provide the advantages of high interfacial area,
transparency, low viscosity, long time stability of colloids, both hydrophilic and hydrophobic
drugs carrying potential, enhanced drug stability, greater transmucosal and transdermal drug
delivery, fabrication of nanoparticles and hence improved bioavailability [41-45]. Not only these,
nanoemulsions carry remarkable wetting, spreading and penetration abilities and can be scaled
up due to ease of manufacture [4, 39, 46, 47]. Solid formulation of nanoemulsions has also been
reported successfully which further improves their stability and beneficial role [48]. There is
evidence that bioavailability of emulsions improves appreciably, their stability increases
remarkably and their appearance becomes transparent when the droplet size approaches 100 nm,
90 nm and 30 nm respectively [3].
Methods of fabrication of nanoemulsions are divided into two, including a) High energy
emulsification systems (involving high energy to increase surface area by size reduction)
comprising ultrasonification, using micro fluidizers and high pressure homogenizers, and b) Low
energy emulsification methods (take advantage of physicochemical properties of compounds)
consisting of Phase inversion temperature method, solvent displacement method and Phase
inversion composition method [49-51].
2.2 Misunderstandings between microemulsions and nanoemulsions
Nanoemulsions and microemulsions are the most famous colloidal dispersions.
Nanoemulsions are conventional emulsions with droplets in nanometric size range (strictly
below 200nm and generally below 300nm) [34, 36, 38]. Whereas, microemulsions are actually
“swollen micelle” systems in which dispersed phase is incorporated into the core of surfactant
micelles at some specific environmental conditions and composition [34, 52]. These two systems
are physicochemically different (Figure 1). Nevertheless, they are quite similar in their molecular
and structural aspects [34]. In some special circumstances like specific compositions and
selective temperature ranges microemulsions become much identical to nanoemulsions reaching
exactly the same length nano sized, spherical droplets [34]. There is a lot of confusion in
classifying these fundamentally different colloidal dispersions as nanoemulsions or

microemulsions leading to wrong interpretation of the system.
Nanoemulsions and microemulsions are prepared from same materials. Both dispersions
comprise an aqueous phase, an oil phase, a surfactant and possibly a co-surfactant [3]. They
share almost common nanometric size range i.e. <300 nm for nanoemulsions and <100 nm for
microemulsions. These particles have same basic structure with hydrophilic and hydrophobic
parts which are arranged according to continuous phase. In o/w dispersions hydrophilic part
(surfactant heads) forms shell which surrounds the hydrophobic core (surfactant tails and oil
phase) [34]. Moreover, microemulsions are formed spontaneously and nanoemulsions need high
energy methods for their fabrication but both systems need some external energy to overcome
kinetic energy barriers and support mass transport [34, 42]. Ambiguity arises where
microemulsions need high activation energy hence high external energy for their formulation and
nanoemulsions need low activation energy demanding very low external energy [3]. Also,
nanoemulsions can be prepared through spontaneous emulsification methods as well, which
further perpetuates the mater [34, 35]. These close molecular aspects and their formulation
processes combined with occasional wrong interpretation of nanoemulsions as mini, ultrafine or
submicron emulsions are the major sources of generating confusion between these two
physically different colloidal systems [34, 53, 54].
Nanoemulsions and microemulsions are physicochemically different systems. Microemulsions

are thermodynamically stable and nanoemulsions are thermodynamically unstable systems [34,
38]. Free energy of the separate components of microemulsion is higher than that of
microemulsion while free energy of nanoemulsion is higher than the free energy of separate
phases of nanoemulsion (Figure 2) [35]. Nanoemulsions are at non equilibrium stage whereas
microemulsions are at equilibrium stage (surfactant molecules dispersed as micelles at CMC,
critical micelle concentration). Nanoemulsions are kinetically stable i.e. their destabilizing
process is very slow (in months) having high energy barriers and slow mass transport
phenomenon [35]. On the other hand microemulsions are kinetically unstable systems.
Nanoemulsions need lesser surfactant to oil ratio (SOR) than microemulsions [34].
Microemulsions are prepared normally from small molecule surfactants generating ultralow
interfacial tension at monolayer curvatures. Microemulsion particles may be spherical or non-
spherical. Their shape and size depends upon the optimum curvature of the surfactant monolayer
and the amount of oil incorporated into hydrophobic core of surfactant micelles (o/w
microemulsion) [3, 38, 52]. At optimum curvature, minimum interfacial tension is present and
the spherical shape may or may not be present because different surfactants have different
molecular arrangements hence different interfacial tension and optimum curvatures. Interfacial
tension in nanoemulsion droplets is relatively higher which reduces the droplet radius and
enhances the Laplac pressure. This pressure produces the lowest interfacial area favoring the
spherical shaped nanoemulsion droplets (Figure 1) [34]. Fabrication of nanoemulsions involves
specific mixing order in which, surfactant must be mixed first with oil phase (Figure 3).
Microemulsions do not need any specific mixing order for their formulation [34, 52, 54].
The confusions in the basic concepts lead to erroneous detection and then invalid
characterization of the colloidal system influencing their fabrication methods, physical and
chemical properties and stability factors. Therefore, it is important to distinguish between them.
Some differences between nanoemulsions and microemulsions are summarized in the table 1.
Some principles and methods have been described to specify the true nature of the system, which
are as follows;
1. In their particle size distribution, microemulsions show a single narrow peak and
nanoemulsions have narrow or broad peaks which may be single or multiple (Figure 3).
2. Particle shape may be spherical or non-spherical for microemulsions but it is spherical for
nanoemulsions (Figure1).
3. Structure and properties of nanoemulsion change on long term storage but not for
microemulsions at same temperature, pressure and composition.
4. Dilution of the microemulsion sample with continuous phase disturbs the surfactant
concentration, changes the droplet size measured through dynamic light scattering (DLS) and
can even destroy micelles but the droplet size of nanoemulsion remains the same.
5. Temperature change slowly affects the nanoemulsion droplet structure but microemulsions
are strongly affected by temperature increase.
6. Structure and size of nanoemulsion droplets is dependent upon the fabrication method but
microemulsion droplets must be same whatever the method used to formulate them because
these are thermodynamically stable systems at equilibrium condition.
7. Returning back to original condition after cooling, heating or agitating mechanically

microemulsions should achieve the original properties again but nanoemulsions can show
different properties after returning to original conditions.
These methods distinguish between nanoemulsions and microemulsions and are “in theory” or
“in principle” methods which will be fairly true when these colloidal systems behave “ideally”.
These are according to the basic and fundamental concepts of the two colloidal systems and in
practice these might not be possible always due to different conditions and hence different
behaviors [3, 34, 35].
2.3 Way towards SNEDDS

Although nanoemulsions are comparatively stable systems, even then they break
through “Ostwald ripening” arising due to the polydispersity [36]. Some other factors limiting
their use include poor palatability, unsuitability for delivery through hard or soft gelatin capsule
and hydrolysis of drugs due to lipid content, greater water content and long term storage
respectively [4, 36, 56].
Issues with nanoemulsions have been coped up by the emergence of spontaneously

nanoemulsifying drug delivery system which has restored the prominence of nanoemulsions to
much extent. Self nanoemulsifying drug delivery systems are isotropic mixtures of surfactant,
oil, active pharmaceutical ingredient (API), and hydrophilic co-surfactant or co-solubilizer[57,
58]. These are anhydrous preconcentrates of nanoemulsions. Upon administration into aqueous
phase followed by mild agitation due to gastric motililiy, they form oil in water nanoemulsions
quickly and spontaneously with globules ranging in size from a few nanometers to less than 200
nm [59].
These fine droplets contain drug already dissolved inside the oil phase and provide enhanced
interfacial surface area for dispersion into GI fluid [43, 58, 60].This increase in surface area
improves drug solubilization and permeation by influencing transport properties [43]. Nano sized
droplets undergo quick digestion and hence quick drug absorption in gastrointestinal tract (GIT).
SNEDDS can administer dose ranging from less than 25mg to greater than 2g [61]. As SNEDDS
can be encapsulated into capsules as single dosage forms and do not contain water, they provide
improved physical and chemical stability, palatability and patient compliance [60]. They are
associated with the advantages of improved permeability and high drug loading capacity as
compared to lipid solutions as a result of high concentration of surfactant and co-surfactant [43,
62]. These lipidic nanocarriers can increase lymphatic uptake of highly lipophilic drugs (log P >5
and lipid solubility >50 mg/g), shrinking the first pass effect and cytochrome P450 enzymes
(CYP450) metabolism [5].Bypassing the elementary rate limiting step of dissolution due to pre-
dissolved drug, they produce rapid onset of action[60]. Further, lipophilic part of fatty food helps
in absorption of SNEDDS[62].Use of pharmaceutically acceptable and generally regarded as safe
excipients (GRAS)is another significant advantage [63]. So, not only they can elevate the
bioavailability, SNEDDS are also easy to manufacture and scale up [5, 64-69].3.Novel
applications of SNEDDS and recent developments
In the previous decade, SNEDDS has been employed extensively by the formulation
scientists to tackle the low solubility issues of various drugs and lift the bioavailability profile.
But the potential of SNEDDS is not limited to augment the dissolution profile only. Research is
now heading towards some novel applications of SNEDDS e.g. solid SNEDDS, super saturated
SNEDDS, self-double emulsions (w/o/w), controlled release SNEDDS, SNEDDS for
overcoming mucus gel barrier, delivery of biomolecules and even drug targeting [70-76].
Researchers are also interested in developing some reliable in-vitro/in-vivo correlation for these
formulations [77]. Next in the article, these novel applications are described briefly and recent
work is summarized in the tables accordingly.
3.1 Novel applications of SNEDDS and current research
3.1.1 Supersaturated SNEDDS

Solubility of drugs in lipidic excipients is the factor that determines the loading
dose of drugs in preconcentrates [78]. As the lipidic content of SNEDDS is reduced, the
solubilizing capability of SNEDDS is declined in-vivo due to dispersion and digestion leading to
precipitation of the drugs [78, 79]. Drugs which are more soluble in surfactant or co-surfactant
than lipophilic phase are at risk of precipitation because solvent capacity of surfactant and co-
surfactant decreases upon dilution. This is why most SNEDDS contain drug less than
equilibrium solubility (50-90% of Seq). In one such study, researchers concluded that presence
of higher quantity of hydrophilic surfactants also leads to greater drug precipitation [61, 65, 78].
To surmount this problem supersaturated SNEDDS (s-SNEDDS) containing hydrophilic
precipitation inhibitors have been introduced successfully.
Thermodynamically stable s-SNEDDS inhibit and minimize the nucleation process and
subsequent drug precipitation in GIT by achieving and then sustaining the metastable
supersaturated state [80]. This technology involves incorporation of polymeric precipitation
inhibitors (PPI’s) which are soluble in water and result in longer precipitation time as compared
to mean absorption time [68, 81]. Poly vinyl pyrrolidone (PVP), hydroxylpropyl methyl cellulose
(HPMC), sodium carboxymethyl cellulose (NaCMC) and methyl cellulose (MC) polymers are
some commonly used PPI’s [80, 82]. Hydrophobic HPMC can also be used and in fact
hydrophobic and high molecular weight HPMC polymers are more effective in maintaining
supersturable state [82]. Some drugs precipitate in amorphous form and show notable faster rates
of dissolution after precipitation when tested in-vitro. It implies that precipitation of drugs
showing such behavior, leads to increase the bioavailability, which remains to be illuminated and
clarified in-vivo[80, 83, 84].
Interestingly, supersaturated SNEDDS can also be formulated without polymer or PPI

incorporation into conventional SNEDDS. Subjection of preconcentrates of SNEDDS to
“heating and cooling cycle” is the alternate method described in literature [85]. Employing this
technique Nicky et al. developed s-SNEDDS of simvastatin at 200% of equilibrium solubility
(Seq.) compared to conventional SNEDDS with simvastatin at only 75% of Seq. Relative
bioavailability of 180% and increased half-life of simvastatin from s-SNEDDS (2.3 hr. compared
to 1.4 hr. for conventional SNEDDS) were observed in-vivo. In-vitro lipolysis showed decreased
metabolism of simvastatin from s-SNEDDS, perhaps due to saturation of metabolizing enzymes
and this super saturation reduced the pill burden by enhancing drug content of SNEDDS [65,
85].
s-SNEDDS improved stability, concentration vs. time profile, dissolution rate and extent of
absorption, bioavailability, terminal half-life and performance of hydrophobic and less lipophilic
drugs [57, 82, 85-87]. Recently s-SNEDDS for ezetimibe, halofantrine, AMG 517, silybin,
docetaxel, trans-resveratrol, paclitaxel, hydrocortisone and simvastatin have been reported
showing comparatively increased bioavailability [68, 81-85, 87-90].
3.1.2 Solid SNEDDS

Conventional liquid SNEDDS (L-SNEDDS) are associated with some restrictions
such as liquid drug-drug interactions, drug-excipient interactions and reactions between
preconcentrate and capsule shell, precipitation at lower temperature, high cost, palatability,
manufacturing, handling and stability issues [76, 91]. Solidification of L-SNEDDS surpassed
these limitations, joining the benefits of both traditional SNEDDS and the solid dosage forms. s-
SNEDDS provide the advantages of improved solubility and bioavailability, control over
manufacturing process, less overall cost, reproducibility, enhanced stability, robustness and
scalability [48, 92].
Adsorption of L-SNEDDS on some solid carrier is the most promising technique utilized for
solidification [93-96]. Aerosil, aeroperl, neusilin, coffee husk and avicel are frequently used solid
carriers used to adsorb L-SNEDDS which can produce dry powder, granules and even tablets
[74, 91, 94, 97]. Wet granulation, freeze drying, solvent evaporation, spray drying and extrusion
spheronization can be employed depending upon the physicochemical properties of excipients
and API’s, as well as resulting powder properties [75, 97]. Also dry powders and small granules
of S-SNEDDS can be filled in hard gelatin capsules [98].
A simple alternative of adsorption for solidification is the use of emulsifiers that are themselves
solid or semisolid. Examples of semisolid amphiphiles include Cithrol DPHS and Kolliphor HS
15 while Soluplus and Cithrol GSM 40 are solid amphiphiles [99, 100]. The excipient’s selection
for semisolid SNEDDS is based on their melting points, solubility of drug, HLB values, solid
character, toxicity, dispersibility and droplet size in different media [97, 100]. In one such
research tablet shaped semisolid SNEDDS formulation composed of Cithrol DPHS and Capmul
MCM in 2:1 with Kolliphor HS 15 produced pH independent nano scale dispersions [100].
These formulations avoid co-solvents, are semisolid at room temperature but melt at body
temperature, less susceptible to oxidation and show considerable lipid mobility following
dilution [100].
Solidification of L-SNEDDS is achieved without compromising the drug loading capacity and
bioavailability. Komal et al. compared the in-vitro drug release of pure drug, L-SNEDDS, S-
SNEDDS and S-SNEDDS tablets. Drug release from these formulations did not show
considerable difference except that of pure drug. Results show that almost 99% drug was
released within 30 min from L-SNEDDS, S-SNEDDS and S-SNEDDS tablets but only 10%
from pure drug. The only difference observed among these formulations is the slightly faster
release rate for L-SNEDDS (99.6%, 97.8%, 96.4% and 5.7% after 15 minutes for L-SNEDDS,
S-SNEDDS, S-SNEDDS tablets and pure drug respectively). This might be attributed to the fact
that S-SNEDDS tablets require additional disintegration process and S-SNEDDS need
“SNEDDS releasing step” from the adsorbent materials. As solidification is introduced to
enhance stability and reduce interactions of drug and excipients, accelerated stability studies at
40 °C and RH 75% for 6 months showed no considerable change in parameters like self-
emulsification time, drug release and globule size [101]. Some current research is summarized in
table 3.
3.1.3 Controlled release solid SNEDDS

SNEDDS show the pharmacokinetic parameters which are identical to traditional
oral dosage forms [110]. Normally SNEDDS produce quick absorption leading to higher peak
(Cmax) with shorter Tmax and then deep trough in between two doses (peaks) [110]. This leads
to high fluctuations in plasma drug concentration requiring close drug monitoring especially in
case of drugs which are potent and show severe side effects [111-114]. Therefore, growing
interest is seen in formulating solid SNEDDS with sustained or controlled release characters.
Researchers have shown that not only sustained release, but controlled release SNEDDS with
zero order kinetics can also be achieved without compromising bioavailability [110, 115-117].
These sustained release SNEDDS as compared to conventional SNEDDS generate plasma drug
profiles with same or even higher bioavailability, considerably reduced Cmax, prolonged mean
residence time (MRT) and Tmax, and remarkable reduction in plasma drug level fluctuations
[116].
Various techniques for sustained release SNEDDS include microencapsulation, sustained release
(SR) pellets, gastro-retentive SR tablets, polymer coating, matrix based tablets and controlled
release osmotic pump tablets [115, 118-120]. Xi Zhang et al. prepared self nanoemulsifying
osmotic pump tablet (SNEOPT) of BCS class IV drug with low aqueous solubility and low
permeability. Solid SNEDDS of cyclosporine A were prepared and then coated them with
cellulose acetate with PEG4000 as plasticizer. Rate controlled release was obtained when
reconstituted nano sized emulsion droplets were released at nearly zero order from the surface
orifice of the coated tablet [110]. Different polymers have been used for developing sustained or
controlled release SNEDDS. These include hydroxy propyl methyl cellulose (HPMC),
microcrystalline cellulose (MCC), poly lactic glycolic acid (PLGA) and hydrophobic Gelucire
[110, 115, 119-121].
3.1.4 SNEDDS; as mucus permeation enhancing strategy

Mucosal surfaces are covered by adhesive mucus layer which adds to the barrier
properties of mucosa [122]. Mucus is chiefly composed of glycoproteins called mucins. These
glycoproteins are abundant in cysteine which is S containing amino acid. Because of ester
sulfates and sialic acid mucus is negatively charged at physiological pH [123]. Due to rapid
mucus secretion and faster clearance rates, this viscoelastic mucus barrier sets a challenge for
drug carriers to reach the epithelial surface and remain there for sufficient time. Development of
mucus gel permeating carriers is an important concern in research now a day [122-124].
SNEDDS are explored as better mucus permeating nano carriers. The importance of any mucus
permeating strategy can be understood by realizing the fact that mucus barrier is present in
buccal cavity, nasal cavity, ocular cavity, intestine, lungs and vagina [122, 125, 126]. Interaction
of self-emulsified nano droplets with mucus is low due to hydrophobic surfaces and can cross the
mucus layer without being entrapped. Fine droplet size of less than 50 nm and shape deforming
potential aids SNEDDS in mucus layer permeation [126]. In one such research Friedl et al.
evaluated that the permeation ability of SNEDDS formulations is dependent upon the size of
generated droplets. They observed diffusion potential of different droplet sized SNEDDS
formulations across mucus membrane and showed that SNEDDS 2nd formulation with droplet
size of 12 nm was having greater permeation (70%) as compared to the permeation (8%) of 19th
formulation with 450 nm droplet diameter (Figure 4A) [127]. Surface modification with
surfactants bearing both positive and negative charged moieties has resulted in improved
permeation [126]. Mucoadhesive polymers (e.g. HPMC hydroxypropyl methyl cellulose,
modified chitosan) can be used which can cover the droplet surface and bind to the mucus, hence
prolonging the residence time and chances of permeating the mucus layer [126, 128]. Also
composition of SNEDDS is important and among various components tested Friedl et al. showed
cremophor RH 40 and triacetin have greater mucus permeation enhancing ability. Further, the
permeation is strongly affected by the concentration of these excipients having permeation
enhancing ability as elaborated in the (Figure 4 B & C) [127].
3.1.5 SNEDDS for the delivery of bio macromolecules

Bio macromolecules (Lipids, proteins, genes and polysaccharides) have earned
great interest these days as modern therapeutics due to their high selectivity, specificity and low
toxic effects. US-FDA has approved lot of biopharmaceuticals especially therapeutic proteins
and many more are in the pipeline including gene products for genetic disorders [129, 130].
More than 1800 successful clinical trials for gene therapy are on record and many are under
progress. Pharmaceutical sector is now interested in developing some refined delivery system for
recombinant proteins, gene delivery and other biotechnology products [130-132].
Low bioavailability of biomolecules as a result of 1) poor permeation due to large size and
hydrophilicity (proteins) and 2) enzymatic degradation, is a significant challenge [133]. As
SNEDDS can improve drug solubilization, increase droplet surface area, protect from enzymatic
degradation, modify GIT retention time and enhance permeation, they have potential to tackle
this hiccup. Interestingly, SNEDDS can incorporate hydrophilic drugs in oil droplets as well, by
using slight modifications [125]. Solid dispersion is one such technique in which hydrophilic
protein is first dissolved in amphiphile like phospholipids and then this dispersion is dissolved in
oil [134]. Insulin incorporation into SNEDDS in the presence of thiolated chitosan has also been
tried successfully [125]. Hydrophobic ion pairing is another technique used which involves
replacing the counter ions of peptide drugs with groups inducing lipophilicity without altering
structure and activity [135]. Theodora et al. used this technique and formed hydrophobic ion pair
of insulin with dimyristoyl phosphatidyl glycerol (DMPG). At acidic pH insulin acquires net
positive charge and it can undergo ion complexation with anionic part of amphiphilic molecules
like fatty acids, surfactants and phospholipids. This ion pair of insulin with DMPG was
incorporated into SNEDDS. These SNEDDS showed greater mucus permeation with much
decreased enzymatic degradation of insulin. Incubation in trypsin and chymotrypsin solutions
depicted that 70% insulin was degraded from insulin solution and insulin loaded SNEDDS, while
only 21% insulin was degraded from INS/DMPG hydrophobic complex loaded SNEDDS [136].
SNEDDS loaded with pDNA and proteins such as B-lactamase, insulin, leuprorelin (hormone)
have been successfully developed, demonstrating increased permeability and many folds reduced
enzymatic degradation [133-136].
3.1.6 Self double nanoemulsifying drug delivery system (SDEDDS)
Hydrophilic drugs like proteins and most of the anti-cancer drugs are difficult to administer
orally in the form of SNEDDS [72]. Findings suggest that thermodynamically stable (SEDDS)
self-double emulsifying drug delivery systems (w/o/w spontaneous emulsions) are also a
promising technique for the delivery of hydrophilic actives like peptide and protein drugs [137].
SDEDDS consist of hydrophilic surfactant and water in oil emulsion (comprising water as
dispersed phase, oil as continuous phase and surfactant) which produces w/o/w emulsion
spontaneously upon dilution with water and mild agitation. SDEDDS can save peptide and other
macromolecular drugs from enzymatic inactivation in gastrointestinal tract, improve efficiency
and decrease the dose volume [137-140].
3.1.7 Targeted SNEDDS

Improved therapeutic efficacy and reduced toxicity can be achieved
simultaneously through targeted drug delivery [146]. SNEDDS got the ability to be considered
for this approach. Surface functionalization of nanoparticulate systems have been attempted
successfully [147]. Nanoemulsion droplets generated remain in the body circulation for a longer
duration of time escaping mononuclear phagocyte system. Cationic nanoemulsion droplets can
be directed towards anionic membrane barriers [148]. These lipid based systems are taken by the
liver and spleen and it can be a smart way to target these organs [149]. Droplet surfaces can be
tailored for stealth properties by linking hydrophilic polymers [150].PEGylation is one such
technique in which Poly Ethylene Glycol can be linked to the surface of the nano droplet through
interaction with the surfactant molecules. As PEG is hydrophilic in nature it attracts water
making the surface of droplets slippery. This water layer inhibits the opsonins binding to the
surface of nanocarriers providing stealth properties [151]. It also provides steric hindrance by
forming barrier at the surface inhibiting enzyme degradation. These effects result in increased
stability and help nanocarriers reach the desired site [152]. Mucoadhesive polymers like HPMC
and thiolated chitosan are also an option to increase the retention of droplets in GIT. Thiolated
mucoadhesive polymerscan surround the nanoemulsion droplets as well as bind to the
subdomains of mucus glycoproteins which are rich in cysteine, through (S-S bonds) disulfide
linkages simultaneously [126, 128]. Active and passive targeting can be achieved by attaching
appropriate ligands (antibodies, peptides or nucleic acids) of target site receptors and using
enhanced permeation and retention effect (EPR), respectively [38, 146].
Several diseases including autoimmune diseases, leukemia, lymphoma and tissue rejection are
associated with lymphatic system for their progress [153]. Studies have shown that HIV
reservoirs include lymphoid organs, resting CD4+ T cells, follicular dendritic cells in lymph
nodes and macrophages [73, 154]. As SNEDDS are preferentially taken up into lymphatic
system, they can be used to target these sites. Targeting lymphatic system is also an opportunity
for targeting macrophages, an indirect way for increasing CNS drug levels [154, 155]. M2
phenotype macrophages are also involved in tumor cell activation, angiogenesis, anti-
inflammatory response and tissue remodeling [73, 156]. Interestingly, recent researches have
shown that lymphatic system is involved in tumor metastasis as well [157]. Therefore, these
targeted SNEDDS can be fruitful in future for attainment of therapeutic levels of hydrophobic
drugs at only desired targeted sites.
3.2 Recent developments and modifications3.2.1 IVIVC for SNEDDS
Despite enormous research work, very few SNEDDS products are available in the
market. This is due to poor understanding of biopharmaceutical and pharmacokinetic behavior of
SNEDDS in-vivo and lack of reflective in-vitro tests. Knowledge of processes involved after
ingestion of LBDDS is the dark area which needs to be illuminated [158, 159]. Evaluation of in-
vitro dispersion/precipitation and lipolysis is the preferred testing here instead of dissolution, as
drug is already solubilized in excipients [160]. Currently, in-vitro models developed for
dispersion and lipid digestion are more predictive and reliable. In-vitro dispersion model rank-
orders the formulations between fast, slow and no precipitation. It allows precipitation
determination using a 96-well-plate-technique involving different durations and diluting factors
in biological fluids. But this rank-ordering is challenged if the precipitated drug is redissolved
due to pH change or drug’s state change, later in the GIT [161]. In-vitro lipolysis experiment
uses simulated in-vivo conditions including digestion buffers, bile salts, phospholipids and
lipases/co-lipases, categorizing the formulations according to their performance. Fasted and fed
conditions can be simulated and effect of food can also be determined [77]. These in-vitro
techniques have shown acceptable correlation with in-vivo findings [162, 163].
3.2.2 HLB-response surface methodology
Commonly ‘Trial and Error’ and ‘Ternary Phase Diagram’ approaches are used
in the development of SNEDDS [164].Several errors and shortcomings are associated with these
‘titration’ based methods. This technique consists of fixing the oil, surfactant and co-surfactant
concentrations while varying the concentration of one parameter at one time and gradually
adding the aqueous phase to judge the nanoemulsion formation from the formulation
transparency [58, 71]. In this process when aqueous phase is limited then concentrated
nanoemulsions are generated which are milky, opaque and are not transparent. Further addition
of aqueous phase (mostly water) leads to a bluish, transparent and translucent nanoemulsion
formulations. This change from opaque to transparent formulation is referred to as ‘phase
transition’ which is wrong interpretation. These two systems are actually ‘concentrated’ and
‘diluted’ nanoemulsions respectively [34]. This misinterpretation raises questions about the
validity of ‘Ternary phase diagrams’ build this way. These techniques are time consuming,
costly and demand greater number of experiments [165].
Above mentioned problems emphasize the need for alternate approaches for SNEDDS’
development. Sagitani revealed that “hydrophilic lipophilic balance (HLB)” is a key parameter in
the production of nanoemulsions. Minimum droplet size is achieved when the HLB values of
emulsifier and oil are matched [166]. It is shown that molecular structure of emulsifier is another
important factor in determining the droplet size of nanoemulsions [167, 168]. Lijuan et al.
investigated the effects of constituents’ concentration, structure and HLB values. Results suggest
that droplet size depends upon HLB values and structures of constituents. Minimum droplet size
was achieved with matched HLB values of oil and emulsifier. Hence, these factors might be used
for screening constituents as well as their optimized concentrations for nanoemulsion
development [169].
Bahloul et al. developed fenofibrate SNEDDS through an inexpensive, quick and robust
hydrophilic lipophilic balance-response surface methodology “HLB-RSM” strategy in order to
streamline the formulation approach [70]. HLB and response surface are introduced as
“determinant factors” in the development and optimization of SNEDDS. As optimal HLB is
demonstrated to be in correspondence with optimal concentration mixture, an experimental
domain of HLB (7.8-15) is selected [70, 164]. This domain is supposed to contain the optimal
HLB associated with optimal o/w selfemulsion [170]. HLB-RSM marks the minimal and
maximal concentration of excipients based on HLB, optimizing the formulation and could be an
efficient alternative to conventional approaches.
4. Conclusion
Low water solubility of BCS class II and IV drugs is responsible for poor oral absorption and has
been fixed through a “key strategy” called lipid based drug delivery system. LBDDS are
versatile carriers assuming different forms including emulsions. Nanoemulsions and
microemulsions are thermodynamically different systems having droplets in almost same
nanometric range. With the arrival of low energy and self-emulsification methods,
nanoemulsions have regained their importance as SNEDDS. SNEDDS have shown high drug
loading capacity, improve bioavailability and therapeutic efficiency of hydrophobic drugs. They
have been further modified as supersaturated, solid and even controlled release SNEDDS. Their
potential for carrying and delivering biomolecules such as insulin, leuprorelin etc. for improved
permeability and reduced enzymatic degradation is well established.SNEDDS are now well
known for their mucus permeating capacity as well as their capability of enhancing lymphatic
uptake. As SNEDDS are suitable for surface functionalization, they can be designed for active
targeting to desired organs. Gap between SNEDDS and their commercial products is due to lack
of complete understanding of their in-vivo behavior and so far has been filled by development of
reflective in-vitro test. In recent times, some new SNEDDS development methods like HLB
response surface methodology have been adopted to surpass the drawbacks of old methodologies
and thus making SNEDDS an eminent and favorable drug delivery technique.
5. Expert opinion
Low aqueous solubility of drugs is a major challenge in their development as it leads to poor
bioavailability and low clinical response. Currently approximately 40% of marketed products
and many in developmental phase are poorly water soluble. These facts motivate scientists to
work on various methods to improve the solubility of drugs. Among them one of most promising
method is use of lipid based drug delivery systems. Use of lipids in drug carriers is based on
earlier observations that co administration of food and drugs such as griseofulvin, danazol,
halofantrine etc. enhances their absorption. Co administration of drugs and lipids utilizes several
mechanisms including increased solubilization, changes in biochemical and physical barriers and
utilization of endogenous lipid processing pathways to enhance drug absorption. LBDDS are
also preferred carriers due to their biocompatibility, versatility of pharmaceutical lipid excipients
and their compatibility with liquid, semi-solid, and solid dosage forms. Different lipid based
carriers such as self-emulsifying (SEDDS), self microemulsifying (SMEDDS) and self
nanoemulsifying (SNEDDS) are widely used to enhance bioavailability and dissolution rate of
poorly water soluble drugs. These systems share the advantage of spontaneous emulsification
without need for high energy processes. Commercial success of lipid based formulation such as
SandimuneNeoral, (Cyclosporine A), Lipirex (fenofibrate), Fortovase (Saquinavir), Norvir
(Ritonavir) etc. have encouraged further research in this area.
Previously SNEDDS were employed to tackle solubility and bioavailability related issues
of drugs. But scope of SNEDDS is far beyond dissolution and solubility issues. In recent times
they have evolved into supersaturated, solid, controlled and targeted SNEDDS to overcome
issues related with simple SNEDDS and to make new modifications for different applications.
For instance supersaturated SNEDDS were developed to enhance drug loading capacity, solid
SNEDDS were used for ease of handling, manufacturing and enhance stability, controlled
SNEDDS avoided plasma drug fluctuations and targeted SNEDDS avoided side effects of drugs
on normal tissues. Furthermore, due to their small size, use of mucoadhesive and charged
surfactant coating, results in effective permeation of various mucus membranes in human body.
Encapsulation of nanodroplets with various polymers can provide diverse properties like
mucoadhesion, long GIT retention time, protection against enzymes, targeting lower GI tract and
providing sites for attaching specific targeting moieties. SNEDDS can also overcome poor
permeation, solubility and enzymatic degradation problem of bio macromolecules.
Despite above mentioned advancement and modifications in SNEDDS, still there are
areas which need to be focused to make SNEDDS future drug delivery carrier. Although
different efficient and predictive in-vitro tests were developed to understand SNEDDS but still
we lack enough in-vivo information. Apart from this, mechanism of generation of nanodroplets
especially when blended with polymer is not fully understood and needs clarification. Such
ingredients especially surfactants should be identified which are safe, effective and less toxic
even at higher concentrations. Adsorbents which can carry greater amounts of L-SNEDDS
should be searched. SNEDDS are prospective carrier for delivering bio macromolecules and
“difficult to formulate” phytochemicals and should be explored further as they can be an ideal
platform for such kind of drugs. In case of bio macromolecules we need further work on their
formulation ratio, loading capacity and effect of processing parameters on their stability. Another
issue is how to select a careful and optimum ratio of components in SNEDDS. One possible way
out is to replace traditional hit and trial method by HLB response surface technique. This
technique can minimize cost and cut short the number of formulations needed to identify the
optimum composition but still needs additional evaluation.
Acknowledgement
All authors thankfully acknowledge Higher Education Commission of Pakistan (HEC) for their
support in order to complete this review.
Funding
This paper was not funded
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials discussed in
the manuscript. This includes employment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or royalties.
Bibliography
Papers of special note have been highlighted as either of interest (•) or of considerable interest
(••) to readers.
1. Kawabata Y, Wada K, Nakatani M, et al. Formulation design for poorly water-soluble

drugs based on biopharmaceutics classification system: basic approaches and practical
applications. International Journal of Pharmaceutics 2011;420:1-10.
2. Jain S, Patel N, Lin S. Solubility and dissolution enhancement strategies: current
understanding and recent trends. Drug development and industrial pharmacy 2015;41:875-87.
3. McClements DJ. Nanoemulsions versus microemulsions: terminology, differences, and
similarities. Soft matter 2012;8:1719-29.
•• Reviews differences and similarities between nanoemulsions and microemulsions.
4. Date AA, Desai N, Dixit R, et al. Self-nanoemulsifying drug delivery systems:
formulation insights, applications and advances. Nanomedicine 2010;5:1595-616.
5. Gupta S, Chavhan S, Sawant KK. Self-nanoemulsifying drug delivery system for
adefovir dipivoxil: design, characterization, in vitro and ex vivo evaluation. Colloids and
Surfaces A: Physicochemical and Engineering Aspects 2011;392:145-55.
6. Fong SYK, Martins SM, Brandl M, et al. Solid Phospholipid Dispersions for Oral
Delivery of Poorly Soluble Drugs: Investigation Into Celecoxib Incorporation and Solubility-In
Vitro Permeability Enhancement. Journal of pharmaceutical sciences 2016;105:1113-23.
7. Lee H, Lee J. Dissolution enhancement of celecoxib via polymer-induced crystallization.
Journal of Crystal Growth 2013;374:37-42.
8. Gidwani B, Vyas A. A comprehensive review on cyclodextrin-based carriers for delivery
of chemotherapeutic cytotoxic anticancer drugs. BioMed research international 2015;2015.
9. Chen J, Mosquera-Giraldo LI, Ormes JD, et al. Bile Salts as Crystallization Inhibitors of
Supersaturated Solutions of Poorly Water-Soluble Compounds. Crystal Growth & Design
2015;15:2593-97.
10. Gaba B, Fazil M, Ali A, et al. Nanostructured lipid (NLCs) carriers as a bioavailability
enhancement tool for oral administration. Drug delivery 2015;22:691-700.
11. Gautam SP, Gupta AK, Wani SUD, et al. PAMAM Dendrimers mediated solubility
enhancement of poorly soluble drugs: a concise review. 2015.
12. Čerpnjak K, Zvonar A, Gašperlin M, et al. Lipid-based systems as a promising approach
for enhancing the bioavailability of poorly water-soluble drugs. Acta pharmaceutica
2013;63:427-45.
13. Pouton CW, Porter CJ. Formulation of lipid-based delivery systems for oral
administration: materials, methods and strategies. Advanced Drug Delivery Reviews
2008;60:625-37.
•• Discusses lipid formulation classification system and basics of lipid formulations.
14. Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-
emulsifying and ‘self-microemulsifying’drug delivery systems. European Journal of

Pharmaceutical Sciences 2000;11:S93-S98.
•• Discusses the lipid formulation focussing on self emulsifying systems.
15. Brüsewitz C, Schendler A, Funke A, et al. Novel poloxamer-based nanoemulsions to
enhance the intestinal absorption of active compounds. International journal of pharmaceutics
2007;329:173-81.
16. Seeballuck F, Lawless E, Ashford MB, et al. Stimulation of triglyceride-rich lipoprotein
secretion by polysorbate 80: in vitro and in vivo correlation using Caco-2 cells and a cannulated
rat intestinal lymphatic model. Pharmaceutical research 2004;21:2320-26.
17. Porter CJ, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing
the oral delivery of lipophilic drugs. Nature Reviews Drug Discovery 2007;6:231-48.
18. Subramanian R, Wasan KM. Effect of lipid excipients on in vitro pancreatic lipase
activity. Drug development and industrial pharmacy 2003;29:885-90.
19. Mohsin K, Shahba A, Alanazi F. Lipid based self emulsifying formulations for poorly
water soluble drugs-an excellent opportunity. Indian journal of pharmaceutical educational and
research 2012;46:88-196.
20. Ren S, Park M-J, Kim A, et al. In vitro metabolic stability of moisture-sensitive
rabeprazole in human liver microsomes and its modulation by pharmaceutical excipients.
Archives of pharmacal research 2008;31:406-13.
21. Vemula RB. Lipid based self-emulsifying drug delivery system (SEDDS) for poorly
water-soluble drugs: A review. Journal of Global Pharma Technology 2010;2.
22. Chime SA, Onyishi IV. Lipid-based drug delivery systems (LDDS): Recent advances and
applications of lipids in drug delivery. African Journal of Pharmacy and Pharmacology
2013;7:3034-59.
23. Wadhwa J, Nair A, Kumria R. Emulsion forming drug delivery system for lipophilic
drugs. Acta Pol Pharm 2012;69:179-91.
24. Wang AZ, Gu F, Zhang L, et al. Biofunctionalized targeted nanoparticles for therapeutic
applications. Expert opinion on biological therapy 2008;8:1063-70.
25. Pathak K, Raghuvanshi S. Oral Bioavailability: Issues and Solutions via
Nanoformulations. Clinical pharmacokinetics 2015;54:325-57.
26. Zhang L, Gu F, Chan J, et al. Nanoparticles in medicine: therapeutic applications and
developments. Clinical pharmacology and therapeutics 2008;83:761-69.

27. Puri A, Loomis K, Smith B, et al. Lipid-based nanoparticles as pharmaceutical drug
carriers: from concepts to clinic. Critical Reviews™ in Therapeutic Drug Carrier Systems
2009;26.
28. Alonso MJ. Nanomedicines for overcoming biological barriers. Biomedicine &
Pharmacotherapy 2004;58:168-72.
29. Mishra B, Patel BB, Tiwari S. Colloidal nanocarriers: a review on formulation
technology, types and applications toward targeted drug delivery. Nanomedicine:
Nanotechnology, biology and medicine 2010;6:9-24.
30. Alaouie AM, Sofou S. Liposomes with triggered content release for cancer therapy.
Journal of Biomedical Nanotechnology 2008;4:234-44.
31. Hadinoto K, Sundaresan A, Cheow WS. Lipid–polymer hybrid nanoparticles as a new
generation therapeutic delivery platform: a review. European Journal of Pharmaceutics and
Biopharmaceutics 2013;85:427-43.
32. Boyd BJ. Past and future evolution in colloidal drug delivery systems. Expert Opinion on
Drug Delivery 2008;5:69-85.
33. Solans C, Izquierdo P, Nolla J, et al. Nano-emulsions. Current opinion in colloid &
interface science 2005;10:102-10.
34. Anton N, Vandamme TF. Nano-emulsions and micro-emulsions: clarifications of the
critical differences. Pharmaceutical research 2011;28:978-85.
•• Clears the misconception between the two terms i.e micro and nanoemulsions.
35. Tadros T, Izquierdo P, Esquena J, et al. Formation and stability of nano-emulsions.
Advances in colloid and interface science 2004;108:303-18.
•• Describes formation techniques, mechanism and stability of nano-emulsions.
36. Gutiérrez J, González C, Maestro A, et al. Nano-emulsions: New applications and
optimization of their preparation. Current Opinion in Colloid & Interface Science 2008;13:245-
51.
• Describes the basics of nanoemulsions.
37. Constantinides PP, Chaubal MV, Shorr R. Advances in lipid nanodispersions for
parenteral drug delivery and targeting. Advanced drug delivery reviews 2008;60:757-67.
38. Anton N, Vandamme TF. The universality of low-energy nano-emulsification.
International Journal of Pharmaceutics 2009;377:142-47.

39. Anton N, Benoit J-P, Saulnier P. Design and production of nanoparticles formulated from
nano-emulsion templates—a review. Journal of Controlled Release 2008;128:185-99.
40. Bates TR, Carrigan PJ. Apparent absorption kinetics of micronized griseofulvin after its
oral administration on single‐and multiple‐dose regimens to rats as a corn oil‐in‐water emulsion
and aqueous suspension. Journal of pharmaceutical sciences 1975;64:1475-81.
41. Anwer MK, Jamil S, Ibnouf EO, et al. Enhanced antibacterial effects of clove essential
oil by nanoemulsion. Journal of oleo science 2014;63:347-54.
42. Sonneville-Aubrun O, Simonnet J-T, L'alloret F. Nanoemulsions: a new vehicle for
skincare products. Advances in Colloid and Interface Science 2004;108:145-49.
43. Shafiq S, Shakeel F, Talegaonkar S, et al. Development and bioavailability assessment of
ramipril nanoemulsion formulation. European Journal of Pharmaceutics and Biopharmaceutics
2007;66:227-43.
44. Shafiq-un-Nabi S, Shakeel F, Talegaonkar S, et al. Formulation development and
optimization using nanoemulsion technique: a technical note. AAPS pharmscitech 2007;8:E12-
E17.
45. Gorain B, Choudhury H, Kundu A, et al. Nanoemulsion strategy for olmesartan
medoxomil improves oral absorption and extended antihypertensive activity in hypertensive rats.
Colloids and Surfaces B: Biointerfaces 2014;115:286-94.
46. Bali V, Ali M, Ali J. Study of surfactant combinations and development of a novel
nanoemulsion for minimising variations in bioavailability of ezetimibe. Colloids and Surfaces B:
Biointerfaces 2010;76:410-20.
47. Puglia C, Rizza L, Drechsler M, et al. Nanoemulsions as vehicles for topical
administration of glycyrrhetic acid: characterization and in vitro and in vivo evaluation. Drug
delivery 2010;17:123-29.
48. Singh S, Pathak K, Bali V. Product development studies on surface-adsorbed
nanoemulsion of olmesartan medoxomil as a capsular dosage form. AAPS PharmSciTech
2012;13:1212-21.
49. Roger K, Cabane B, Olsson U. Formation of 10− 100 nm size-controlled emulsions
through a sub-PIT cycle. Langmuir 2009;26:3860-67.

50. Roger K, Cabane B, Olsson U. Emulsification through surfactant hydration: the PIC
process revisited. Langmuir 2010;27:604-11.
51. Solans C, Solé I. Nano-emulsions: formation by low-energy methods. Current Opinion in
Colloid & Interface Science 2012;17:246-54.
52. Wennerström H, Balogh J, Olsson U. Interfacial tensions in microemulsions. Colloids
and Surfaces A: Physicochemical and Engineering Aspects 2006;291:69-77.
53. Kong M, Chen XG, Kweon DK, et al. Investigations on skin permeation of hyaluronic
acid based nanoemulsion as transdermal carrier. Carbohydrate Polymers 2011;86:837-43.
54. Huang Q, Yu H, Ru Q. Bioavailability and delivery of nutraceuticals using
nanotechnology. Journal of Food Science 2010;75:R50-R57.
55. Oh DH, Kang JH, Kim DW, et al. Comparison of solid self-microemulsifying drug
delivery system (solid SMEDDS) prepared with hydrophilic and hydrophobic solid carrier.
International journal of pharmaceutics 2011;420:412-18.
56. Wilking JN, Mason TG. Irreversible shear-induced vitrification of droplets into elastic
nanoemulsions by extreme rupturing. Physical Review E 2007;75:041407.
57. Singh B, Bandopadhyay S, Kapil R, et al. Self-emulsifying drug delivery systems
(SEDDS): formulation development, characterization, and applications. Critical Reviews™ in
Therapeutic Drug Carrier Systems 2009;26.
58. Shakeel F, Iqbal M, Ezzeldin E. Bioavailability enhancement and pharmacokinetic
profile of an anticancer drug ibrutinib by self‐nanoemulsifying drug delivery system. Journal of
Pharmacy and Pharmacology 2016;68:772-80.
59. Nanjwade BK, Patel DJ, Udhani RA, et al. Functions of lipids for enhancement of oral
bioavailability of poorly water-soluble drugs. Sci Pharm 2011;79:705-27.
60. Khan AW, Kotta S, Ansari SH, et al. Potentials and challenges in self-nanoemulsifying
drug delivery systems. Expert opinion on drug delivery 2012;9:1305-17.
61. Chime S, Kenechukwu F, Attama A. Nanoemulsions—Advances in Formulation,
Characterization and applications in drug delivery. Ali DS Application of nanotechnology in
drug delivery Croatia: In Tech 2014;77-111.
62. Cherniakov I, Domb AJ, Hoffman A. Self-nano-emulsifying drug delivery systems: an

update of the biopharmaceutical aspects. Expert opinion on drug delivery 2015;12:1121-33.
63. Shakeel F, Haq N, El-Badry M, et al. Ultra fine super self-nanoemulsifying drug delivery
system (SNEDDS) enhanced solubility and dissolution of indomethacin. Journal of Molecular
Liquids 2013;180:89-94.
64. Larsen AT, Ohlsson AG, Polentarutti B, et al. Oral bioavailability of cinnarizine in dogs:
relation to SNEDDS droplet size, drug solubility and in vitro precipitation. European Journal of
Pharmaceutical Sciences 2013;48:339-50.
65. Thomas N, Müllertz A, Graf A, et al. Influence of lipid composition and drug load on the
In Vitro performance of self‐nanoemulsifying drug delivery systems. Journal of pharmaceutical
sciences 2012;101:1721-31.
66. Bandivadekar M, Pancholi S, Kaul-Ghanekar R, et al. Single non-ionic surfactant based
self-nanoemulsifying drug delivery systems: formulation, characterization, cytotoxicity and
permeability enhancement study. Drug development and industrial pharmacy 2013;39:696-703.
67. Rane SS, Anderson BD. What determines drug solubility in lipid vehicles: is it
predictable? Advanced drug delivery reviews 2008;60:638-56.
68. Singh G, Pai RS. Trans-resveratrol self-nano-emulsifying drug delivery system
(SNEDDS) with enhanced bioavailability potential: optimization, pharmacokinetics and in situ
single pass intestinal perfusion (SPIP) studies. Drug delivery 2015;22:522-30.
69. Patel A, Shelat P, Lalwani A. Development and optimization of solid self-
nanoemulsifying drug delivery system (S-SNEDDS) using Scheffe’s design for improvement of
oral bioavailability of nelfinavir mesylate. Drug delivery and translational research 2014;4:171-
86.
70. Bahloul B, Lassoued MA, Seguin J, et al. Self-emulsifying drug delivery system
developed by the HLB-RSM approach: Characterization by transmission electron microscopy
and pharmacokinetic study. International journal of pharmaceutics 2015;487:56-63.
71. El-Badry M, Haq N, Fetih G, et al. Solubility and dissolution enhancement of tadalafil
using self-nanoemulsifying drug delivery system. Journal of oleo science 2014;63:567-76.
72. Shakeel F, Haq N, Al-Dhfyan A, et al. Double w/o/w nanoemulsion of 5-fluorouracil for
self-nanoemulsifying drug delivery system. Journal of Molecular Liquids 2014;200:183-90.
• Describes Self double nanoemusifying system for hydrophilic drugs.
73. Shahnaz G, Hartl M, Barthelmes J, et al. Uptake of phenothiazines by the harvested

chylomicrons ex vivo model: Influence of self-nanoemulsifying formulation design. European
Journal of Pharmaceutics and Biopharmaceutics 2011;79:171-80.
74. Abbaspour M, Jalayer N, Makhmalzadeh BS. Development and evaluation of a solid self-
nanoemulsifying drug delivery system for loratadin by extrusion-spheronization. Advanced
pharmaceutical bulletin 2014;4:113.
75. Wang Z, Sun J, Wang Y, et al. Solid self-emulsifying nitrendipine pellets: preparation
and in vitro/in vivo evaluation. International journal of pharmaceutics 2010;383:1-6.
76. Singh SK, Prasad Verma PR, Razdan B. Glibenclamide-loaded self-nanoemulsifying
drug delivery system: development and characterization. Drug development and industrial
pharmacy 2010;36:933-45.
77. Larsen AT, Sassene P, Müllertz A. In vitro lipolysis models as a tool for the
characterization of oral lipid and surfactant based drug delivery systems. International journal of
pharmaceutics 2011;417:245-55.
78. Mohsin K, Long MA, Pouton CW. Design of lipid‐based formulations for oral
administration of poorly water‐soluble drugs: precipitation of drug after dispersion of
formulations in aqueous solution. Journal of pharmaceutical sciences 2009;98:3582-95.
79. Do Thi T, Van Speybroeck M, Barillaro V, et al. Formulate-ability of ten compounds
with different physicochemical profiles in SMEDDS. European Journal of Pharmaceutical
Sciences 2009;38:479-88.
80. Bandyopadhyay S, Katare O, Singh B. Development of optimized supersaturable self-
nanoemulsifying systems of ezetimibe: effect of polymers and efflux transporters. Expert opinion
on drug delivery 2014;11:479-92.
81. Chen Y, Chen C, Zheng J, et al. Development of a solid supersaturatable self-emulsifying
drug delivery system of docetaxel with improved dissolution and bioavailability. Biological and
Pharmaceutical Bulletin 2011;34:278-86.
82. Wei Y, Ye X, Shang X, et al. Enhanced oral bioavailability of silybin by a
supersaturatable self-emulsifying drug delivery system (S-SEDDS). Colloids and Surfaces A:
Physicochemical and Engineering Aspects 2012;396:22-28.
83. Sassene PJ, Knopp MM, Hesselkilde JZ, et al. Precipitation of a poorly soluble model
drug during in vitro lipolysis: characterization and dissolution of the precipitate. Journal of
pharmaceutical sciences 2010;99:4982-91.
84. Gao P, Akrami A, Alvarez F, et al. Characterization and optimization of AMG 517
supersaturatable self‐emulsifying drug delivery system (S‐SEDDS) for improved oral absorption.
Journal of Pharmaceutical sciences 2009;98:516-28.
85. Thomas N, Holm R, Garmer M, et al. Supersaturated self-nanoemulsifying drug delivery
systems (super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug
simvastatin in dogs. The AAPS journal 2013;15:219-27.
86. Gao P, Morozowich W. Development of supersaturatable self-emulsifying drug delivery
system formulations for improving the oral absorption of poorly soluble drugs. Expert opinion on
drug delivery 2006;3:97-110.
87. Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: The
answer to solubility‐limited oral bioavailability? Journal of pharmaceutical sciences
2009;98:2549-72.
88. Gao P, Rush BD, Pfund WP, et al. Development of a supersaturable SEDDS (S‐SEDDS)
formulation of paclitaxel with improved oral bioavailability. Journal of pharmaceutical sciences
2003;92:2386-98.
89. Raghavan S, Kiepfer B, Davis A, et al. Membrane transport of hydrocortisone acetate
from supersaturated solutions; the role of polymers. International journal of pharmaceutics
2001;221:95-105.
90. Singh G, Pai RS. In vitro and in vivo performance of supersaturable self-nanoemulsifying
system of trans-resveratrol. Artificial cells, nanomedicine, and biotechnology 2015;1-7.
91. Shakeel F, Haq N, Alanazi FK, et al. Polymeric solid self-nanoemulsifying drug delivery
system of glibenclamide using coffee husk as a low cost biosorbent. Powder Technology
2014;256:352-60.
92. Kamel AO, Mahmoud AA. Enhancement of human oral bioavailability and in vitro
antitumor activity of rosuvastatin via spray dried self-nanoemulsifying drug delivery system.
Journal of biomedical nanotechnology 2013;9:26-39.
93. Seo YG, Kim DH, Ramasamy T, et al. Development of docetaxel-loaded solid self-
nanoemulsifying drug delivery system (SNEDDS) for enhanced chemotherapeutic effect.

94. Kallakunta VR, Bandari S, Jukanti R, et al. Oral self emulsifying powder of lercanidipine
hydrochloride: formulation and evaluation. Powder Technology 2012;221:375-82.
95. Tang B, Cheng G, Gu J-C, et al. Development of solid self-emulsifying drug delivery
systems: preparation techniques and dosage forms. Drug discovery today 2008;13:606-12.
96. Jain AK, Thanki K, Jain S. Solidified self-nanoemulsifying formulation for oral delivery
of combinatorial therapeutic regimen: part I. Formulation development, statistical optimization,
and in vitro characterization. Pharmaceutical research 2014;31:923-45.
97. Van Speybroeck M, Williams HD, Nguyen T-H, et al. Incomplete desorption of liquid
excipients reduces the in vitro and in vivo performance of self-emulsifying drug delivery systems
solidified by adsorption onto an inorganic mesoporous carrier. Molecular pharmaceutics
2012;9:2750-60.
98. Beg S, Sandhu PS, Batra RS, et al. QbD-based systematic development of novel
optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with
enhanced biopharmaceutical performance. Drug delivery 2015;22:765-84.
99. Song WH, Park JH, Yeom DW, et al. Enhanced dissolution of celecoxib by
supersaturating self-emulsifying drug delivery system (S-SEDDS) formulation. Archives of
pharmacal research 2013;36:69-78.
100. Hassan TH, Metz H, Mäder K. Novel semisolid SNEDDS based on PEG-30-
dipolyhydroxystearate: development and characterization. International journal of pharmaceutics
2014;477:506-18.
101. Parmar K, Patel J, Sheth N. Self nano-emulsifying drug delivery system for Embelin:
Design, characterization and in-vitro studies. asian journal of pharmaceutical sciences
2015;10:396-404.
102. Abdelbary G, Amin M, Salah S. Self nano-emulsifying simvastatin based tablets: design
and in vitro/in vivo evaluation. Pharmaceutical development and technology 2013;18:1294-304.
103. Mohd AB, Sanka K, Bandi S, et al. Solid self-nanoemulsifying drug delivery system (S-
SNEDDS) for oral delivery of glimepiride: development and antidiabetic activity in albino
rabbits. Drug delivery 2015;22:499-508.
104. Agrawal AG, Kumar A, Gide PS. Formulation of solid self-nanoemulsifying drug
delivery systems using N-methyl pyrrolidone as cosolvent. Drug development and industrial
pharmacy 2015;41:594-604.
105. Shakeel F, Haq N, Alanazi FK, et al. Surface-adsorbed reverse micelle-loaded solid self-
nanoemulsifying drug delivery system of talinolol. Pharmaceutical development and technology
2014;1-9.
106. Kang JH, Oh DH, Oh Y-K, et al. Effects of solid carriers on the crystalline properties,
dissolution and bioavailability of flurbiprofen in solid self-nanoemulsifying drug delivery system
(solid SNEDDS). European Journal of Pharmaceutics and Biopharmaceutics 2012;80:289-97.
107. Beg S, Swain S, Singh HP, et al. Development, optimization, and characterization of
solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers. AAPS
PharmSciTech 2012;13:1416-27.
108. Reddy MS, Rudra R, Haq MF. Formulation and evaluation of solid self nano emulsifying
drug delivery system (S-SNEDDS) of ritonavir drug. Indo American Journal of Pharmaceutical
Research 2015;5:2910-24.
109. Fagir W, Hathout RM, Sammour OA, et al. Self-microemulsifying systems of Finasteride
with enhanced oral bioavailability: multivariate statistical evaluation, characterization, spray-
drying and in vivo studies in human volunteers. Nanomedicine 2015;10:3373-89.
110. Zhang X, Yi Y, Qi J, et al. Controlled release of cyclosporine A self-nanoemulsifying
systems from osmotic pump tablets: Near zero-order release and pharmacokinetics in dogs.
• Describes controlled release SNEDDS with almost zero order release kinetics.
111. Guan P, Lu Y, Qi J, et al. Enhanced oral bioavailability of cyclosporine A by liposomes
containing a bile salt. Int J Nanomedicine 2011;6:e974.
112. Wang Y, Sun J, Zhang T, et al. Enhanced oral bioavailability of tacrolimus in rats by self-
microemulsifying drug delivery systems. Drug development and industrial pharmacy
2011;37:1225-30.
113. Jyothi BJ, Sreelakshmi K. Design and evaluation of self-nanoemulsifying drug delivery
system of flutamide. Journal of young pharmacists 2011;3:4-8.
114. Lu Y, Qi J, Wu W. Absorption, disposition and pharmacokinetics of nanoemulsions.
Current drug metabolism 2012;13:396-417.
115. Miao Y, Chen G, Ren L, et al. Characterization and evaluation of self-nanoemulsifying
sustained-release pellet formulation of ziprasidone with enhanced bioavailability and no food

effect. Drug delivery 2014;1-10.
116. Wei L, Li J, Guo L, et al. Investigations of a novel self-emulsifying osmotic pump tablet
containing carvedilol. Drug development and industrial pharmacy 2007;33:990-98.
117. Nazzal S, Khan MA. Controlled release of a self-emulsifying formulation from a tablet
dosage form: Stability assessment and optimization of some processing parameters. International
journal of pharmaceutics 2006;315:110-21.
118. Zhang Y, Wang R, Wu J, et al. Characterization and evaluation of self-microemulsifying
sustained-release pellet formulation of puerarin for oral delivery. International journal of
119. Park M-J, Balakrishnan P, Yang S-G. Polymeric nanocapsules with SEDDS oil-core for
the controlled and enhanced oral absorption of cyclosporine. International journal of
120. Yi T, Wan J, Xu H, et al. Controlled poorly soluble drug release from solid self-
microemulsifying formulations with high viscosity hydroxypropylmethylcellulose. european
journal of pharmaceutical sciences 2008;34:274-80.
121. Patil PR, Biradar SV, Paradkar AR. Extended release felodipine self-nanoemulsifying
system. AAPS PharmSciTech 2009;10:515-23.
122. Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. Journal of
controlled release 2011;153:106-16.
123. Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the
gastrointestinal mucus barriers. Advanced drug delivery reviews 2012;64:557-70.
124. Crater JS, Carrier RL. Barrier properties of gastrointestinal mucus to nanoparticle
transport. Macromolecular bioscience 2010;10:1473-83.
125. Sakloetsakun D, Dünnhaupt S, Barthelmes J, et al. Combining two technologies:
multifunctional polymers and self-nanoemulsifying drug delivery system (SNEDDS) for oral
insulin administration. International journal of biological macromolecules 2013;61:363-72.
• Describes succesful oral insulin delivery using a strategy to combine SNEDDS and
thiolated chitosan.
126. Dünnhaupt S, Kammona O, Waldner C, et al. Nano-carrier systems: Strategies to
overcome the mucus gel barrier. European Journal of Pharmaceutics and Biopharmaceutics
2015;96:447-53.
• Provides an overview of nanotechnology-based strategies to overcome various mucus gel
barriers.
127. Friedl H, Dünnhaupt S, Hintzen F, et al. Development and Evaluation of a Novel Mucus
Diffusion Test System Approved by Self‐Nanoemulsifying Drug Delivery Systems. Journal of
• Discusses a mucus diffusion test system for SNEDDS.
128. Barthelmes J, Dünnhaupt S, Hombach J, et al. Thiomer nanoparticles: stabilization via
covalent cross-linking. Drug delivery 2011;18:613-19.
129. SILVA CO, REIS CP. Drug Nanocarriers Based on Biomacromolecules: How Far We’ve
Come?
130. Dimitrov DS. Therapeutic proteins. Therapeutic Proteins: Methods and Protocols 2012;1-
26.
131. Kayser O, Warzecha H. Pharmaceutical biotechnology: drug discovery and clinical
applications: John Wiley & Sons, 2012.
132. Ginn SL, Alexander IE, Edelstein ML, et al. Gene therapy clinical trials worldwide to
2012–an update. The journal of gene medicine 2013;15:65-77.
133. Hauptstein S, Prüfert F, Bernkop-Schnürch A. Self-nanoemulsifying drug delivery
systems as novel approach for pDNA drug delivery. International journal of pharmaceutics
2015;487:25-31.
• Investigates a novel strategy for oral gene delivery utilizing a selfnanoemulsifying drug
delivery system (SNEDDS).
134. Rao SVR, Shao J. Self-nanoemulsifying drug delivery systems (SNEDDS) for oral
delivery of protein drugs: I. Formulation development. International journal of pharmaceutics
2008;362:2-9.
•• Describes development of Self-nanoemulsifying drug delivery system (SNEDDS) for
non-invasive delivery of protein drugs.
135. Hintzen F, Perera G, Hauptstein S, et al. In vivo evaluation of an oral self-
microemulsifying drug delivery system (SMEDDS) for leuprorelin. International journal of
136. Karamanidou T, Karidi K, Bourganis V, et al. Effective incorporation of insulin in mucus

permeating self-nanoemulsifying drug delivery systems. European Journal of Pharmaceutics and
137. Qi X, Wang L, Zhu J, et al. Self-double-emulsifying drug delivery system (SDEDDS): a
new way for oral delivery of drugs with high solubility and low permeability. International
journal of pharmaceutics 2011;409:245-51.
138. Wang X, Jiang S, Wang X, et al. Preparation and evaluation of nattokinase-loaded self-
double-emulsifying drug delivery system. asian journal of pharmaceutical sciences 2015;10:386-
95.
139. Venkata Siddhartha T, Senthil V, Sai Kishan I, et al. Design and development of oral
nanoparticulated insulin in multiple emulsion. Current drug delivery 2014;11:472-85.
140. Shima M, Tanaka M, Fujii T, et al. Oral administration of insulin included in fine
W/O/W emulsions to rats. Food Hydrocolloids 2006;20:523-31.
141. Allam AN, Komeil IA, Fouda MA, et al. Preparation, characterization and in vivo
evaluation of curcumin self-nano phospholipid dispersion as an approach to enhance oral
bioavailability. International journal of pharmaceutics 2015;489:117-23.
142. Taha EI, Al-Suwayeh SA, Anwer MK. Preparation, in vitro and in vivo evaluation of
solid-state self-nanoemulsifying drug delivery system (SNEDDS) of vitamin A acetate. Journal
of drug targeting 2009;17:468-73.
143. Shanmugam S, Baskaran R, Balakrishnan P, et al. Solid self-nanoemulsifying drug
delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of
highly lipophilic bioactive carotenoid lutein. European Journal of Pharmaceutics and
144. Rao SVR, Agarwal P, Shao J. Self-nanoemulsifying drug delivery systems (SNEDDS)
for oral delivery of protein drugs: II. In vitro transport study. International journal of
145. Rao SVR, Yajurvedi K, Shao J. Self-nanoemulsifying drug delivery system (SNEDDS)
for oral delivery of protein drugs: III. In vivo oral absorption study. International journal of
146. Park JH, Saravanakumar G, Kim K, et al. Targeted delivery of low molecular drugs using
chitosan and its derivatives. Advanced drug delivery reviews 2010;62:28-41.
147. Hallouard F, Anton N, Choquet P, et al. Iodinated blood pool contrast media for
preclinical X-ray imaging applications–a review. Biomaterials 2010;31:6249-68.
148. Hörmann K, Zimmer A. Drug delivery and drug targeting with parenteral lipid
nanoemulsions—A review. Journal of Controlled Release 2016;223:85-98.
149. Nikonenko B, Reddy VM, Bogatcheva E, et al. Therapeutic efficacy of SQ641-NE
against Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy 2014;58:587-89.
150. Hua S, Marks E, Schneider JJ, et al. Advances in oral nano-delivery systems for colon
targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus
healthy tissue. Nanomedicine: Nanotechnology, Biology and Medicine 2015;11:1117-32.
151. Laine A-L, Gravier J, Henry M, et al. Conventional versus stealth lipid nanoparticles:
formulation and in vivo fate prediction through FRET monitoring. Journal of Controlled Release
2014;188:1-8.
152. Feeney OM, Williams HD, Pouton CW, et al. ‘Stealth’lipid-based formulations: Poly
(ethylene glycol)-mediated digestion inhibition improves oral bioavailability of a model poorly
water soluble drug. Journal of Controlled Release 2014;192:219-27.
• Investigates escaping and targeting potential of stealth oral lipid-based formulations.
153. Hunter AC, Elsom J, Wibroe PP, et al. Polymeric particulate technologies for oral drug
delivery and targeting: a pathophysiological perspective. Nanomedicine: Nanotechnology,
Biology and Medicine 2012;8:S5-S20.
154. Shegokar R, Singh K. Stavudine entrapped lipid nanoparticles for targeting lymphatic
HIV reservoirs. Die Pharmazie-An International Journal of Pharmaceutical Sciences
2011;66:264-71.
155. das Neves J, Amiji MM, Bahia MF, et al. Nanotechnology-based systems for the
treatment and prevention of HIV/AIDS. Advanced drug delivery reviews 2010;62:458-77.
• Reviews antiretroviral drug targeting to HIV reservoirs using nanotechnology and lipid
formulations.
156. Komohara Y, Fujiwara Y, Ohnishi K, et al. Tumor-associated macrophages: Potential
therapeutic targets for anti-cancer therapy. Advanced drug delivery reviews 2015.
157. Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels
for drug delivery, factors involved, and limitations and augmentation of the effect. Advanced
drug delivery reviews 2011;63:136-51.
158. Kollipara S, Gandhi RK. Pharmacokinetic aspects and in vitro–in vivo correlation
potential for lipid-based formulations. Acta Pharmaceutica Sinica B 2014;4:333-49.
•• Pharmacokinetic aspects and in-vitro/in-vivo correlation (IVIVC) perspectives of lipid
formulations are discussed.
159. Porter CJ, Pouton CW, Cuine JF, et al. Enhancing intestinal drug solubilisation using
lipid-based delivery systems. Advanced Drug Delivery Reviews 2008;60:673-91.
160. Kohli K, Chopra S, Dhar D, et al. Self-emulsifying drug delivery systems: an approach to
enhance oral bioavailability. Drug discovery today 2010;15:958-65.
• Provides an acount on in-vitro analysis of SNEDDS.
161. Dai WG, Dong LC, Shi X, et al. Evaluation of drug precipitation of solubility‐enhancing
liquid formulations using milligram quantities of a new molecular entity (NME). Journal of
162. Donato EM, Martins LA, Fröehlich PE, et al. Development and validation of dissolution
test for lopinavir, a poorly water-soluble drug, in soft gel capsules, based on in vivo data. Journal
of pharmaceutical and biomedical analysis 2008;47:547-52.
163. Sek L, Boyd BJ, Charman WN, et al. Examination of the impact of a range of Pluronic
surfactants on the in‐vitro solubilisation behaviour and oral bioavailability of lipidic formulations
of atovaquone. Journal of pharmacy and pharmacology 2006;58:809-20.
164. Bahloul B, Lassoued MA, Sfar S. A novel approach for the development and
optimization of self emulsifying drug delivery system using HLB and response surface
methodology: application to fenofibrate encapsulation. International journal of pharmaceutics
2014;466:341-48.
•• Evaluates development and optimization of SNEDDS through novel (HLB-RSM)
approach.
165. Dahan A, Hoffman A. Rationalizing the selection of oral lipid based drug delivery
systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water
soluble drugs. Journal of Controlled Release 2008;129:1-10.
166. Sagitani H. Making homogeneous and fine droplet O/W emulsions using nonionic
surfactants. Journal of the American Oil Chemists’ Society 1981;58:738-43.

167. Malcolmson C, Satra C, Kantaria S, et al. Effect of oil on the level of solubilization of
testosterone propionate into nonionic oil‐in‐water microemulsions. Journal of pharmaceutical
sciences 1998;87:109-16.
168. Warisnoicharoen W, Lansley A, Lawrence M. Nonionic oil-in-water microemulsions: the
effect of oil type on phase behaviour. International Journal of Pharmaceutics 2000;198:7-27.
169. Wang L, Dong J, Chen J, et al. Design and optimization of a new self-nanoemulsifying
drug delivery system. Journal of colloid and interface science 2009;330:443-48.
170. Gullapalli RP, Sheth BB. Influence of an optimized non-ionic emulsifier blend on
properties of oil-in-water emulsions. European journal of pharmaceutics and biopharmaceutics
1999;48:233-38.
Table 1; Comparison and conceptual differences between nanoemulsions and microemulsions [3,
12, 19, 34, 55].
Sr. Characteristics Nanoemulsions Microemulsions

No.
1. Definition and droplet Colloidal dispersions of two “swollen micelle” systems
diameter immiscible liquids (consist of (micelles ranging in size below
tiny droplets with diameter 100 nm or <140 nm )
<300 nm)
2. Importance of order of Only formed when Order of mixing does not matter
mixing surfactants are first mixed (after equilibrium time)
with oils
3. Dilution and Robust, only increase Strongly affected even can be

temperature changes destability process broken up
4. Thermodynamic At non equilibrium state All the components of
stability microemulsion are at
thermodynamic equilibrium
5. Kinetic stability Kinetics of destabilization are Kinetically less stable
too slow ~months, kinetically
stable
6. Droplet size control Depends on surfactant/oil Exhibit different phases with
ratio different nanometric size
morphologies e.g. bicontinuous,
worm like, sponge like,
spherical, hexagonal etc. size
depends upon the specific phase
and morphology
7. Methods for High energy methods Spontaneous emulsification
generation (ultrasound generators, high (depends upon temperature,
pressure homogenizers) Low composition and pressure)
energy methods (spontaneous
emulsification)
8. Destabilizing process Ostwald ripening only Dilution, temperature change
etc.
9. Detection Can withstand without Affect the size and structure
a) temperature undergoing destabilization and can even reach the limit of
change and stability domain. Also conc. is
dilution lowered than CMC (critical
micelle concentration).
b) Parenteral Robust Drug is precipitated (due to
administration temperature and concentration
change)
10. Characterization Valid Invalid (droplet size increases)
methods with dilution
step
SNEDDS SMEDDS
11. Definition Preconcentrates of Preconcentrates of
nanoemulsions which upon microemulsions which upon
dilution with aqueous phase dilution with aqueous phase
produce nanoemulsions produce microemulsions with
commonly with droplet size droplet size < 200 nm
10-100 nm
12. Preparation method Ternary phase diagrams are Ternary phase diagrams are
required required which should be
coherent with different phases
involved in microemulsion
generation
Table 2; Summary of selected research articles describing formulation of supersaturated

SNEDDS.
Sr. Drug Excepients Formulation Supersaturating Bioavailability Ref.

No. (Oil, technique used (in-vitro/in
Surfactant, vivo results)
Co-surfactant,
respectively)
1. trans- LCT, Supersaturated Polymer (HPMC 1.33 fold Inc.
Resveratrol Lauroglycol L-SNEDDS 5%) AUC, 3.92 fold [68]
FCC, Inc. effective
Transcutol P permeability
2. Ezetimibe LCT, Maisine Supersaturated Polymer (HPMC 63.34 % Inc. [80]
35-1, Labrasol L-SNEDDS E5LV) plasma HDL
level as
compared to
46.5% for
SNEDDS.
3. Simvastatin Captex 300 and 200% Seq. Heating and 180% relative [85]
Capmul MCM simvastatin Cooling cycle bioavailability
mix (1:2), loaded and 2.3 hrs.
Cremophor RH Supersaturated half-life of
40, Ethanol SNEDDS simvastatin (s-
pellets SNEDDS)
compared to
1.4 hrs.
(conventional
SNEDDS)
Table 3; Summary of selected research articles describing Solid or S-SNEDDS formulations.
Sr Active Excepient Formulation Solidifying Bioavailabil Ref.

. Pharmaceutical s technique or ity (in-
No Ingredient (Oil, agent vitro/in vivo
. Surfactan results)
t, Co-
surfactant
,
respective
ly)
1. Embelin Capryol Tablets Aerosil 200 and 96.5 % drug [10
(Antibacterial,antica 90, Neusilin released 1]
ncer) Acrosyl within 15

EL 135, min in-vitro
PEG 400 compared to
5% pure
drug
2. Simvastatin Labrafil, Tablets Aeroperl as 149.62% [10
(Cholesterol Tween 80, coating material relative 2]
lowering agent) Transcutol and Avicel or bioavailabili
Starch 1500 as ty
carrier material
3. Glimperide Miglyol S-SNEDDS Aerosol 200 95 % in- [10
(Hypoglycemic 812, powder filled vitro drug 3]
agent) Tween 80, hard gelatin release
PEG 400 capsules within 1 hr.
as compared
to 15% in
case of pure
drug
4. Atorvastatin calcium Caprol Granules of Neusilin US2 90% [10
(Cholesterol 3GO, adsorbed cumulative 4]
lowering agent) Tween 20, SNEDDS drug release
N-methyl- in-vitro as
2- compared to
pyrrolidon 40% plain
e drug. 4.45
fold
Increased
permeability
coefficient
ex-vivo.
5. Talinolol Reverse Powder of S- Coffee husk 99.6 % in- [10
(anti-hypertensive) micells SNEDDS vitro drug 5]
(1:2 filled in hard release
mixture of gelatin within 2 hrs.
Capryol capsules
PGMC
and
Miglyol
1944 CS),
HCO-30,
Transcutol
HP
6. Flurbiprofen Labrafil M Powder of Aerosil 200 80 % in- [10
(NSAID) 1944 CS, adsorbed or (Silicon vitro drug 6]
Labrasol, S-SNEDDS dioxide) release after
Transcutol 20 min
HP compared to
only 40 %
for
flurbiprofen
powder.
7. Valsartan Capmul Tablets Sylysia 350 3-3.5 fold [10
(anti-hypertensive) MCM, Increased 7]
Labrasol, dissolution
Tween 80 rate with
almost all
drug
released
within one
hr.
8. Docetaxel Capryol Spray dried Colloidal Silica 17 % [93]
(Chemotherapeutic 90, SNEDDS bioavailabili
agent) Labrasol, powder ty as
Transcutol compared to
HP 2.6% for
DCT sol.
with
decreased
toxicity
profile.
9. Lovastatin Capmul Hard gelatin Filled in hard 1.62 fold [98]
(Cholesterol MCM, capsules gelatin capsules Increased.
lowering agent) Nikkol filled with dissolution
HCO-50, SNEDDS with 7.4 fold
Lutrol formulation increased
F127 effective
permeability
10 Ritonavir Peppermin Self- Neusilin 72.6% in- [10
. (Anti-retroviral) t oil, nanoemulsify vitro drug 8]
Cremopho ing granules release
re, compared to
Transcutol 66.6% pure
drug.
11 Finasteride Labrafac Spray dried Maltodextrin/le 129.35 % [10
. (5-alpha reductase cc, Tween flow able ucin carrier relative 9]
inhibitor) 80, powder of system bioavailabili
Labrasol finasteride ty compared
SMEDDS with
commercial
tablet
Table 4; Summary of some research articles describing sustained and controlled release
SNEDDS formulations;
Sr. Drug Excepients Formulation Polymer Bioavailability Ref.

No. (Oil, used (In-vitro/In-vivo
Surfactant, Co- Results)
surfactant,
respectively)
1. Cyclosporine Labrafil Controlled Cellulose 80% drug release [110]
A M1944CS, release with acetate in 12 hrs.
Transcutol P, almost zero
Cremophor EL order release
kinetics
2. Ziprasidone Capmul MCM, Sustained HPMC and 95% drug release [115]
Labrasol, release MCC within 12 hrs.
PEG400 pellets
3. Felodipine Miglyol 840, Extended Gelled 73% drug release [121]
Cremophor EL, release SNES within 12 hrs.
Capmul MCM, (formulation encased in
Aerosil 200 dependent) hydrophobic
Gelucire
coat
4. Puerarin Castor oil, Sustained HPMC and 90% drug release [118]
Cremophor EL, release MCC in 10 hrs.
1,2 Propanediol, pellets
Table 5; Summary of selected research articles describing biomolecules loaded SNEDDS
formulations.
Sr. Active Excepients Formulation Loading Bioavailability Ref.

No. pharmaceutical (Oil, efficiency (in-vitro/in-
ingredient Surfactant, and loading vivo Results)
Co- technique
surfactant,
respectively)
1. Insulin Lauroglycol L-SNEDDS 70.89 % 79 % intact [136]
FCC, (30-45 nm encapsulation insulin
Cremophor droplet of observed in-
EL, Labrafil M diameter) Hydrophobic vitro after 180
1944 CS ion pair of min, sustained

Insulin with release with 30
DMPG in % release after
SNEDDS 7 hrs.
2. Insulin Miglyol 840, L-SNEDDS 95% 3.3 fold [125]
Cremophor (80-160 nm entrapment increased AUC
EL, DMSO droplet efficiency in-vivo as
and Glycerol diameter) with polymer compared to
mixture thiolated oral insulin
chitosan solution
3. Leuprorelin Capmul MCM, L-SNEDDS Hydrophobic 17.2 fold [135]
(gonadotropin Captex 355, (50.1 nm ion pairing of improved oral
releasing Cremophor droplet leuprolide bioavailability
hormone EL, Poly diameter) acetate with in-vivo
GnRH) ethylene glycol sodium
oleate
4. pDNA Capmul MCM, L-SNEDDS Hydrophobic 8 fold [133]
(plasmid) Captex 355, (45.8-47.5 ion pairing of increased
Cremophor nm droplet lipofectin- resistant time
EL, Poly diameter) pDNA against
ethylene glycol DNAase with
improved
transfection
5. Curcumin Miglyol 812, L-SNEDDS Phospholipid 80% in-vitro [141]
(natural Phosal 53 (158-610 nm (PC) drug released
polyphenol, droplet containing within 15 min
antitumor, diameter) Phosal 53
antioxidant, increased
antidiabetic) Curcumin
solubility in
SNEDDS
6. Vitamin A Soyabean oil, S-SNEDDS Avicel used 143.68% [142]
Cremophor Tablets for relative
EL, Capmul solidifying bioavailability
MCM-C8 SNEDDS
7. Bioactive Phosal 53 S-SNEDDS Aerosil 200 2.74 fold Inc. [143]
carotenoid MCT, (100 nm for relative
lutein Labrasol, droplet solidifying bioavailability
(anti-oxidant, Transcutol HP diameter) SNEDDS, compared with
vital component Phosphatidyl commercial
found in macula choline used product
of retina ) as oil phase
8. B-Lactamase Lauroglycol L-SNEDDS Solid Only 10%
(fluorescent FCC, (22-50 nm dispersion decrease in [134,
labeled model Cremophor droplet technique enzymatic 144,
protein) EL, Transcutol diameter) activity of 145]
BLM after 12
weeks, 33 %
transportation
rate across
MDCK
monolayer, 1.5
fold Inc. BA
in-vivo
Fig. 1; Schematic diagram showing the structures of (A) Nanoemulsion droplet and (B)
Microemulsion droplet. Both are made up of surfactant, co surfactant and oil. Nanoemulsion
droplets are spherical and show polydispersity in their size (A) whereas microemulsion droplets
can be of a shape that is not necessarily spherical and all droplets are of same diameter and
shape (B).
Fig. 2; Free energy differences between separated phases of microemulsion (A), nanoemulsion
(B), microemulsion (C) and separated phases of nanoemulsion (D).A and B have higher free
energies, while C and D have lower free energies. Nanoemulsions are thermodynamically
unstable but microemulsions are thermodynamically stable systems.
Fig. 3; Fabrication of nanoemulsions involves specific mixing order in which, surfactant must be
mixed first with oil phase whereas microemulsions do not need any specific mixing order for
their formulation. Nanoemulsion particles have spherical shapes but different sizes (below 200
nm) within single formulation. *Particle size and shape of nanoemulsions is dependent on
fabrication method.
Fig. 4; Amount of permeated fluorescein diacetate across mucus barrier, from different
SNEDDS\r\nformulations with different droplet sizes (A). Effect of varying concentrations of
Triacetin (B) and\r\nCremophor RH 40 (C) on permeation of SNEDDS spiked with FDA across
mucus layer (fluorescein\r\ndiacetate).
Adapted from [127] with permission from Elsevier. ?© 2016

Expert Opinion On Drug Delivery From Nan

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Expert Opinion On Drug Delivery From Nan

Uploaded by

Copyright:

Available Formats

Expert Opinion on Drug Delivery

ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: http://www.tandfonline.com/loi/iedd20

From nanoemulsions to self-nanoemulsions, with

To link to this article: http://dx.doi.org/10.1080/17425247.2016.1218462

Accepted author version posted online: 02

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

Journal: Expert Opinion on Drug Delivery

From nanoemulsions to self-nanoemulsions, with recent advances in self-nanoemulsifying

Shefaat Ullah Shah

Ikram Ullah Khan

• Nanoemulsions provide the benefits of both “lipid formulations” and “nanotechnology”.

4 decades ago. Nanoemulsions are sometimes also referred to as “Approaching thermodynamic

classifying these fundamentally different colloidal dispersions as nanoemulsions or

Nanoemulsions and microemulsions are physicochemically different systems. Microemulsions

these are thermodynamically stable systems at equilibrium condition.

7. Returning back to original condition after cooling, heating or agitating mechanically

2.3 Way towards SNEDDS

Issues with nanoemulsions have been coped up by the emergence of spontaneously

3.1 Novel applications of SNEDDS and current research

3.1.1 Supersaturated SNEDDS

Interestingly, supersaturated SNEDDS can also be formulated without polymer or PPI

3.1.2 Solid SNEDDS

3.1.3 Controlled release solid SNEDDS

3.1.4 SNEDDS; as mucus permeation enhancing strategy

3.1.5 SNEDDS for the delivery of bio macromolecules

3.1.6 Self double nanoemulsifying drug delivery system (SDEDDS)

3.1.7 Targeted SNEDDS

3.2 Recent developments and modifications3.2.1 IVIVC for SNEDDS

3.2.2 HLB-response surface methodology

This paper was not funded

1. Kawabata Y, Wada K, Nakatani M, et al. Formulation design for poorly water-soluble

emulsifying and ‘self-microemulsifying’drug delivery systems. European Journal of

developments. Clinical pharmacology and therapeutics 2008;83:761-69.

International Journal of Pharmaceutics 2009;377:142-47.

through a sub-PIT cycle. Langmuir 2009;26:3860-67.

62. Cherniakov I, Domb AJ, Hoffman A. Self-nano-emulsifying drug delivery systems: an

73. Shahnaz G, Hartl M, Barthelmes J, et al. Uptake of phenothiazines by the harvested

International journal of pharmaceutics 2013;452:412-20.

sustained-release pellet formulation of ziprasidone with enhanced bioavailability and no food

136. Karamanidou T, Karidi K, Bourganis V, et al. Effective incorporation of insulin in mucus

surfactants. Journal of the American Oil Chemists’ Society 1981;58:738-43.

Sr. Characteristics Nanoemulsions Microemulsions

3. Dilution and Robust, only increase Strongly affected even can be

Table 2; Summary of selected research articles describing formulation of supersaturated

Sr. Drug Excepients Formulation Supersaturating Bioavailability Ref.

Sr Active Excepient Formulation Solidifying Bioavailabil Ref.

ncer) Acrosyl within 15

Sr. Drug Excepients Formulation Polymer Bioavailability Ref.

Sr. Active Excepients Formulation Loading Bioavailability Ref.

1944 CS ion pair of min, sustained

Adapted from [127] with permission from Elsevier. ?© 2016

You might also like