Review

Potentials and challenges in

self-nanoemulsifying drug
delivery systems
1. Introduction
Abdul Wadood Khan, Sabna Kotta, Shahid H Ansari,
2. Lipid formulation
Rakesh Kumar Sharma & Javed Ali†
classification system †
Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar,
3. Advantages of SNEDDS over New Delhi, India
micro/nanoemulsions
4. Formulation of SNEDDS Introduction: A significant number of new chemical entities (almost 40%),
that are outcome of contemporary drug discovery programs, have a potential
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5. Phase behavior
therapeutic promise for patient, as they are highly potent but poorly water
6. Mechanism of soluble resulting in reduced oral bioavailability. Self-nanoemulsifying drug
self-emulsification delivery systems (SNEDDS) have emerged as a vital strategy to formulate these
7. Characterization of SNEDDS poorly soluble compounds for bioavailability enhancement.
8. Applications of SNEDDS Areas covered: The review gives an insight about potential of SNEDDS with
9. Biological aspects in selection regards to oral drug delivery. The effect of various key constituents on formu-
of SNEDDS lation of SNEDDS and their applications in oral drug delivery is also discussed.
Various aspects of formulation, characterization and biopharmaceutical
10. Future trends
aspects of SNEDDS are also been explored. The choice and selection of
11. Expert opinion
excipients for development of SNEDDS is also discussed.
For personal use only.

Expert opinion: The ability of SNEDDS to present the drug in single unit
dosage form either as soft or hard gelatin capsule with enhanced solubility
maintaining the uniformity of dose is unique. With the ease of large-scale
production, high drug-loading capacity, improvement in release behavior of
poorly water-soluble drugs and improvement of oral bioavailability, SNEDDS
have emerged as preferable system for the formulation of drug compounds
with bioavailability problems due to poor aqueous solubility.

Keywords: bioavailability, lipid-based systems, oral delivery, poorly soluble drugs,

self-emulsifying

Expert Opin. Drug Deliv. [Early Online]

1. Introduction

Almost 50% of the new drugs discovered recently have poor solubility problem and
most of them encounter poor bioavailability problem when formulated as oral dos-
age form [1,2]. The poor water solubility of the drug leads to poor bioavailability
with wide inter- and intra-subject variations, presenting the formulation scientists
challenge to formulate them as oral dosage form. These poorly soluble molecules
can be classified according to the Biopharmaceutics Classification System (BCS)
either as class II or class IV. According to BCS classification, class I drugs are highly
soluble and highly permeable. BCS class II and class IV drugs are poorly soluble
compounds while class III drugs have permeability issues associated with them.
To overcome the poor aqueous solubility problem, many approaches have been
exploited such as, particle size reduction, complexation with cyclodextrins, salt for-
mation, solid dispersions, use of surfactant, nanoparticles, etc. [3-9]. The advantages
and disadvantages with these systems are well known and available in number of
reviews. However, lipid-based formulations have a great potential to improve oral
bioavailability of poor water-soluble drugs by presenting the drug in a solubilized
state in colloidal dispersion. Incorporating the lipophilic drug into inert lipid

10.1517/17425247.2012.719870 © 2012 Informa UK, Ltd. ISSN 1742-5247 1

All rights reserved: reproduction in whole or in part not permitted
 A. W. Khan et al.

into an absorbable form. The resemblance of their degrada-

Article highlights. tion product with end product of intestinal degradation has
. Objective of lipid formulation classification system is to contributed in their wide acceptance for SNEDDS.
identify the most suitable formulation system for specific
drugs based on their physicochemical properties and the 2. Lipid formulation classification system
same for the excipients.
. Self-nanoemulsifying drug delivery systems (SNEDDS)
offer more drug-loading capacity when compared with Pouton [12] and Pouton and Porter [13] introduced the lipid
lipids solution. formulation classification in 2000 in order to identify the
. Safety and regulatory status (generally regarded as safe factors affecting the in vivo behavior of formulation. One of
status (GRAS)) of the surfactant being used are the main objectives of this classification system is to identify
important factors in the formulation of SNEDDS. the most suitable formulation system for specific drugs
. The choice of the oil phase is often a compromise
between ability of oil to solubilize the drug and its based on their physicochemical properties and the same for
ability to facilitate formation of nanoemulsion with the excipients. Table 1 briefly describes the characteristics of
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desired characteristics. different systems.

. Surfactants with high hydrophilic--lipophilic balance
(HLB) and high hydrophilicity assist in formation of small
2.1 Type I
oil-in-water (o/w) droplets and rapid spreading of
formulation in aqueous media. Type I systems consist of formulations which comprise drug
. Self-emulsification occurs when the entropy change that in solution in triglycerides and/or mixed glycerides. Typically,
favors dispersion is greater than the energy required to lipophilic materials are blends of food glycerides derived from
increase the surface area of the dispersion. vegetable oils, which are safe for oral ingestion, rapidly
. Droplet size is a crucial factor in self-emulsification digested and absorbed completely from the intestine. Because
performance because it determines the rate and
extent of drug release, as well as the stability of type I systems do not contain surfactant, these systems exhibit
the emulsion. poor initial aqueous dispersion and have very limited ability
to self-disperse in water. They depend on digestion by pancre-
For personal use only.

This box summarizes key points contained in the article. atic lipase/co-lipase in the GI tract to generate more amphi-
philic lipid digestion products and promote drug transfer
into the colloidal aqueous phase. Theses system are suitable
vehicle such as oils (tri-, di- and monoglycerides), surfactant, for highly lipophilic drugs (logP > 4), where drug solubility
liposomes, self-nanoemulsifying drug delivery systems in oil is sufficient to allow incorporation of the required
(SNEDDS) can improve the poor bioavailability problem dose. The advantage of type I system lies in the generally
associated with lipophilic drugs. The present review describes regarded as safe status (GRAS) of excipients, simplicity and
how SNEDDS can be used as a strategy to improve bioavail- their compatibility with capsules.
ability of poorly water-soluble drugs. Various methods of
characterization and biopharmaceutical aspects of SNEDDS 2.2 Type II
have been discussed. The authors have tried to explain Type II lipid formulations (typically referred to as SEDDS) are
the effect of the key constituents for the formulation of isotropic mixtures of lipids and lipophilic surfactants (hydro-
SNEDDS. The selection criteria of different components philic--lipophilic balance (HLB) < 12) that self-emulsify to
and the application of SNEDDS in oral drug delivery are form fine o/w emulsions when introduced in aqueous media.
also discussed. Self-emulsifying systems are formed when the surfactant con-
SNEDDS are defined as isotropic mixtures of natural or centration exceeds 25%w/w, the optimum concentration range
synthetic oils, solid or liquid surfactants or alternatively, one being 30 -- 40% surfactant. Above 50% surfactant, these sys-
or more hydrophilic solvents and co-solvents/surfactants that tems emulsify slowly due to the formation of viscous liquid
have a unique ability of forming fine oil-in-water (o/w) emul- crystalline phases at the oil/water interface. Poorly soluble
sions on mild agitation followed by dilution in aqueous drugs can be dissolved in these systems and encapsulated in
media, such as gastrointestinal (GI) fluids [10]. SEDDS are hard or soft gelatin capsules to produce convenient single
mixtures of oils and surfactants, ideally isotropic, and some- unit dosage forms. Type II lipid-based formulations generate
times containing co-solvents, which emulsify spontaneously large interfacial areas which in turn allows efficient partitioning
to produce fine o/w emulsions when introduced into aqueous of drug between the oil droplets and the aqueous phase from
phase under gentle agitation [11]. where absorption occurs. An advantage of type II formulations
These lipid-based systems as opposed to the polymeric is that they are unlikely to lose solvent capacity on dispersion.
system are easily taken up by the body. The digestion of these
formulations involve dispersion of fat globules into a coarse 2.3 Type III
emulsion of high surface area, enzymatic hydrolysis of fatty Type III lipid-based formulations are defined by the inclusion
acid glyceryl esters (primarily triglyceride lipid) at the oil/ of hydrophilic surfactants (HLB > 12) and co-solvents such as
water interface and dispersion of the products of lipid digestion ethanol, propylene glycol (PG) and polyethylene glycol

2 Expert Opin. Drug Deliv. [Early Online]

 Potentials and challenges in self-nanoemulsifying drug delivery systems

Table 1. Lipid formulation classification system and their characteristics.

Type I Type II Type III A Type III B Type IV

No surfactant Surfactant (moderate HLB) Surfactant (higher HLB) Surfactant and co-solvent High concentration of
surfactant and co-solvent
Poor self-dispersion Self-dispersing Self-dispersing Transparent dispersion Micelle or mixed micelle
Digestion required Will be digested May function without May function without Thought to be limited
digestion digestion digestion

Reprinted from [12] with permission of Elsevier.

HLB: Hydrophilic--lipophilic balance.

(PEG). These have the potential to disperse quickly to form suitable solvent, the initial rate-limiting step of particulate
fine submicron dispersions, often fine enough to form trans- dissolution in the aqueous environment within the GI tract
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parent dispersions. Type III formulations can be further segre- is overcome by SNEDDS. The ability of SNEDDS to present
gated (somewhat arbitrarily) into type IIIA and type IIIB the drug in single unit dosage form with enhanced solubility
formulations in order to identify more hydrophilic systems maintaining dose uniformity is unique.
(type IIIB), where the content of hydrophilic surfactants and SNEDDS offers a number of advantages over the con-
co-solvents increases and the lipid content reduces. Type ventional micro/nanoemulsion systems. According to Graves
IIIB formulations typically achieve greater dispersion rates et al. [14]., nanoemulsions are metastable dispersions of submi-
when compared with type IIIA, although the risk of drug pre- crometer droplets that have a significant surface tension,
cipitation on dispersion of the formulation is higher given the which form only when extreme shear is applied to fragment
lower lipid content. The best-known example of a successfully droplets strongly and are kinetically inhibited against recom-
marketed type III is the Neoral cyclosporin formulation. In bining by repulsive interfacial stabilization due to the surfac-
contrast to the earlier Sandimmune cyclosporin formulation tant. SNEDDS on the other hand are preconcentrates that
For personal use only.

(comprising corn oil, polyoxyethylated glycerides (labrafil on mild agitation followed by dilution in aqueous media,
M-2125-CS) and ethanol) which formed a coarse emulsion form fine o/w emulsions, typically with droplet sizes between
on dispersion into water, Neoral spontaneously forms a trans- 20 and 200 nm.
parent and thermodynamically stable dispersion with a drop-
let size below 100 nm when introduced into an aqueous 3.1 Stability
media. These systems mix with water easily and take up so As these systems do not contain water, they improve the phys-
much water that penetration of water into the formulation ical and/or chemical stability on long-term storage as com-
and subsequent dispersion proceeds rapidly. pared with nanoemulsions that contain considerable amount
2.4 Type IV of water. Mahmoud et al. [15]. prepared self-nanoemulsifying
Type IV systems are essentially pure surfactants or mixtures of tablets of carvedilol and showed successful incorporation
surfactants and co-solvents, do not contain natural lipids and of carvedilol within the SNEDDS, which also improved its
represent the most hydrophilic formulations. These formula- stability on dilution with aqueous media in the presence of
tions commonly offer increased drug-loading capacity (due cellulosic polymers.
to higher drug solubility in the surfactants and co-solvents)
when compared with formulations containing simple glycer- 3.2 Patient compliance
ide lipids and also produce very fine dispersions when intro- Most of the SNEDDS formulation comes as capsule/tablet
duced in aqueous media. The blending of water-soluble dosage form, the dose is maintained and these show more
surfactants with co-solvents aids the dispersion of surfactant patient compliance [16-18].
and reduces the loss of solvent capacity. An example of a
type IV formulation is the current capsule formulation of 3.3 Palatability
the HIV protease inhibitor amprenavir (Agenerase) which As these formulations can be filled into capsules, no palatability
contains TPGS (tocopheryl polyethylene glycol succinate) as issues are there compared with other liquid formulations.
a surfactant and PEG 400 and PG as co-solvents.
3.4 Drug loading
3.Advantages of SNEDDS over micro/ Since the solubility of compounds with intermediate partition
nanoemulsions coefficient (logP 1 -- 3) are low in natural lipids compared
with amphiphilic surfactants/co-surfactants, SNEDDS offers
SNEDDS have a unique ability of forming fine o/w emul- more drug-loading capacity when compared with lipids
sions on mild agitation followed by dilution in aqueous solution owing to high concentration of surfactant and
media, such as GI fluids. As the drug is pre-dissolved in a co-surfactants and less of oil. Thomas et al. [19]. found that

Expert Opin. Drug Deliv. [Early Online] 3

 A. W. Khan et al.

SNEDDS formulated with medium-chain (MC) lipids could oil droplets are two main factors that determine the efficient
dissolve more drug compared with those formulated using release of the drug compounds from these systems. In addi-
long-chain (LC) lipids containing Cremophor
RH40 as tion, the safety and regulatory status GRAS of the surfactant
surfactant. The high drug-loading capacity is also a key factor being used are important factors in the formulation of
in success of commercial products like Fortovase
, which SNEDDS. Table 2 provides a brief account of marketed
contain 200 mg of drug per capsule. formulations formulated as self-emulsifying system.

3.5 Effect of food 4.1 Drug molecule

SNEDDS have little or no effect on absorption of drug when Drug lipophilicity and dose of drug are the main criteria that
administered with diet. The lipophilic contents of fatty diet need to be considered before development of SNEDDS. Drug
aid in absorption of these systems. In a study conducted on molecules with a logP value of greater than 4 are desirable
minipigs, Nielsen et al. [20]. found that bioavailability of pro- candidate for such system. Dose of drug should be soluble
bucol was not affected by fed and fasted state in minipigs in small quantity of oil so that it can be easily emulsified on
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when administered as SNEDDS, whereas powder formula- dilution by GI tract fluids when ingested. If higher quantities
tion showed considerable variation in fed and fasted state of oil are required for solubilization of drug, it may lead to a
bioavailability. Similarly, Grove et al. [21]. found that bioavail- formulation that can’t be filled in single dosage unit.
ability of seocalcitol in minipigs from PG solution was Charman et al. [25]. proposed that drug candidates for lym-
affected by the presence of food, whereas the bioavailability phatic transport should have a logP > 5 and, in addition, a
from the lipid-based formulations was less affected by the triglyceride solubility > 50 mg/ml. The importance of lipid
presence of food. Woo et al. [22]. observed that food had a solubility was illustrated by comparing the lymphatic trans-
marked effect on absorption of itraconazole from the mar- port of dichlorodiphenyltrichloroethane (DDT, logP 6.19)
keted formulation (Sporanox capsule), whereas the influence with hexachlorobenzene (HCB, logP 6.53). While both com-
was less pronounced for the self-emulsifying formulation of pounds have similar logP values, the difference in lymphatic
itraconazole (ITRA-GSMP capsule) in human volunteers. transport on administration in oleic acid, 33.5% of the dose
For personal use only.

in the case of DDT and 2.3% with HCB, was attributed to

3.6 Quick onset of action the 13-fold difference in triglyceride solubility. However,
Quick onset of action is required in many conditions, such as combination of a high logP and high triglyceride solubility
inflammation, hypertension and angina. SNEDDS have the does not always guarantee significant lymphatic transport.
ability to facilitate oral absorption of the drug, which results Penclomedine, an experimental cytotoxic agent with a logP
in quick onset of action. Taha et al. [23]. found that the tmax of 5.48 and a triglyceride solubility of 175 mg/ml, was poorly
(an indirect measure of quick onset of action) is reduced transported in the intestinal lymph, ~ 3% of the dose [26].
and bioavailability is increased when vitamin A is given as
SNEDD capsule and SNEDD tablet compared with vitamin 4.2 Oils
A oily solution-filled capsules without any additives. Many The choice of the oily phase is often a compromise between
other studies also reflect the potential of SNEDDS to increase ability of oil to solubilize the drug and its ability to facilitate
the bioavailability of drug. formation of nanoemulsion with desired characteristics.
Unmodified edible oils provide the most natural basis for
3.7 Ease of manufacture and scale-up lipid vehicles, but are not frequently preferred in the formula-
The success of any drug delivery system lies in its industrial tion of self-emulsifying formulations due to their poor ability
applicability. Ease of manufacture and scale-up are key to dissolve large amounts of lipophilic drugs [27,28]. Modified
parameters that govern success of industrialization. As LC and MC triglyceride oils, with varying degrees of satura-
SNEDDS require very simple and economical manufacturing tion or hydrolysis have contributed widely to the success of
facilities, such as simple mixer with an agitator and volumetric SNEDDS and are accepted for the design of self-
liquid filling equipment, they can be easily manufactured at emulsifying formulations as they offer formulative and physi-
large-scale and offer economical benefits as well. ological advantages. Their ability to form good emulsification
system with most of surfactant having GRAS status and
4. Formulation of SNEDDS resemblance of their degradation product with end product
of intestinal degradation has contributed in their wide accep-
A number of factors needed to be considered before the tance for SNEDDS [29,30]. The semi-synthetically derived oils
formulation of SNEDDS. These include the nature and form good emulsification systems when used with a large
concentration of oily phase, surfactant and co-surfactant or number of solubility enhancing surfactants approved for oral
solubilizer, the ratio of the components, especially oil-to- administration. Using a mixture of oils can also be used to
surfactant ratio, physicochemical properties of the drug, such meet optimum properties of the oily phase. Kassem
as hydrophilicity/lipophilicity, pKa, polarity, etc. Silva et al. [31]. used a mixture of oleic acid and coconut oil (in
et al. [24]. found that small particle size and polarity of resulting a ratio of 7.5:2.5 and 6.7:3.3) for the preparation of

4 Expert Opin. Drug Deliv. [Early Online]

 Potentials and challenges in self-nanoemulsifying drug delivery systems

Acute promyelocytic leukemia

clotrimazole (CT), a lipophilic imidazole derivative with anti-
mycotic action, loaded SNEDDS. The prepared SNEDDS

Recalcitrant nodular acne

provided satisfactory properties in terms of droplet size,
Immune suppressant

Immune suppressant
Immune suppressant
Indication
turbidity values and immediate drug release that could

Calcium regulator
increase the bioavailability profile of CT. Basalious et al. [32].

Antineoplastic
used a mixture of Labrafil
/Capmul
in the ratio of 2:1 w/w

antiviral
antiviral
antiviral
antiviral
for preparing SNEDDS to improve dissolution and oral
absorption of lacidipinee, a calcium channel blocker.
HIV
HIV
HIV
HIV
Prajapati et al. [33]. performed a comparative evaluation of
Hoffmann-La Roche Inc. mono-, di- and triglyceride of MC fatty acids in order to
select component for optimal lipid-based formulation.
Boehringer Ingelheim
Abbott Laboratories

Abbott Laboratories

They found that with same surfactant monoglyceride

Company

GlaxoSmithKline

formed a clear microemulsion while gel phase was formed

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in case of di- and triglycerides. When a mixture of mono-

glyceride with di- or triglyceride was used at a ratio of 1:1,
Polyoxyl 40 hydrogenated castor oil Novartis

Novartis

Ligand
Roche
Roche

Roche the gel phase eliminated and microemulsions were formed.

This clearly indicated that using a mixture of lipids is
superior to individual lipid alone.
Surfactant/Co-surfactant used

Partially hydrogenated soybean oil

Thomas et al. studied the influence of lipid composition

and drug load on the in vitro performance of SNEDDS and
found that triglyceride chain length can influence the amount
of drug that can be loaded in SNEDDS formulation. When
Cremophor RH is used as surfactant, MC lipids could
dissolve more simvastatin compared with those formulated
DL-a-Tocopherol
For personal use only.

Polysorbate 80

using LC lipids [19]. In addition, since MC triglycerides are

Table 2. Examples of marketed formulations formulated as self-emulsifying systems.

Polysorbate

not subject to oxidation, they are popular choice for use in

Oleic acid
PEG 400

PEG 400

lipid-based products.
PEG
NA

NA

NA

4.3 Surfactants
Hydrogenated soybean oil

Hydrogenated soybean oil

Surfactants are essential components in the formulation of

Mono-, di-, triglycerides

Mono- and diglycerides

SNEDDS, as these provide the emulsifying properties. The

Hard gelatin capsule Polyoxyl 35 castor oil

Polyoxyl 35 castor oil

Polyoxyl 35 castor oil
Oil/Lipid used

D-a Tocopheryl PEG

type of surfactant and concentration of the surfactant in the

MC triglycerides

SNEDDS has considerable influence on the droplet size of

1000 succinate

the formed nanoemulsions. The two important factors that

Soybean oil

Soybean oil
Macrogol

are to be considered while selecting a surfactant are its HLB

Corn oil

Soft gelatin capsule Corn oil

value and concentration. The HLB of a surfactant gives

vital information on its potential utility in formulation of
SNEDDS. For attaining high emulsifying performance, the
Soft gelatin capsule

capsule
capsule
capsule
capsule

Soft gelatin capsule

Soft gelatin capsule
Soft gelatin capsule

Soft gelatin capsule

emulsifier involved in formulation of SNEDDS should have

Dosage form

CsA: Cyclosporin; MC: Medium-chain; PEG: Polyethylene glycol.

high HLB (> 12) and high hydrophilicity which assists in for-
mation of small o/w droplets and rapid spreading of formula-
gelatin
gelatin
gelatin
gelatin

tion in aqueous media. It would keep drug solubilized for a

prolonged period of time at the site of absorption for effective
Soft
Soft
Soft
Soft

absorption, so precipitation of drug compound within GI

lumen is prevented. Certain surfactants might cause irritation
Trade name Active ingredient

to the GI mucosa and skin at higher concentrations. In such

cases, a mixture of surfactants can be used [34]. Thus, the selec-
Amprenavir

Bexarotene

Isotretinoin
Saquinavir

tion of surfactant is crucial for the formulation of SNEDDS

Tipranavir

Tretinoin
Ritonavir

Calcitriol

and the surfactant concentration in SNEDDS should be

CsA/III
Sandimmune CsA/II
CsA/I

kept at a minimal level as far as possible.

As a general rule, non-ionic and zwitterionic surfactants
tend to be less toxic than ionic surfactants and are therefore
Fortovase

Agenerase

Targretin

Rocaltrol

Gengraf

Accutane

Vesanoid

more widely used as pharmaceutical excipients [35]. Assuming

Aptivus
Neoral

Norvir

that the surfactants do not degrade into toxic materials,

surfactants having biodegradable/chemically unstable linkers

Expert Opin. Drug Deliv. [Early Online] 5

 A. W. Khan et al.

tend to exhibit less chronic toxicity than those that are chemi- It should be noted that not every combination of components
cally stable. For example, as a group, the polyoxyethylene produce nanoemulsions over the whole range of possible
n-acyl surfactants exhibit ~ 10 times less chronic toxicity compositions, in some instances the extent of nanoemulsion
than their n-alkyl counterparts, mainly due to their quicker formation may be very limited.
degradation time of days as opposed to weeks. When it comes Construction of phase diagram is a useful approach to
to comparing acute toxicity, the two groups of surfactants illustrate the complex series of interactions that can occur
exhibit comparable toxicity [36,37]. when different components are mixed. Constructing phase
It has also been shown that micellar solubilization of diagrams is time consuming, particularly when the aim is
lipophilic drugs with high concentrations of surfactants in to accurately delineate a phase boundary, as the time taken
the formulation significantly affected the amount of free for the system to equilibrate can be greatly increased as the
drug and extent of absorption [38,39]. The intestinal absorption phase boundary is approached. The procedure most often
of griseofulvin in rats was reported to decrease in the presence employed is to prepare a series of (pseudo)binary composi-
of 20 mM taurocholate as a result of micellar solubi- tions and titrate with the third component, evaluating the
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lization [39]. In a study carried out on a formulation of cyclo- mixture after each addition. Care must be taken to ensure
sporin A (CsA) containing surfactant such as Cremophor EL not only that the temperature is precisely and accurately
or RH40 and TPGS at concentrations above 0.02% w/v, controlled, but also that observations are not made on
demonstrated a decrease in permeability of CsA, which was metastable systems [37].
attributed to micellar solubilization [39]. Garti et al. [45]. studied the effects of polyols (PG and
glycerol) and a short-chain alcohol (ethanol) on the phase
4.4 Co-solvents behavior of non-ionic and non-ionic/PC (phosphatidylcho-
Co-solvents such as ethanol, PG and PEG are required to line) surfactant mixtures and food grade oils and found
enable the dissolution of large quantities of hydrophilic surfac- that the formulation of food grade o/w microemulsions
tant. Inclusion of the co-solvents or solubilizers in SNEDDS was difficult to formulate from a three-component systems
may result in expansion of self-nanoemulsification region in based on water, oil and single surfactant. However, it was
For personal use only.

the phase diagrams. It should be noted while the incorporation possible to formulate these microemulsions by using a suit-
of solubilizers can improve drug loading into SNEDDS, able non-ionic surfactant and by the addition of polyols
they might compromise droplet size of the nanoemulsion in and short-chain alcohols. The phase behavior of the system
certain cases, as observed by Anton and Vandamme [40]. The of R(+)-limonene, ethanol, water/PG (1:1) and polyoxyethy-
lipid mixture with higher surfactant and co-surfactant:oil lene sorbitan monostearate (Tween 60) containing a 1:1:3 R
ratios leads to the formation of SMEDDS [41,42]. Alcohol (+)-limonene/ethanol/surfactant weight ratio was characte-
and other volatile co-solvents have the disadvantage of rized by a single continuous microemulsion region starting
evaporating into the shell of soft or hard gelatin capsules, from a pseudobinary solution (surfactant/oil phase) to the
leading to precipitation of drug. microemulsion water/PG (1:1) corner. On dilution, the vis-
cosity measurements indicated that at a certain composition
5. Phase behavior the system inverted from w/o to o/w microemulsion. They
proposed that optimal composition of the polar and apolar
The relationship between the phase behavior of a mixture and phases led to formation of a large isotropic area with a
its composition can be captured with the aid of a phase dia- high content of solubilized oil.
gram. The phase behavior of simple nanoemulsion systems At low surfactant concentration multiple phases may exist.
comprising oil, water and surfactant can be studied with the Within this region and other multiphase regions of the
aid of ternary phase diagram in which each corner of the dia- ternary phase diagram, nanoemulsion can exist in equilibrium
gram represents 100% of that particular component. More with the excess water or oil phase, these phases are referred to
commonly, however, the nanoemulsion will contain addi- as Winsor phases [37,43,44,46]:
tional components such as a co-surfactant and/or drug [37].
When oil, water and surfactants (with or without co-surfac- 1. Winsor I: With two phases, the lower (o/w) nanoemulsion
tant) are mixed, nanoemulsions are one of a number of asso- phase in equilibrium with the upper excess oil.
ciation structures (including emulsion, micelles, lamellar, 2. Winsor II: With two phases, the upper (w/o) nanoemulsion
hexagonal and cubic and various gels and oily dispersion) phase in equilibrium with the lower excess water.
that can form, depending on the chemical composition and 3. Winsor III: With three phases, middle nanoemulsion phase
concentration of each component [43,44]. In the case where (o/w plus w/o, called bicontinuous) in equilibrium with upper
four or more components are investigated, pseudoternary excess oil and lower excess water.
phase diagrams are used where a corner will typically represent 4. Winsor IV: In single phase, with oil, water and surfactant
a binary mixture of two components such as surfactant/co- homogeneously mixed. In the Winsor classification, the
surfactant, water/drug or oil/drug. The number of different one phase nanoemulsions that are generally explored as drug
phases present for a particular mixture can be visually assessed. delivery systems are known as Winsor IV systems.

6 Expert Opin. Drug Deliv. [Early Online]

 Potentials and challenges in self-nanoemulsifying drug delivery systems

Drug in capsule taken orally

Nanoemulsion formed in GI fluid

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Figure 1. Process of nanoemulsion formation from SNEDDS taken orally.

For personal use only.

6. Mechanism of self-emulsification phases effectively swells, thereby allowing spontaneous

formation of an interface between the oil droplets and water.
The mechanism by which self-emulsification take place is not The combination of particle size analysis and low frequency
fully understood. Spontaneous emulsification is produced by dielectric spectroscopy was used by Craig et al. [50]. to examine
different mechanisms which seem to be affected by the system the self-emulsifying properties of a series of IMWITOR 742
composition, the physicochemical characteristics and the (is a blend of mono-, di- and triglycerides of capric and
protocol of emulsification (i.e., the way in which the compo- caprylic acids)/Tween 80 systems [50-52]. The dielectric studies
nents are added and how the thermodynamic properties of the gave evidence that the formation of the emulsions may
system are changed). be associated with liquid crystalline phase formation,
The thermodynamic treatment of conventional emulsion although the relationship was clearly complex [52]. Figure 1
formation has been described by Reiss [47], where the free describes the process of nanoemulsion formation from
energy of emulsion formation is a direct function of the SNEDDS taken orally.
energy required to create a new surface between the formed Solans and collaborators [53,54] studied the formation of
phases. This can be given as: nanoemulsions in a system consisting of water/Brij 30/decane
at 25 C by three low-energy emulsification methods. In the
ΔG = ∑ i (N i 4 πri 2 σ) first method, oil was added stepwise to a water--surfactant
Where DG is the free energy associated with the process, N is mixture, the second method was stepwise addition of water
the number of droplets of radius r and s is the interfacial to a solution of the surfactant in oil and in third method all
energy. Formed phases will tend to separate over time in order the components were mixed together. The emulsion compo-
to reduce the interfacial energy, and hence reduce the free sition had a 5.0% by weight surfactant and an oil weight
energy of the system. Conventional emulsifying agents such fraction, ranging between 0.2 and 0.8. They obtained nanoe-
as surfactants reduce the interfacial energy by forming a layer mulsions with average droplet size of 50 nm and high kinetic
around the emulsion particles, which in turn provides a stability only with second method, at oil weight fractions,
barrier to coalescence. In this case, however, the separation lower than 0.3. Independent of oil fraction, emulsions
of the phases is merely being delayed as these emulsions obtained by method 2 had lower polydispersity than those
are still thermodynamically unstable. In the case of self- obtained by methods 1 and 3.
emulsifying systems, the free energy required to form the Similarly, Sole et al. [55]. also studied the effect of different
emulsion is either very low or negative when the formation dilution procedures on the formation of nanoemulsions
is thermodynamically spontaneous. It was reported by obtained by dilution of w/o and o/w microemulsions in the
Groves and Galindez [48] and Wakerly et al. [49]. that a liquid water/SDS (sodium dodecyl sulfate)/co-surfactant/dodecane
crystalline phase formed between the oil/surfactant and water system, with hexanol or pentanol as co-surfactants. They

Expert Opin. Drug Deliv. [Early Online] 7

 A. W. Khan et al.

found that dilution with water induced part of the co- an oil droplet is negative because of the presence of free
surfactant molecules to dissolve into water, and the system fatty acids [64]. Since SNEDDS are preconcentrate mixture
became thermodynamically unstable giving rise to the of drug in oil and surfactant and emulsify in vivo only,
nanoemulsion droplets. some investigators consider zeta potential as secondary
7. Characterization of SNEDDS characterization parameter.

The primary means of self-emulsification assessment is visual 7.5 Dispersibility tests

evaluation. The efficiency of self-emulsification could be The efficiency of self-emulsification is assessed using the
estimated by determining the rate of emulsification, droplet standard European Pharmacopoeia (Ph. Eur., 2008) dissolu-
size distribution and turbidity measurements. tion apparatus 2 (Erweka, Germany). One milliliter of each
formulation was added drop wise to 200 ml of simulated
7.1 Determination of emulsification time
intestinal fluid (SIF) pH 6.8 without enzymes at 37 C.
In order to quantify the efficiency of emulsification of system
A standard stainless steel dissolution paddle rotating at
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Serials Unit - Library on 09/10/12

comprising Tween 85 with MC triglyceride, Pouton [56] uti-

60 rpm provides the gentle agitation. Precipitation was
lized rotating paddle to promote emulsification in crude
evaluated by visual inspection of the resultant emulsion after
nephelometer. This enabled an estimation of the time taken
24 h. The formulations were then categorized according to
for emulsification. On completion of emulsification, samples
their appearance as whitish, dull white and milky, and
were taken for particle sizing by photon correlation spect-
stable (no precipitation after 24 h) or unstable (showing
roscopy and self-emulsified systems were compared with
precipitation within 24 h) [65].
homogenized systems. The process of self-emulsification was
observed using light microscopy. The mechanism of emulsifi-
cation was found to involve erosion of a fine cloud of small
8. Applications of SNEDDS
particles from the surface of large droplets, rather than a
8.1 Application to drug delivery
progressive reduction in droplet size.
To improve the solubility and dissolution of lutein, a natu-
For personal use only.

rally occurring oxygenated carotenoid that acts as a potent

7.2 Droplet size antioxidant and effective screening agent of high energy blue
Droplet size is a decisive factor in self-emulsification perfor- light and plays important role in the prevention of age-
mance because it determines the rate and extent of drug related macular degeneration (AMD), cataracts and other
release, as well as the stability of the emulsion. The techniques blinding disorders, Yoo et al. [66]. prepared SNEDDS that
that are mainly used for the determination of droplet size are consists of Phosal 53 MCT as oily phase, Labrasol as surfac-
photon correlation spectroscopy, microscopic techniques or a tant and Transcutol-HP as co-surfactant. The prepared
Coulter Nanosizer [57,58]. Wang et al. found that the ibupro- formulation consists of 25% oil, 60% surfactant and 15%
fen release rate relied on the mean droplet size of carrier emul- co-surfactant. Immediate dissolution of drug within 5 min
sions generated from SNEDDS in dilute media. SNEDDS was obtained from the optimized SNEDD formulation which
that yielded nanoemulsion of droplet size 58 nm released was mixed with Aerosil 200 to solidify it, while there was no
more than 95% of the encapsulated ibuprofen within dissolution from lutein powder or a commercial product
30 min, which was significantly faster than the control (Eyelac
).
experiment using a conventional tablet [59]. In order to improve the problems associated with the deli-
very of Gliclazide, an antidiabetic drug, Wankhade et al. [67].
7.3 Turbidity measurement developed SNEDDS formulation. Gliclazide showed poorly
This identifies efficient self-emulsification by establishing bioavailability and pH-dependent solubility. The developed
whether the dispersion reaches equilibrium rapidly and in a formulation consisting of Cremophor EL, Akoline MCM
reproducible time [60]. These measurements are carried out on and Caproyl 90 as oily phase, surfactant and co-surfactant
turbidity meters, most commonly the Hach turbidity meter yielded nanoemulsion with mean globule size 146 nm, which
and the Orbeco-Helle turbidity meter [61,62]. In this method was not affected by the pH of dilution medium. The opti-
to determine clarity of nano- or microemulsion formed and mized SNEDDS released the Gliclazide drug completely
emulsification time, the apparatus is connected to a dissolution within 20 min irrespective of the pH of dissolution medium.
apparatus and optical clarity of formulation is taken every 15 s.
Turbidity can also be observed in terms of spectroscopic 8.2 Improvement in solubility and bioavailability
characterization of optical clarity (i.e., absorbance of suitably Incorporation of a drug into a SNEDDS improves the
diluted aqueous dispersion at 400 nm) [63]. solubility and hence the bioavailability of drug as the dissolu-
tion step is bypassed. The drug is presented solubilized in
7.4Zeta potential the carries at the site of absorption, which makes it easy to
The charge of the oil droplets is another property that cross the biological membrane and reach the site of action.
should be assed. In conventional SNEDDS, the charge on Ketoprofen, a moderately hydrophobic (logP 0.979)

8 Expert Opin. Drug Deliv. [Early Online]

 Potentials and challenges in self-nanoemulsifying drug delivery systems

non-steroidal anti-inflammatory drug (NSAID), is a drug of In a different approach, Nazzal et al. [72]. determined the
choice for sustained-release formulation that has high poten- potential of a reversibly induced re-crystallized semi-solid
tial for gastric irritation during chronic therapy. Also because SNEDDS, based on a eutectic interaction between the drug
of its low solubility, ketoprofen shows incomplete release and the carrying agent, as an alternative to a conventional
from sustained release formulations. Different formulation SEDDS. In these eutectic-based self-nanoemulsified systems,
approaches that have been sought to achieve sustained release, the melting point depression method allows the oil phase con-
increase the bioavailability, and decrease in the gastric irrita- taining the drug itself to melt at body temperature from its semi-
tion of ketoprofen include preparation of matrix pellets of solid consistency, and disperse to form emulsion droplets in the
nanocrystalline ketoprofen, sustained-release ketoprofen nanometer size range. Emulsion systems based on a eutectic
microparticles and formulations, floating oral ketoprofen mixture of lidocaine--prilocaine [73] and lidocaine--menthol [74]
systems and transdermal systems of ketoprofen. have been used in the preparation of topical formulations.
Preparation and stabilization of nanocrystalline or improved However, little is known of the use of eutectic mixtures for the
solubility forms of drug may pose processing, stability and eco- preparation of self-(micro)emulsified formulations.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Serials Unit - Library on 09/10/12

nomic problems. This problem can be successfully overcome

when ketoprofen is presented in self-emulsifying formulation. 8.3 Protection against biodegradation
This formulation enhanced bioavailability due to increase in The ability of self-emulsifying drug delivery system to reduce
the solubility of drug and minimizes the gastric irritation. degradation as well as improve absorption may be especially
Also incorporation of gelling agent in SEDDS sustained the useful for drugs, for which both low solubility and degradation
release of ketoprofen [68]. in the GI tract contribute to a low oral bioavailability. Many
In SNEDDS, the lipid matrix interacts readily with water, drugs are degraded in physiological system, may be because
forming a fine particulate o/w emulsion. The emulsion drop- of acidic pH in stomach, enzymatic degradation or hydrolytic
lets will deliver the drug to the GI mucosa in the dissolved degradation, etc. Such drugs when presented in the form of
state readily accessible for absorption. Therefore, increase in SNEDDS can be well protected against these degradation
area under curve (AUC), that is, bioavailability and Cmax is processes as liquid crystalline phase in SNEDDS might act as
For personal use only.

observed with many drugs when presented in SNEDDS. barrier between degrading environment and the drug. Acetyl-
Lipid-based formulations have showed a great potential to salicylic acid (logP = 1.2, Mw = 180), is readily hydrolyzed
improve the bioavailability of chemotherapeutic drug. Hanan to salicylic acid in the acidic environment of GI tract and
and El-Laithy [69] developed SNEDDS containing biphenyl show degradation in the GI tract. When the drug was formu-
dimethyl dicarboxylate (BDD), a hepatoprotector that is cur- lated in a Galacticles Oral Lipid Matrix System (SEDDS
rently employed as an agent against virally induced hepatic formulation) and compared with a commercial formulation,
injury, using Tween 80 to Transcutol as surfactant and co- it showed the good plasma profile as compared with reference
surfactant, respectively and Miglyol 812 as oil and found formulation. The oral bioavailability of undegraded acetylsali-
that the oral absorption and bioavailability of SNEDDS con- cylic acid improved by 73% by the Galacticles Oral Lipid
taining BDD in albino rats were significantly enhanced Matrix System formulation compared with the reference for-
(p < 0.01) with an average improvement of 1.7- and 6-fold mulation. This suggests that the self-emulsifying formulation
that of commercial Chinese pilules
and Pennel capsules
, has a capacity to protect drugs from degradation in the GI
respectively. The study revealed the potentials of self- tract. Supersaturable SEDDS contain a reduced amount of
emulsifying system over the orally administered conventional a surfactant and a water-soluble cellulosic polymer (or other
formulations. polymers) to prevent precipitation of the drug by generating
Similarly, Zhao et al. observed an increase of 1.7- and and maintaining a supersaturated state in vivo.
2.5-fold in AUC and Cmax, respectively when Zedoary An approach which will increase drug solubility and protect
turmeric oil (ZTO), an essential oil extracted from the dry drug from degradation by cholinesterase in intestinal washings
rhizome of Curcuma zedoaria was administered as SNEDDS is highly desirable for optimizing the therapeutic performance
orally to rats [70]. The optimized formulation consisted of cefpodoxime proxetil (CFP), a poorly bioavailable high-
of ZTO, ethyl oleate, Tween 80, Transcutol P in a ratio of dose antibiotic having pH-dependent solubility. Date and
30.8:7.7:40.5:21 w/w, respectively. Nagarsenker [75] developed CFP SNEDDS consisting of
Khoo et al. [71]. reported the preparation of a halofantrine- Cremophor EL, Akoline MCM and Capryol 90 that yielded
containing lipid-based solid self-emulsifying system using nanoemulsion of mean globule size 170 nm, released CFP
either vitamin E TPGS or a blend of Gelucire 44:14 and completely within 20 min. The system provided 100% release
Vitamin E TPGS as the base. On dispersal, these systems which is independent of pH of dissolution media.
produced dispersions that the authors described as microe-
mulsions. Studies in fasted dogs showed that these solid 9. Biological aspects in selection of SNEDDS
dispersions exhibited a five- to sevenfold improvement in
absolute oral bioavailability, when compared with the Very few biopharmaceutical studies have been performed with
commercially available tablet formulation. SNEDDS [76], and there is a need for more comparative

Expert Opin. Drug Deliv. [Early Online] 9

 A. W. Khan et al.

studies, particularly against simple oils and solid dosage formulations, for poorly water-soluble drugs. Successful
forms. At this stage, however, it is worth speculating on the large-scale production of the SNEDDS exemplified by
issues that will influence the absorption from SNEDDS [77]. immunosuppressive agent CsA (Neoral, 165 Novartis Phar-
The rate of gastric emptying of SNEDDS is similar to maceuticals Corp., East Hanover, NJ, USA), and for the
solutions, so they are particularly useful where rapid onset of two HIV protease inhibitors ritonavir (Norvir, Abbott Labo-
action is desirable. Conversely, if the therapeutic index of ratories, Abbott Park, IL, USA) and saquinavir (Fortovase,
the drug is low, the rapid onset and accompanying high Thalf Roche Pharmaceuticals, Nutley, NJ, USA), has generated
might lead to undesirable side effects. With regard to bioavail- considerable interest not only among the scientists commu-
ability, there are differences between formulations that nity but also among different pharmaceutical companies.
contain water-soluble surfactants or co-solvents and those These systems offer a number of advantages including mainte-
that do not. The former systems can produce emulsions or nance of dose and stability among several others. The high
micellar solutions with a lower capacity for solubilization of drug-loading efficiency and positive food effect make them
drugs, which might result in precipitation of drugs in the unique system for the enhancing absorption of poorly soluble
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Serials Unit - Library on 09/10/12

gut. SNEDDS formed with relatively hydrophobic surfactants drugs (BCS class II and class IV). However, a considerable gap
(HLB 8 -- 12), such as Tween 85 or Tagat TO, which do not exists between the need for lipid-based drug delivery systems
migrate into the aqueous phase, tend to have lower solvent and their application, as reflected by the low number of
capacities for drugs unless logP (drug) > 4. These SNEDDS marketed drug products relying on oral lipid-based formula-
should be preferable, however, if the drug can be dissolved tions. Questions regarding the physical and chemical stability
to an adequate extent. Highly potent but poorly water- of drugs solubilized in lipid and excipients mixture have
soluble drug candidates are a common outcome of contempo- not yet been adequately addressed. These formulations must
rary drug discovery programs and present several challenges be designed to work in harmony with the physiological
to drug development, most notably, the issue of reduced environment.
systemic exposure after oral administration [78]. Formulating a lipophilic drug as SNEDDS requires careful
selection of the components. From the formulation point of
For personal use only.

10. Future trends view, it is necessary to consider the emulsification properties

of lipid vehicle and the solubility of drug in an oil or oil--
In relation to formulation development of poorly soluble drugs surfactant mixture. Since the concentration of surfactants is
in the future, there are now techniques being used to convert high in SNEDDS, chronic use of these systems requires care-
liquid/semi-solid SNEDDS formulations into powders and ful monitoring. The regulatory status of various ingredients
granules, which can then be further processed into conventional and their safety are of prime concern. The physical and chem-
‘powder-fill’ capsules or even compressed into tablets. There is ical changes in the excipients over time could potentially
also increasing interest in using inert adsorbents, such as the impact drug stability and formulation performance with
Neusilin (Fuji Chemicals, Toyama, Japan) and Zeopharm time. The incorporation of bioactive excipients should be
(J.M. Huber Corp., Edison, NJ, USA) products for converting explored, and known biochemical processes in the GI tract
liquids into powders that help in formulation of solid should be exploited. Self-emulsifying drug delivery system in
SNEDDS. But to obtain solid SNEDDS with suitable proces- solid dosage form has improved solubility/dissolution,
sing properties, the ratio of SNEDDS to solidifying excipients absorption and bioavailability for poorly water-soluble drug.
must be very high [79], which seems to be practically non- The area of solid SNEDDS is to be explored for development
feasible for drugs having limited solubility in oil phase. In into different solid dosage form for oral and parenteral
this regard, it was hypothesized that the amount of solidifying administrations.
excipients required for transformation of SNEDDS in solid In future, effective tests should be developed and utilized to
dosage forms will be significantly reduced if SNEDDS is gelled. understand and predict the in vivo behavior of these systems.
Colloidal silicon dioxide (Aerosil 200) is selected as a gelling The role of individual component in dispersion process,
agent for the oil-based systems, which may serve the dual pur- drug solubilization and emulsion formation should be the
pose of reducing the amount of solidifying excipients required focus area.
and aiding in slowing drug release.
Declaration of interest
11. Expert opinion
The authors are grateful to the Life Sciences Research Board,
Recently, lipid-based drug delivery systems have been getting Government of India for providing fellowship as financial
more attention among scientists for the development of assistance.

10 Expert Opin. Drug Deliv. [Early Online]

 Potentials and challenges in self-nanoemulsifying drug delivery systems

Bibliography
Papers of special note have been highlighted as system: a review. Res J Pharm Tech formulations to minipigs in the fasted
either of interest () or of considerable interest 2008;1(4):313-23 and fed state. Eur J Pharm Sci
() to readers. 12. Pouton CW. Lipid formulations for oral 2007;31(1):8-15

1. Stegemann S, Leveiller F, Franchi D, administration of drugs: non-emulsifying, 22. Woo JS, Song YK, Hong JY, et al.
et al. When poor solubility becomes an self-emulsifying and Reduced food-effect and enhanced
issue: from early stage to proof of ‘self-microemulsifying’ drug delivery bioavailability of a self-microemulsifying
concept. Eur J Pharm Sci systems. Eur J Pharm Sci formulation of itraconazole in healthy
2007;31:249-61 2000;11(Suppl 2):S93-8 volunteers. Eur J Pharm Sci
. Describes the lipid formulation 2008;33(2):159-65
2. Liversidge EM. Nanocrystals: resolving
classification system based on the 23. Taha E, Ghorab D, Zaghloul AA.
pharmaceutical formulation issues
composition of formulation. Bioavailability assessment of vitamin a
associated with poorly water-soluble
compounds, paper 45. Particles; 13. Pouton CW, Porter CJ. Formulation of self-nanoemulsified drug delivery systems
lipid-based delivery systems for oral in rats. A Comp Study Med Princ Pract
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Serials Unit - Library on 09/10/12

Orlando, Florida: 2002. p. 20-3

administration: materials, methods and 2007;16:355-9
3. York P. The design of dosage forms. In:
strategies. Adv Drug Deliv Rev 24. Silva BFB, Marques EF, Olsson U, et al.
Aulton ME, editor. Pharmaceutics the
2008;60:625-37 Size, Shape, and charge of salt-free
science of dosage form design. Churchill
Livingstone; Edinburgh: 1988. p. 1-13 14. Graves S, Meleson K, Wilking J, et al. catanionic microemulsion droplets:
Structure of concentrated nanoemulsions. a small-angle neutron scattering and
4. Cavallari C, Abertini B,
J. Chem. Phys 2005;122:134703-6 modeling study. J Phys Chem B
Gonzalez-Rodriguez ML, Rodriguez L.
15. Mahmoud EA, Bendas ER, 2009;113:10230-9
Improved dissolution behaviour of
steam-granulated piroxicam. Eur J Mohamed MI. Preparation and 25. Charman WN, Noguchi T, Stella VJ. An
Phar Biopharm 2002;54:65-73 evaluation of self-nanoemulsifying tablets experimental system designed to study
of carvedilol. AAPS PharmSciTech the in situ intestinal lymphatic transport
5. Serajuddin ATM. Solid dispersion of
2009;10(1):183-92 of lipophilic drugs in anesthetized rats.
poorly water soluble drugs: early
For personal use only.

16. Gao P, Morozowich W. Development of Int J Pharm 1986;33:155-64

promises, subsequent problems and
recent breakthroughs. J Pharm Sci supersaturatable selfemulsifying drug 26. Myers RA, Stella VJ. Factors affecting
1999;88:1058-66 delivery system formulations for the lymphatic transport of penclomedine
improving the oral absorption of poorly (NSC-338720), a lipophilic cytotoxic
6. Aungst BJ. Novel formulation strategies
soluble drugs. Expert Opin Drug Discov drug: comparison to DDT and
for improving oral bioavailability of
2006;3:97-110 hexachlorobenzene. Int J Pharm
drugs with poor membrane permeation
17. Nazzal S, Khan MA. Controlled release 1992;80:511-162
or presystemic metabolism. J Pharm Sci
1993;82:979-86 of a self-emulsifying formulation 27. Zhao Y, Wang C, Chow AHL, et al.
formulation from a tablet dosage form: Self-nanoemulsifying drug delivery
7. Paradkar A, Ambike AA, Jadhav BK,
stability assessment and optimization of system (SNEDDS) for oral delivery of
Mahadik KR. Characterization of
some processing parameters. Int J Pharm Zedoary essential oil: formulation and
curcumin-PVP solid dispersion obtained
2006;315:110-21 bioavailability studies. Int J Pharm
by spray drying. Int J Pharm
18. Gao P, Rush BD, Pfund WP. 2010;383:170-7
2004;271:281-6
Development of a supersaturable SEDDS 28. Odeberga JM, Kaufmannb P,
8. Aungst BJ, Nguyen N, Rogers NJ, et al.
(S-SEDDS) formulation of paclitaxel Kroonc KG, H€oglunda P. Lipid drug
Improved oral bioavailability of an HIV
with improved oral bioavailability. delivery and rational formulation design
protease inhibitor using Gelucire 44/
J Pharm Sci 2003;92:2386-98 for lipophilic drugs with low oral
14 and Labrasol vehicles. B T Gattefosse
19. Thomas N, Müllertz A, Graf A, bioavailability, applied to cyclosporine.
1994;87:49-54
Rades T. Influence of lipid composition Eur J Pharm Sci 2003;20:375-82
9. Kotta S, Khan AW, Pramod K, et al.
and drug load on the in vitro 29. Kimura M, Shizuki M, Miyoshi K, et al.
Exploring oral nanoemulsions for
performance of self-nanoemulsifying drug Relationship between the molecular
bioavailability enhancement of poorly
delivery systems. J Pharm Sci structures and emulsification properties
water-soluble drugs. Expert Opin
2012;101:1721-31 of edible oils. Biosci Biotech Biochem
Drug Deliv 2012;9(5):585-98
20. Nielsen FS, Petersen KB, Müllertz A. 1994;58:1258-61
10. Singh B, Bandopadhyay S, Kapil R, et al.
Bioavailability of probucol from lipid 30. Hauss DJ, Fogal SE, Ficorilli JV, et al.
Self-emulsifying drug delivery systems
and surfactant based formulations in Lipid-based delivery systems for
(SEDDS): formulation development,
minipigs: influence of droplet size and improving the bioavailability and
characterization, and applications.
dietary state. Eur J Pharm Biopharm lymphatic transport of a poorly
Crit Rev Ther Drug Carrier Syst
2008;69(2):553-62 water-soluble LTB4 inhibitor.
2009;26:427-521
21. Grove M, Müllertz A, Pedersen GP, J Pharm Sci 1998;87:164-9
11. Patel PA, Chaulang GM, Akolkotkar A,
Nielsen JL. Bioavailability of seocalcitol 31. Kassem AA, Marzouk MA, Ammar AA,
et al. Self emulsifying drug delivery
III. Administration of lipid-based Elosaily GH. Preparation and in vitro

Expert Opin. Drug Deliv. [Early Online] 11

 A. W. Khan et al.

evaluation of self-nanoemulsifying drug clarifications of the Critical Differences. 52. Craig DQM, Barker SA, Banning D,
delivery systems (SNEDDS) containing Pharm Res 2011;28:978-85 Booth SW. An investigation into the
clotrimazole. Drug Discov Ther . Describes the critical differences mechanisms of self-emulsification using
2010;4(5):373-9 between micro- and nanoemulsions. particle size analysis and low frequency
32. Basalious EB, Shawky N, 41. Meinzer A, Mueller E, Vondersher J. dielectric spectroscopy. Int J Pharm
Badr-Eldin SM. SNEDDS containing Microemulsion: a suitable galenical 1995;114:103-10
bioenhancers for improvement of approach for the absorption enhancement 53. Forgiarini A, Esqucna J, Gonza´lez C,
dissolution and oral absorption of of low soluble compounds? Solans C. Formation of nano-emulsions
lacidipine. I: development and B T Gattefosse 1995;88:21-6 by low-energy emulsification methods at
optimization. Int J Pharm 42. Vonderscher J. Meinzer, A. Rationale constant temperature. Langmuir 2001;
2010;391:203-11 for the development of Sandimmune 17:2076-83
33. Prajapati HN, Dalrymple DM, Neoral. Transplant Proc 1994; 54. Forgiarini A, Esqucna J, Gonzalez C,
Serajudin ATM. A comparative 26:2925-2927A Solans C. Studies of the relation between
evaluation of mono-, di- and triglyceride 43. Ghosh PK, Majithiya RJ, Umertiia ML, phase behavior and emulsification
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Serials Unit - Library on 09/10/12

of medium chain fatty acids by lipid/ Murthy RS. Design and development of methods with nanoemulsion formation.
surfactant/water phase diagram, solubility microemulsion drug delivery system of Prog Colloid Polym Sci 2000;115:36-9
determination and dispersion testing for acyclovir for improvement of oral 55. Sole I, Solans C, Maestro A, et al. Study
application in pharmaceutical dosage bioavailability. APPS PharmSciTech of nano-emulsion formation by dilution
form development. Pharm Res 2006;7:77 of microemulsions. J Colloid
2012;29:285-305 Interface Sci 2012;376:133-9
..
44. Ghosh PK, Murthy RS. Microemulsion a
Compare properties of different
potential drug delivery system. 56. Pouton CW. Formulation of
glycerides of MC fatty acids for
Curr Drug Deliv 2006;3:167-80 self-emulsifying drug delivery systems.
development of oral pharmaceutical
45. Garti N, Yaghmur A, Leser ME, et al. Adv Drug Deliv Rev 1997;25:47-58
dosage forms.
Improved oil solubilization in oil/water 57. Goddeeris C, Cuppob F, Reynaersb H,
34. Parmar N, Singla N, Amina S, Kohli K.
food grade microemulsions in the et al. Light scattering measurements on
Study of cosurfactant effect on
For personal use only.

presence of polyols and ethanol. J Agric microemulsions: estimation of droplet

nanoemulsifying area and development of
Food Chem 2001;49:2552-62 sizes. Int J Pharm 2006;312:187-95
lercanidipine loaded (SNEDDS) self
nanoemulsifying drug delivery system. 46. Eccleston J. Microemulsions. In: 58. Yang S, Gursoy RN, Lambert G,
Colloids Surf B Biointerfaces Swarbrick J, Boylan JC, editors. Benita S. Enhanced oral absorption of
2011;86(2):327-38 Encyclopedia of pharmaceutical paclitaxel in a novel
technology. Marcel Dekker; New York: self-microemulsifying drug delivery
35. Rowe RC, Sheskey PJ, Weller PJ.
1994. p. 375-421 system with or without concomitant use
Pharmaceutical excipients handbook.
47. Reiss H. Entropy induced dispersion of of P-glycoprotein inhibitors. Pharm Res
Pharmaceutical Press and American
bulk liquids. J Colloids Interface Sci 2004;21:261-70
Pharmaceutical Association; Dundee:
2003 1975;53:61-70 59. Wang L, Dong J, Chen J, et al. Design
48. Groves MJ, Galindez DAD. The and optimization of a new
36. Torchlin VP. Nanoparticulates as drug
self-emulsifying action of mixed self-nanoemulsifying drug delivery
carriers. ICP; London: 2006
surfactants in oil. Acta Pharma Suecica system. J Colloids Interface Sci 2009;
37. Lawrence MJ, Rees GD. Microemulsion 330:0443-8
1976;13:361-72
based media as novel drug delivery
49. Wakerly MG, Pouton CW, Meakin BJ, 60. Gursoy N, Garrigue JS,
systems. Adv Drug Deliv
Morton FS. Self-emulsification of Razafindratsita A, et al. Excipient effects
2000;45:89-121
vegetable oil-nonionic surfactant mixture: on in vitro cytotoxicity of a novel
38. Poelma FG, Breäs R, Tukker JJ. paclitaxel self-emulsifying drug delivery
a proposed mechanism of action. ACS
Intestinal absorption of drugs. III. system. J Pharm Sci 2003;92:2411-18
Symp. Ser 1986;311:242-55
The influence of taurocholate on the
50. Craig DQM, Lievens HSR, Pitt KG, 61. Nazzal S, Smalyukh II,
disappearance kinetics of hydrophilic
Storey DE. An investigation into the Lavrentovich OD, Khan MA.
and lipophilic drugs from the small
physicochemical properties of Preparation and in vitro characterization
intestine of the rat. Pharm Res
self-emulsifying systems using low of a eutectic based semisolid
1990;7:392-7
frequency dielectric spectroscopy, self-nanoemulsified drug delivery system
39. Chiu YY, Higaki K, Neudeck BL, et al. (SNEDDS) of ubiquinone: mechanism
surface tension measurements and
Human jejunal permeability of and progress of emulsion formation.
particle size analysis. Int J Pharm
cyclosporin A: influence of surfactants on Int J Pharm 2002;235:247-65
1993;96:147-55
P-glycoprotein efflux in Caco-2 cells.
51. Craig DQM. The use of self-emulsifying 62. Palamakula A, Khan MA. Evaluation of
Pharm Res 2003;20:749-56
systems as a means of improving cytotoxicity of oils used in coenzyme
40. Anton N, Vandamme TF. Q10 self-emulsifying drug delivery
drug delivery. B.T. Gattefosse
Nano-emulsions and Micro-emulsions: systems (SEDDS). Int J Pharm 2004;
1993;86:21-31
273:63-73

12 Expert Opin. Drug Deliv. [Early Online]

 Potentials and challenges in self-nanoemulsifying drug delivery systems

63. Subramanian N, Ray S, Ghosal SK, et al. 70. Zhao Y, Wang C, Chow AH, et al. 77. Patel D, Sawant KK. Oral bioavailability
Formulation design of Self-nanoemulsifying drug delivery enhancement of acyclovir by
self-microemulsifying drug delivery system (SNEDDS) for oral delivery of self-microemulsifying drug delivery
systems for improved oral bioavailability zedoary essential oil: formulation and systems (SMEDDS). Drug Dev.
of celecoxib. Biol Pharm Bull bioavailability studies. Int J Pharm Ind Pharm 2007;33:1318-26
2004;27:1993-9 2010;383:170-7 78. Porter CJ, Trevaskis NL, Charman WN.
64. Gershanik T, Benita S. Positively charged 71. Khoo S-M, Porter CJH, Charman WN. Lipids and lipid-based formulations:
self-emulsifying oil formulation for The formulation of halofantrine as either optimizing the oral delivery of lipophilic
improving the oral bioavailability of non-solubilising PEG 6000 or drugs. Nat Rev Drug Discov
progestrone. Pharm Dev Technol solubilising lipid based solid dispersions: 2007;6:231-48
1996;1:147-57 physical, stability and absolute 79. Oh DH, Kang JH, Kim DW, et al.
65. Shahnaz G, Hartl M, Barthelmes J, et al. bioavailability assessment. Int J Pharm Comparison of solid
Uptake of phenothiazines by the 2000;205:65-78 self-microemulsifying drug delivery
harvested chylomicrons ex vivo model: 72. Nazzal S, Guven N, Reddy IK, system (solid SMEDDS) prepared with
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Serials Unit - Library on 09/10/12

Influence of self-nanoemulsifying Khan MA. Preparation and hydrophilic and hydrophobic solid
formulation design. Eur J characterization of coenzyme carrier. Int J Pharm 2011;420:412-18
Pharm Biopharm 2011;79(1):171-80 QlO-Eudragit solid dispersion. Drug Dev
66. Yoo JH, Shanmugam S, Thapa P, et al. Ind Pharm 2002;28:49-57 Affiliation
Novel self-nanoemulsifying drug delivery 73. Nyqvist-Mayer AA, Brodin AF, Abdul Wadood Khan1, Sabna Kotta1,
system for enhanced solubility and Frank SG. Phase distribution studies on Shahid H Ansari2, Rakesh Kumar Sharma3 &
dissolution of lutein. Arch Pharm Res an oil-water emulsion based on a eutectic Javed Ali†1
†
2010;33:417-26 mixture of lidocaine and prilocaine as the Author for correspondence
1
67. Wankhade V, Tapar K, Pande S, dispersed phase. Pharm Sci Department of Pharmaceutics,
Bobade N. Design and evaluation of 1985;74:1192-5 Faculty of Pharmacy, Jamia Hamdard,
Hamdard Nagar,
self-nanoemulsifying drug delivery 74. Kang LS, Jun HW, McCall JW.
systems (SNEDDS) for Gliclazide. Physicochemical studies of New Delhi 110062,
For personal use only.

Der Pharmacia Lett 2010;2:132-43 lidocaine-menthol binary systems for India

Tel: +919811312247;
68. Patil P, Joshi P, Paradkar A. Effect of enhanced membrane transport.
Int J Pharm 2000;206:35-42 Fax: +911126059633;
formulation variables on preparation and E-mail: [email protected].
evaluation of gelled self-emulsifying drug 75. Date AS, Nagarsenker MS. Design and 2
Department of Pharmacognosy &
delivery system (SEDDS) of Ketoprofen. evaluation of self-nanoemulsifying drug Phytochemistry, Faculty of Pharmacy,
AAPS PharmSciTech 2004;5:E42 delivery systems (SNEDDS) for
Jamia Hamdard, Hamdard Nagar,
69. El-Laithy HM. Self-nanoemulsifying cefpodoxime proxetil. Int J Pharm New Delhi 110062, India
drug delivery system for enhanced 2007;329:166-72 3
Division of CBRN Defence,
bioavailability and improved 76. Humberstone AJ, Charman WN. Lipid Institute of Nuclear Medicine
hepatoprotective activity of Biphenyl based vehicles for oral delivery of poorly and Allied Sciences,
Dimethyl Dicarboxylate. water soluble drugs. Adv Drug Deliv Rev Brig S K Muzumdar Marg,
Curr Drug Deliv 2008;5:170-6 1997;25:103-28 New Delhi 110054, India

Expert Opin. Drug Deliv. [Early Online] 13