Micro Emulsion

Advanced Drug Delivery Reviews 45 (2000) 89–121 L
www.elsevier.com / locate / drugdeliv
Microemulsion-based media as novel drug delivery systems

M. Jayne Lawrence a , *, Gareth D. Rees b , *
a
Department of Pharmacy, King’ s College London, Franklin Wilkins Building, 150 Stamford Street, London SE1 9 NN, UK
b
SmithKline Beecham R& D, St. George’ s Avenue, Weybridge, Surrey KT13 0 DE, UK
Abstract
Microemulsions are clear, stable, isotropic mixtures of oil, water and surfactant, frequently in combination with a
cosurfactant. These systems are currently of interest to the pharmaceutical scientist because of their considerable potential to
act as drug delivery vehicles by incorporating a wide range of drug molecules. In order to appreciate the potential of
microemulsions as delivery vehicles, this review gives an overview of the formation and phase behaviour and
characterization of microemulsions. The use of microemulsions and closely related microemulsion-based systems as drug
delivery vehicles is reviewed, with particular emphasis being placed on recent developments and future directions.  2000
Elsevier Science B.V. All rights reserved.
Contents
1. Introduction ............................................................................................................................................................................ 90
2. Overview of microemulsion formation and phase behaviour ....................................................................................................... 92
2.1. Theories of microemulsion formation ................................................................................................................................ 92
2.2. Phase behaviour ............................................................................................................................................................... 93
2.3. The role of surfactant ....................................................................................................................................................... 95
3. Microemulsion characterisation ................................................................................................................................................ 98
4. Microemulsion-based systems in drug delivery .......................................................................................................................... 99
4.1. Pharmaceutically acceptable excipients .............................................................................................................................. 100
4.2. Low viscosity microemulsion systems ............................................................................................................................... 102
4.3. High viscosity systems and microemulsion gels.................................................................................................................. 104
4.4. SMEDDs......................................................................................................................................................................... 105
5. Recent developments and future directions ................................................................................................................................ 107
5.1. Component selection ........................................................................................................................................................ 107
5.2. Phase behaviour ............................................................................................................................................................... 108
5.3. Block copolymer micelles and microemulsions .................................................................................................................. 108
5.4. Comparative drug delivery studies..................................................................................................................................... 109
5.5. Oral delivery — SEDDs and SMEDDs .............................................................................................................................. 109
5.6. Parenteral, pulmonary and ocular delivery ......................................................................................................................... 111
5.7. Topical delivery ............................................................................................................................................................... 111
5.8. New developments ........................................................................................................................................................... 112
*Co-corresponding authors. Tel.: 144-0207-848-4808; fax: 144-0207-848-4800 (M.J. Lawrence). Tel.: 144-1932-822179; fax:
144-1932-822120 (G.D. Rees).
E-mail addresses: jayne.lawrence@kcl.ac.uk (M.J. Lawrence), gareth.d.rees@sb.com (G.D. Rees).
0169-409X / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
PII: S0169-409X( 00 )00103-4
90 M. J. Lawrence, G.D. Rees / Advanced Drug Delivery Reviews 45 (2000) 89 – 121
5.9. Alternative surfactants ...................................................................................................................................................... 113

6. Conclusion ............................................................................................................................................................................. 113
References .................................................................................................................................................................................. 114
1. Introduction other words it includes systems that are co-solvents,

that is, systems in which the constituent components
The microemulsion concept was introduced as are molecularly dispersed. Most researchers in the
early as the 1940s by Hoar and Schulman who field agree however that for a microemulsion to be
generated a clear single-phase solution by titrating a formed it is important that the system contains some
milky emulsion with hexanol [1]. Schulman and definite microstructure, in other words there is a
coworkers (1959) subsequently coined the term definite boundary between the oil and water phases
microemulsion [2], and it has since been defined and at which the surfactant is located. In order to gain an
indeed redefined on many occasions. For the pur- understanding of the reasons for microemulsion
poses of this review, however, the microemulsion formation, it is first useful to consider the properties
definition provided by Danielsson and Lindman in of amphiphiles, such as surfactants, in solution.
1981 will be used as the point of reference [3]. Conventional surfactant molecules comprise a
Microemulsions are thus defined as ‘a system of polar head group region and an apolar tail region, the
water, oil and amphiphile which is a single optically latter having the larger molecular volume particularly
isotropic and thermodynamically stable liquid solu- in the case of ionic surfactants. On dispersal in
tion.’ water, surfactants self-associate into a variety of
In practice, the key difference between emulsions equilibrium phases, the nature of which stems direct-
and microemulsions are that the former, whilst they ly from the interplay of the various inter and inter-
may exhibit excellent kinetic stability, are fundamen- molecular forces as well as entropy considerations.
tally thermodynamically unstable and will eventually Surfactants also self-associate in non-aqueous sol-
phase separate [4]. Another important difference vents, particularly apolar liquids such as alkanes. In
concerns their appearance; emulsions are cloudy this case the orientation of the surfactant molecules
while microemulsions are clear or translucent. In are reversed compared to those adopted in aqueous
addition, there are distinct differences in their meth- solution. This reorientation serves to optimise the
od of preparation, since emulsions require a large solvation requirements of the surfactant and mini-
input of energy while microemulsions do not. The mises the free energy of the system overall. When
latter point has obvious implications when consider- surfactants are incorporated into immiscible mixtures
ing the relative cost of commercial production of the of oil and water, the surfactant molecules can locate
two types of system. at the oil / water interface which is thermodynamical-
It is also useful to note that under the definition ly very favourable. A number of phases can result
given, self-microemulsifying drug delivery systems which may be structured on the microscopic or
(SMEEDS) are not microemulsions, although they macroscopic scale, one example of a phase struc-
may be considered to be a closely related system. A tured on the microscopic scale is an optically iso-
SMEDD typically comprises a mixture of surfactant, tropic microemulsion phase. The schematic given in
oil and drug (known as the concentrate) which when Fig. 1 gives an indication of a few of the wide
introduced into the body is rapidly dispersed to form variety of possible self-association structures that
droplets of approximately the same size range as surfactants can form in the presence of water, oil or
those observed in microemulsion systems. Once combinations of all three. Although outside the scope
dispersed such systems would be expected to behave of this review many of the structures shown in Fig.
in vivo much the same way as oil-in-water (o / w) 1, as well as some of those not shown, have potential
microemulsions. for use as drug delivery systems.
The above broad definition does not require a Fig. 2 shows schematic representations of the
microemulsion to contain any microstructure, in three types of microemulsions which are most likely
M. J. Lawrence, G.D. Rees / Advanced Drug Delivery Reviews 45 (2000) 89 – 121 91
Fig. 1. Schematic representation of the most commonly encountered self-association structures in water, oil or a combination thereof.
Fig. 2. Schematic representation of the three most commonly encountered microemulsion microstructures: (a) oil-in-water, (b) bicontinuous,
and (c) water-in-oil microemulsion.
to be formed depending on composition. It can be fraction of oil is low. Conversely, w / o droplets are
seen while the three structures shown are quite likely when the volume fraction of water is low, and
different, in each there is an interfacial surfactant in systems where the amounts of water and oil are
monolayer separating the oil and water domains. similar, a bicontinuous microemulsion may result. In
Note that while the oil-in-water (o / w) and water-in- the latter case, both oil and water exist as a continu-
oil (w / o) droplets are represented in Fig. 2 as ous phase in the presence of a continuously fluctuat-
spheres, they may be asymmetric in shape, frequent- ing surfactant-stabilised interface with a net curva-
ly adopting the shape of a prolate ellipsoid. The ture of zero.
presence of o / w microemulsion droplets is likely to The relationship between micelles and o / w mi-
be a feature in microemulsions where the volume croemulsion droplets as well as between reverse
solubilisation theories [6–8]: and (iii) thermody-

namic treatments [9–11]. An in depth discussion of
these theories are beyond the scope of this review
but has been addressed by others [12]. However, an
admittedly simplified thermodynamic rationalisation
is presented below. The free energy of microemul-
sion formation can be considered to depend on the
extent to which surfactant lowers the surface tension
of the oil–water interface and the change in entropy
Fig. 3. Penetration of oil molecules between the hydrophobic of the system such that,
chains of the interfacial surfactant monolayer in a bicontinuous
microemulsion. Note the greater extent of oil penetration when the
DGf 5 g DA 2 T DS
film curves towards water (i.e. in a region of reverse curvature). where DGf is the free energy of formation, g is the
Modified from [235].
surface tension of the oil–water interface, DA is the
change in interfacial area on microemulsification, DS
micelles and w / o microemulsion droplets has been is the change in entropy of the system which is
debated on a number of occasions. Clearly there is a effectively the dispersion entropy, and T is the
transition through the series (reverse) micelle, swol- temperature. It should be noted that when a mi-
len micelle and microemulsion droplet but by defini- croemulsion is formed the change in DA is very large
tion micelles and reverse micelles are not mi- due to the large number of very small droplets
croemulsions. Distinguishing between swollen mi- formed. Originally workers proposed that in order
celles and microemulsion droplets is largely a for a microemulsion to be formed a (transient)
semantic exercise, but it is recognised that as the negative value of g was required, it is now recog-
ratio of dispersed phase to surfactant increases, the nised that while value of g is positive at all times, it
physicochemical properties approach those of the is very small (of the order of fractions of mN / m),
pure solvent. It should be noted that while the and is offset by the entropic component. The domi-
definition used in the present study does not differen- nant favourable entropic contribution is the very
tiate between a swollen micelle and a microemul- large dispersion entropy arising from the mixing of
sion, other researchers in the field do however make one phase in the other in the form of large numbers
this distinction. of small droplets. However, there are also expected
Depending upon the nature of the oil, in particular to be favourable entropic contributions arising from
its size relative to the hydrophobic chain of the other dynamic processes such as surfactant diffusion
surfactant, the oil may penetrate to varying extents in the interfacial layer and monomer-micelle surfac-
into the surfactant tails of the interfacial monolayer. tant exchange. Thus a negative free energy of
This is shown schematically in Fig. 3 for a bicon- formation is achieved when large reductions in
tinuous microemulsion; a similar effect has been surface tension are accompanied by significant
proposed to occur in both o / w and w / o microemul- favourable entropic change. In such cases, mi-
sions. croemulsification is spontaneous and the resulting
dispersion is thermodynamically stable.
Qualitatively we know that several factors de-
2. Overview of microemulsion formation and termine whether a w / o or o / w system is formed.
phase behaviour Intuitively, we would summise that the most likely
microemulsion would be that in which the phase
2.1. Theories of microemulsion formation with the smaller volume fraction forms the droplets,
and indeed this is very often although by no means
Historically, three approaches have been used to exclusively the case. By their very nature, o / w
explain microemulsion formation and stability. These microemulsion droplets generally have a larger effec-
are: (i) interfacial or mixed film theories [2,5]: (ii) tive interaction volume than w / o droplets. In the
case of ionic surfactants this is attributable to the not necessarily be capable of forming association
presence of an electrical double layer at the surface structures in its own right. A wide variety of
of the o / w droplet which introduces a strong repul- molecules can function as cosurfactants including
sive term. For o / w microemulsions stabilised by a non-ionic surfactants [17,18], alcohols [19,20], al-
non-surfactant, although there is hydration shell kanoic acids, alkanediols and alkyl amines [21].
associated with the polar headgroups, the predomi- Surprisingly few studies have examined the effect of
nant repulsive factor can be attributed to steric drug on phase behaviour, this is despite the fact that
interactions. Additionally, it is pertinent to note that a large number of drug molecules are themselves
it is easier to arrange surfactant at an interface with surface active [22] and as such would be expected to
high curvature, i.e., small droplets, if the surfactant influence phase behaviour. Fig. 4 shows the effect of
tails extend outwards into a continuous oil phase. the presence of drug (either fenoprofen or fenoprofen
This is also entropically more favourable as the sodium) on the phase behaviour of reverse phos-
hydrocarbon tails have more directional freedom. As pholipid aggregates.
a result, interfacial tension tends to be lower for a In the case where four or more components are
w / o microemulsion than for an o / w microemulsion, investigated, pseudo-ternary phase diagrams are used
thereby making their preparation a more facile where a corner will typically represent a binary
process. It should also be remembered however, that mixture of two components such as surfactant / cosur-
while microemulsions are thermodynamically stable factant, water / drug or oil / drug. The number of
there may be kinetic barriers to their formation. As a different phases present for a particular mixture can
consequence, the order of component addition may be visually assessed. Microstructural features can
impact on the ease of preparation, and in some cases also be investigated with the aid of a wide variety of
mechanical agitation or the input of heat will assist techniques, which are discussed later in this review.
more rapid microemulsification. A highly schematic (pseudo) ternary phase diagram
illustrating these features is presented in Fig. 5. It
2.2. Phase behaviour should be noted that not every combination of
components produce microemulsions over the whole
The relationship between the phase behaviour of a range of possible compositions, in some instances
mixture and its composition can be captured with the the extent of microemulsion formation may be very
aid of a phase diagram. Compositional variables can limited.
also be studied as a function of temperature and Constructing phase diagrams is time consuming,
pressure, although with the exception of microemul- particularly when the aim is to accurately delineate a
sions prepared using supercritical or near critical phase boundary, as the time taken for the system to
solvents [13,14], or with liquefied chlorofluorocarbon equilibrate can be greatly increased as the phase
[15] and HFA propellants [16], the large majority of boundary is approached. Heat and sonication are
systems are studied under conditions of ambient often used, particularly with systems containing
pressure. The phase behaviour of simple microemul- nonionic surfactants, to speed up the process. The
sion systems comprising oil, water and surfactant can procedure most often employed is to prepare a series
be studied with the aid of ternary phase diagram in of (pseudo) binary compositions and titrate with the
which each corner of the diagram represents 100% of third component, evaluating the mixture after each
that particular component. More commonly, how- addition. Care must be taken to ensure not only that
ever, and almost always in the case of microemul- the temperature is precisely and accurately con-
sions in pharmaceutical applications, the microemul- trolled, but also that observations are not made on
sion will contain additional components such as a metastable systems. Clearly, however, time con-
cosurfactant and / or drug. The cosurfactant is also straints impose a physical limit on the length of time
amphiphilic with an affinity for both the oil and systems can be left to equilibrate and consequently
aqueous phases and partitions to an appreciable the elimination of metastable states can be difficult to
extent into the surfactant interfacial monolayer pres- ensure in practice, although centrifugation can be
ent at the oil–water interface. The cosurfactant need useful to speed up any separation. References to
Fig. 4. Schematic representation of the effect of drug on the association of phospholipid in an isopropylmyristate (IPM) system. Top, from
left to right: phospholipid molecules in IPM in the absence of water and drug form ellipsoidal reverse micelles, increasing the amount of
water present causes these aggregates to transform first into rod-like micelles and then finally lamellar liquid crystals. Bottom, from left to
right: drug solubilisation either in its free acid or sodium salt form causes a change in shape of the colloidal aggregates — with fenoprofen
acid rod like micelles transform into more spherical ones, with fenoprofen salt rod-like micelles transform into extremely long rods.
Modified from [222].
rapid screening procedures have appeared in the further addition of one of the components, addition
literature [23]. of a new component such as drug or electrolyte, or
Outside the microemulsion region, particularly for by changing the temperature. Transitions from w / o
compositions close to the oil–water binary axis, to o / w microemulsions may occur via a number of
there is insufficient surfactant to facilitate the forma- different structural states including bicontinuous,
tion of a single microemulsion phase. In this case lamellar and also multiphase systems. Microemul-
multiple phases may exist, the complexity of which sions stabilised by non-ionic surfactants, especially
increases with the number of components in the those based on polyoxyethylene, are very susceptible
mixture. Within this region, and indeed other multi- to temperature because a decrease in surfactant
phase regions of the ternary phase diagram, mi- solubility occurs with increasing temperature, and as
croemulsions can exist in equilibrium with excess a result systems stabilised by non-ionic surfactants or
water or oil phases. These multiphase systems can be mixtures thereof often have characteristic phase
conveniently described using the Winsor classifica- inversion temperatures (PITs), with the PIT of the
tion [24]. In the Winsor classification, the one phase microemulsion varying with a range of experimental
microemulsions that are generally explored as drug factors including the amount and nature of the oil
delivery systems are known as Winsor IV systems. present and the nature of the surfactant(s) present.
Transitions between the various phases mapped This latter case is well illustrated in Fig. 6 which
out in these phase diagrams can be driven by the shows the effect on PIT of increasing the amount of
presence of drug. Although it is considered that the

polyoxyethylene surfactants are the most sensitive,
other non-ionic surfactants such as the alkylamine-N-
oxides and the sugar surfactants are also sensitive to
changes in temperature. In contrast microemulsions
stabilised by ionic surfactants have little or no
sensitivity to temperature.
The presence of a PIT can cause problems for the
exploitation of microemulsions stabilised by non-
ionic surfactants as drug delivery systems. This is a
particular problem where formulations are intended
for intravenous administration as autoclaving, the
preferred means of sterilisation, is likely to destabil-
Fig. 5. A hypothetical pseudo-ternary phase diagram of an oil / ise the microemulsion. However, sterilisation by
surfactant / water system with emphasis on microemulsion and filtration remains an option for low viscosity droplet-
emulsion phases. Within the phase diagram, existence fields are containing microemulsions. In order to avoid any
shown where conventional micelles, reverse micelles or water-in-
complications due to the presence of a PIT, the
oil (w / o) microemulsions and oil-in-water microemulsions are
formed along with the bicontinuous microemulsions. At very high intended temperature of use should be 30 K below
surfactant concentrations two phase systems are observed. the PIT. Although it is possible to envisage circum-
stances whereby the presence of a phase transition in
use can be used to derive a benefit, for example to
release drug at a pre-determined site in the body.
2.3. The role of surfactant
The single-phase microemulsion systems of inter-

est in this review are classified as Winsor IV. The
surfactants used to stabilise such systems may be: (i)
non-ionic, (ii) zwitterionic, (iii) cationic, or (iv)
anionic surfactants. Combinations of these, particu-
larly ionic and non-ionic, can be very effective at
increasing the extent of the microemulsion region.
Fig. 6. Effect of temperature and weight fraction of surfactant Examples of non-ionics include polyoxyethylene
mixture on the phase behaviour of a water / C 12 E 8 / sucrose dilaur- surfactants such as Brij 35 (C 12 E 23 ) or a sugar esters
ate / heptane system. The weight fraction of the lipophilic sucrose such as sorbitan monooleate (Span 80). Phos-
dilaurate in the surfactant mixture are 0.5 (closed circles), 0.7 pholipids are a notable example of Zwitterionic
(open triangle) and 0.8 (open circle). The water / heptane ratio is
50 / 50 (w / w). I, II and III indicate one-, two-, and three phase
surfactants and exhibit excellent biocompatibility.
regions, with the one phase region being the microemulsion Lecithin preparations from a variety of sources
region. Note that as the proportion of the lipophilic sucrose including soybean and egg are available commercial-
dilaurate increases, the I phase microemulsion region is formed at ly and contain diacylphosphatidylcholine as its major
higher temperatures. Redrawn from [131]. constituent [19,21,25,26]. Quaternary ammonium
alkyl salts form one of the best known classes of
the lipophilic sugar surfactant present in a mixed cationic surfactants, with hexadecyltrimethyl-
C 12 E 8 :sucrose dilaurate system. It should be noted ammonium bromide (CTAB) [27–29], and the twin-
that the presence of electrolyte or in some cases tailed surfactant didodcecylammonium bromide
drug, especially if lipophilic in nature, can act to (DDAB) amongst the most well known [30–32].
lower the PIT, illustrating the importance of de- The most widely studied anionic surfactant is prob-
termining microemulsion phase behaviour in the ably sodium bis-2-ethylhexylsulphosuccinate (AOT)
which is twin-tailed and is a particularly effective tants to form particular aggregates to the geometry of
stabiliser of w / o microemulsions [18,30,33–37]. the molecule itself. The CPP can be calculated using
Attempts have been made to rationalise surfactant the following equation:
behaviour in terms of the hydrophile–lipophile bal-
CPP 5 v /a.l
ance (HLB) [38], as well as the critical packing
parameter (CPP) [39,40]. Both approaches are fairly where v is the partial molar volume of the hydro-
empirical but can be a useful guide to surfactant phobic portion of the surfactant, a is the optimal
selection. The HLB takes into account the relative head group area and l is the length of the surfactant
contribution of hydrophilic and hydrophobic frag- tail. The latter parameter is often expressed as l c , that
ments of the surfactant molecule. It is generally is the critical length of the hydrophobic chain,
accepted that low HLB (3–6) surfactants are generally assumed to be 70–80% of its fully extend-
favoured for the formation of w / o microemulsions ed length. The CPP is a measure of the preferred
whereas surfactants with high HLBs (8–18) are geometry adopted by the surfactant, and as a conse-
preferred for the formation of o / w microemulsion quence is predictive of the type of aggregate that is
systems. Ionic surfactants such as sodium dodecyl likely to form. The effect of changing CPP is
sulphate which have HLBs greater than 20, often illustrated in Fig. 7 but put simply, cone-shaped
require the presence of a cosurfactant to reduce their surfactants will pack at curved interfaces whereas
effective HLB to a value within the range required surfactants whose geometry can be represented by
for microemulsion formation. truncated cones or rectangular blocks prefer to form
In contrast, the CPP relates the ability of surfac- worm-like micelles or lamellar structures [41]. Of
Fig. 7. Effect of molecular moieties and solution conditions on the CPP of a surfactant and the resulting range of possible surfactant
aggregates in water or aqueous solution. Redrawn from [236].
course, changes in microemulsion composition will formation as can be seen in Fig. 8. However, whilst
modify the microenvironment of the surfactant, such materials may be referred to as cosurfactants,
which will lead to changes in the apparent CPP of this description is misleading, as they are not am-
the surfactant. For example in a microemulsion phiphilic in their own right. As with traditional
system, penetration of small oil molecules between cosurfactants their presence can lead to destruction
the hydrocarbon tails would be expected to increase of the microemulsion upon dilution. Finally, the
the effective surfactant hydrophobe volume, whereas effect of temperature on these parameters is especial-
large molecular volume oils would not be expected ly pertinent for non-ionics such as polyoxyethylene
to exert much effect on the CPP [42]. Similarly, alkyl ethers as the polyoxyethylene (PEO) group is
increases in ionic strength would be expected to dehydrated with increasing temperature. This has the
result in a decrease in the effective head group area effect of altering substantially the CPP and in
of ionic surfactants as the double layer shrinks and extremis is manifested by phase separation or phase
screening of the head groups allows closer approach. inversion.
The presence of hydrophilic molecules such as In most cases, single-chain surfactants alone are
glycerol and sorbitol in the aqueous phase will also unable to reduce the oil / water interfacial tension
influence optimal head group area by altering the sufficiently to enable a microemulsion to form, a
solubility of the head group in the aqueous phase. point made in a number of pertinent microemulsions
Because of these effects, water-soluble hydrophilic reviews [43–48]. Medium chain length alcohols
materials have been used as to aid microemulsion which are commonly added as cosurfactants, have
the effect of further reducing the interfacial tension,
whilst increasing the fluidity of the interface thereby
increasing the entropy of the system [44,45,48].
Medium chain length alcohols also increase the
mobility of the hydrocarbon tail and also allow
greater penetration of the oil into this region. Fur-
thermore, any alcohol present may also influence the
solubility properties of the aqueous and oily phases
due to its partitioning between these phases. It has
also been suggested that some oils, for example the
ethyl esters of fatty acids, also act as ‘cosurfactants’
by penetrating the hydrophobic chain region of the
surfactant monolayer [49]. All of the aforementioned
mechanisms are considered to facilitate microemul-
sion formation. In the case of microemulsions stabi-
lised by ionic surfactants, the addition of alkanols
also serves to reduce repulsive interactions between
the charged head groups.
A number of double chain surfactants such as
AOT and DDAB are able to form microemulsions
without the aid of cosurfactants [18,30–37,50,51].
These surfactants are characterised by having small
head groups in comparison to their hydrocarbon tails.
Phosphatidylcholine or lecithin is also a twin-tailed
surfactant, but in this case it is generally necessary to
Fig. 8. Partial phase diagrams of the system isopropyl myristate include a cosurfactant in order to disrupt the lamellar
(O), polysorbate 40 and sorbitol (S) and water (W) showing areas
of existence of o / w microemulsions at 378C for polysorbate / structures which characterise its biological behav-
sorbitol mass ratios of a, 1 / 1; b, 1 / 1.5; c, 1 / 2 d, 1 / 2.5; e, 1 / 3; iour. Thus medium chain alcohols have been suc-
and f, 1 / 3.5. Redrawn from [86]. cessfully used as cosurfactants for the formation of
lecithin-based microemulsions [19,26]. Interestingly value of scattering methods is exemplified by the

w / o microemulsions have been prepared using short work of Tabony who identified the presence of a
diacyl chain lecithins and small molecular volume cubic phase in the bicontinuous microemulsion re-
oils where it is possible that the small molecular gion [77,78]. These techniques have also been
volume oils penetrate the hydrophobic chain region extremely useful in the development of microemul-
thereby facilitating microemulsion formation [52]. sion models such as the cubic random cell (CRC)
[76,81] and disordered open connected (DOC)
models [30,79]. Neutron scattering methods using
contrast variation have been used to probe the nature
3. Microemulsion characterisation of the oil penetration into the interfacial surfactant
monolayer of the microemulsion [82]. Freeze-frac-
In contrast to their ease of preparation, it is a far ture electron microscopy has also been used to study
from trivial matter to characterise the microstructure microemulsion structure, however extremely rapid
of a microemulsion, yet such knowledge is essential cooling of the sample is required in order to maintain
for their successful commercial exploitation. For structure and minimise the possibility of artifacts
example, it has been shown that the rate of release of [75,83–85].
sodium salicylate from a lecithin-based microemul- A potentially serious limitation with some of these
sions, is dependent upon their microstructure [53]. methods of analysis lies in the requirement to dilute
Microemulsions have been evaluated using a wide the microemulsion systems in order to eliminate
range of different techniques over the years, but a particle–particle interactions. This is because dilu-
complementarity of methods is generally required in tion can drive a phase transition or a molecular
order to fully characterise these systems. At the reorganisation, and is therefore a particular problem
macroscopic level viscosity, conductivity and di- for techniques such as viscometry, NMR self-diffu-
electric methods provide useful information sion measurements and those relying on scattering. It
[29,35,36,54–56]. Viscosity measurements for exam- is therefore often necessary to work with systems
ple can indicate the presence of rod-like or worm- containing a relatively high dispersed phase con-
like reverse micelles [55,56], and conductivity mea- centration and to account for interparticulate interac-
surements provide a means of determining whether a tions by use of a model. On the one hand this
microemulsion is oil-continuous or water-continuous, provides an opportunity to extract useful information
as well as providing a means of monitoring percola- regarding particle–particle interactions, but on the
tion or phase inversion phenomena [37,55,57]. downside it to makes the structural characterisation
Dielectric measurements are a powerful means of of concentrated systems extremely problematic.
probing both the structural and dynamic features of In spite of the abovementioned complications,
microemulsion systems [37,58,59]. much of the work reported in the pharmaceutical
The isotropic nature of microemulsions and their literature has been conducted using concentrated
optical clarity makes their study by spectroscopic microemulsion systems. For the most part where
techniques straightforward, particularly in compari- particle sizes obtained using photon correlation
son to conventional macroemulsions. Pulsed field spectroscopy, the measurements quoted remain un-
gradient NMR for example has been used extensive- corrected, not least because such corrections are far
ly to measure self-diffusion coefficients of the vari- from trivial. Only a few studies have attempted to
ous components and yields information on the correct for these interactions [86,87], yet without
mobility and microenvironment [25,28,32,38,56,60– such corrections, these data should only be used to
68]. Scattering methods have also been invaluable in establish the presence of microemulsion structure.
elucidating microemulsion structure and methods Whilst neglecting correction factors, some workers
employed include dynamic and static light scattering have attempted to correlate apparent droplet sizes
[16,28,52,55,62,69–74], small-angle neutron scatter- obtained in concentrated systems with oral bioavail-
ing (SANS) [35,60,62,75–79] and small-angle X-ray ability. Unsurprisingly, this approach has met with
scattering (SAXS) [30,60–62,76,79,80]. Indeed the very limited success.
4. Microemulsion-based systems in drug

delivery
Microemulsions have generated considerable inter-

est over the years as potential drug delivery systems
[43–48,88,89]. Advantages associated with mi-
croemulsions include their thermodynamic stability,
optical clarity and ease of preparation. The existence
of microdomains of different polarity within the
same single-phase solution enables both water-solu-
ble and oil-soluble materials to be solubilised, and at
the same time if this is so desired. Furthermore it is
also possible to incorporate amphiphilic drugs into
Fig. 9. Influence of the addition of gelatin to a water-in-dodecane
the microemulsion, sometimes even leading to an microemulsion stabilised by AOT on viscosity and conductivity.
increase in the extent of existence of the microemul- [Water] / [Surfactant] molar ratio of 45 and AOT molarity of 0.15.
sion region. It should be noted that solubilisate Redrawn from [36].
partitions between the microemulsion droplet and
continuous phase and that while there may be a
preferred site of solubilisation within the microemul- small / medium molecular volume oils such as tri-
sion droplet, solubilisate may be located at one of a butyrin or Miglyol 812. In fact formulating a drug in
number of sites. For example the likely preferred a hydrocarbon oil-in-water microemulsion may offer
sites of incorporation of a lipophilic, water-insoluble no advantage in terms of solubilisation over the
drug into an o / w microemulsion are the disperse oil corresponding micelle [92]. The dispersal of the drug
phase and / or hydrophobic tail region of the surfac- as a solution in nanometre-sized droplets enhances
tant molecule, while a water-soluble material would the rate of dissolution into a contacting aqueous
be most likely to be incorporated into the disperse phase, and in vivo generally results in an increase in
aqueous phase of a water-in-oil droplet. In some drug bioavailability. It is also noteworthy that the use
instances the viscosity of the microemulsion may be of o / w microemulsions in drug delivery is more
tailored for a given application through formulation straightforward than is the case with w / o microemul-
changes, or in some instances through the incorpora- sions. This is because the droplet structure of o / w
tion of specific gelling agents such as Carbopol [90] microemulsions is often retained on dilution by a
or gelatin [91] as shown in Fig. 9. biological aqueous phase, thereby permitting oral as
Table 1 illustrates how a number of self-associat- well as parenteral administration. However, the
ing surfactant systems including microemulsions process of dilution will result in the gradual desorp-
could be used in drug delivery applications, and we tion of surfactant located at the droplet interface.
will go on to discuss specific cases in the following This process is thermodynamically driven by the
sections of this review. All of the systems shown in requirement of surfactant to maintain an aqueous
Table 1 have the potential to protect labile com- phase concentration equivalent to its critical micelle
pounds, but it is still the case that there are few concentration (CMC) under the prevailing conditions
examples of microemulsion-based drug delivery of temperature, pH and ionic strength. Because non-
systems used in commercial drug formulations. ionic surfactants typically have lower CMCs than
The attraction of o / w microemulsion systems lies their ionic counterparts, o / w microemulsion dosage
in their ability to incorporate hydrophobic drugs into forms based on non-ionic surfactants and designed
the apolar oil phase thereby enhancing their solu- for oral or parenteral use are likely to offer superior
bility [43–48,88,89]. However it is worth noting that in vivo stability.
most drugs are not especially soluble in hydrocarbon In contrast, the use of w / o microemulsions for
oils, rather the polarity of the majority of poorly oral or parenteral drug delivery is complicated by the
water-soluble drugs favour their solubilisation in fact that they are destabilised to a much greater
Table 1
Equilibrium phase structures encountered in oil–water–surfactant systems. From [46] a
Micelles / swollen micelles / microemulsions
Reverse micelles / reverse swollen micelles / reverse microemulsions
Worm (polymer)-like micelles
Cubic / reverse cubic phases
Hexagonal / reverse hexagonal
Oil and / or water swollen lamellar phases
a
In addition to the above, one phase structures, a range of two and three phase systems are observed, in which one of the above exists in
equilibrium with an excess of oil and / or an excess of water.
extent when diluted by an aqueous phase. This is due tion, it is essential to study the phase behaviour of
to the increase in the volume fraction of the aqueous potential combinations of water, surfactant and oil.
phase which increases the ratio of water to surfactant However, the studies can only ever act as a broad
(vo ) leading to droplet growth and eventually perco- predictor of the likely fate of a microemulsion
lation. If the dilution continues, phase separation or dosage form after delivery. For oral dosage forms in
inversion may occur and this will result in load particular, it is not possible to realistically model the
dumping. However, there are advantages to be in vivo interactions of microemulsion components
gained from formulating drugs in w / o microemul- with the complex variety of food materials and
sion systems. Peptide drugs, for example, generally digestive fluids present in the gastrointestinal tract.
have little or no activity when delivered orally and
are highly susceptible to proteolysis in the gastroin- 4.1. Pharmaceutically acceptable excipients
testinal tract [93]. Parenteral drug administration,
especially for chronic conditions is not well accepted Perhaps the most significant problem associated
by patients and can lead to issues with compliance. with formulating microemulsions is the difficulty
Consequently, the oral delivery of labile drugs is the associated with excipient acceptability. The vast
focus of growing attention, particularly as many of majority of phase behaviour studies have been
the new therapeutic agents in development are carried out using surfactants and oils, which do not
hydrophilic drugs such as peptides or oligonucleo- have regulatory approval for use in pharmaceutical
tides. Hydrophilic drugs of this kind can be success- products. The majority of the work reported in the
fully incorporated into the dispersed aqueous phase scientific literature concerns microemulsion systems
of w / o microemulsion droplets where they are based on either hydrocarbon oils such as heptane or
afforded some protection from enzymatic degrada- dodecane, or cyclic oils such as cyclohexane. The
tion when administered orally [88]. In addition, the most commonly used surfactants contain hydropho-
presence of surfactant and in some cases cosurfac- bes of 12 carbons such as sodium dodecyl sulphate
tant, for example medium chain diglycerides in many (SDS) and tetraethylene glycol monododecyl ether
cases serves to increase membrane permeability (C 12 E 4 ). Based on the results of these studies a
thereby increasing drug uptake [88,89,94–98]. Drug number of workers have developed guidelines to aid
delivery forms based on w / o microemulsions can in the formulation of microemulsions. However care
also be employed where dilution by an aqueous must be taken when extrapolating ‘guidelines’ de-
phase is less likely to occur, such as after in- veloped for such systems to pharmaceutically accept-
tramuscular injection [99]. Similarly, microemulsions able systems. For example it is widely reported that
and microemulsion gels have found application as it is not possible to solubilise an oil which is larger
topical agents where the surfactants and in some than the hydrophobic chain length of the surfactant,
cases the oil phase itself act as penetration enhancers yet recent studies have shown that using C 18:1 E 10 , it
to facilitate transdermal drug delivery [85,90,91, is possible to solubilise long chain triglyceride to a
100,101]. greater extent than its medium or short chain coun-
Clearly then, in order to aid successful formula- terparts [42,92].
Nevertheless, quite a number of studies have It is evident from the literature that there is a move
deliberately chosen to employ naturally occurring toward the use of alternative ‘safe’ surfactants other
excipients such as lecithins and glycerides, and there than lecithin and the non-ionic surfactants named
is even advice in the literature on the formulation of above. Thus there are a number of studies that have
supposedly non-toxic microemulsions [102]. The been conducted using n-alkyl amine N-oxides either
regulatory status of the different excipients will also in isolation or in combination with lecithin [42,114].
depend on their intended use. Thus while a reason- Interestingly these surfactants are much more rapidly
able range of surfactants would be deemed accept- biodegradable than the polyoxyethylene n-alkyl
able for use in topical formulations, the number ethers. Furthermore there has also been a recent
considered safe for oral and especially parenteral use report detailing the potential of a biodegradable
would be very restricted in comparison. This ob- version of the amine N-oxide surfactant, di-
servation may go part way to explaining why a large methyldodecylamine N-oxide, for use in microemul-
number of researchers investigating microemulsions sion formation [134]. Sugar surfactants such as alkyl
for drug delivery have concentrated on developing glucosides have also received a good deal of atten-
topically applied delivery systems. Many of the tion [64,135–140]. Interestingly while sugar surfac-
surfactants and oils that are regarded as acceptable tants are widely considered as biodegradable they
are food grade materials or have a history of use in still exhibit a level of haemolytic activity on a par
the pharmaceutical arena [103], for example as with that exhibited by the polyoxyethylene n-alkyl
parenteral emulsion dosage forms [104]. There are a ethers. The use of sucrose fatty acid esters as
number of comprehensive studies in the literature surfactants in the stabilisation of microemulsion
concerning the preparation and characterisation of phases has also been investigated [75,85,141–144].
lecithin-based microemulsions [15,19–21,25,26, Surfactants based on polyglycerol fatty acid esters
52,56,59,65–69,87,89,97,99,105–125]. have been suggested as ‘orally safe’ in a study
Non-ionic surfactants can be useful alternatives to designed to investigate the potential of microemul-
naturally occurring surfactants, and polyoxyethylene sions for the delivery of protein drugs [145]. Mono-
sorbitan n-acyl esters (Tweens), for example, have glyceride has also been used as surfactant in its own
been reported to have minimal toxicity. Although right to stabilise a triglyceride-in-water microemul-
there are some restrictions, the use of polyoxy- sion system [83], and by Constantinides and co-
ethylene sorbitan monooleate (Tween 80) and poly- workers [96,146] in a self-microemulsifying drug
oxyethylene sorbitan monolaurate (Tween 20) ap- delivery system (SMEDDS).
pear acceptable for oral or parenteral use [126]. In many cases, a requirement for cosurfactant
Importantly in some cases non-ionic surfactants such causes difficulty in the formulation of acceptable
as the polyoxyethylene n-alkyl ethers (C n E m ) are microemulsions because the majority of studies have
able to form microemulsions without the need for chosen to employ medium chain length alcohols as
cosurfactant [127,128]. This is helpful as it reduces the cosurfactant of choice. Unfortunately, there are
the complexity of the phase behaviour, and elimi- significant toxicity and irritancy issues with these
nates the requirement for inclusion of medium chain materials, which preclude their use in pharmaceutical
alcohols, since these cosurfactants have a poor formulations. In addition, the aqueous solubility of
toxicity profile. Furthermore, the insensitivity of non- cosurfactants in o / w microemulsion systems is often
ionic microemulsions to pH and electrolyte con- higher than that of the principal surfactant. Conse-
centration relative to their ionic counterparts repre- quently, when the o / w microemulsion is diluted, the
sents an added benefit. There are consequently a cosurfactant partitions more strongly to the aqueous
large number of formulation studies involving non- phase. This has the effect of depleting the cosurfac-
ionic surfactants as microemulsion excipients tant concentration at the oil / water interface, thereby
[18,38,86,92,127–133]. However, the biodegradabili- destabilising the microemulsion droplet. Alternatives
ty of many non-ionic surfactants raises issues with to medium chain alcohols have been evaluated such
regard to long-term toxicity, especially in chronic as short chain amines [147] and alkanoic acids [21],
use. however these cosurfactants behave in much the
same way as the alcohols and toxicity remains an gels [100,151,156,157]. Ethyl or methyl esters of
issue. A number of small, relatively polar molecules lauric, myristic and oleic acid have also been em-
are also thought to act as cosurfactants. Ethanol, for ployed as pharmaceutical excipients for microemul-
example, has been used as a ‘cosurfactant’ in both sion formulation [63,92,99,108,151]. Ryan and Kaler
o / w and w / o microemulsion systems. Polyhydric have employed alkyl ethylene glycol ethers such as
alcohols such as sorbitol and sucrose have also been ethylene glycol diethyl ether and ethylene glycol
used as additives to facilitate microemulsification but dibutyl ether as the oil phase. The combination of
the resulting o / w formulations were unstable on these rather hydrophilic oil phases with alkyl gluco-
dilution with water as the aqueous solubility of these side surfactants enhances the surfactant solubility in
materials is high [86,148]. the oil phase and microemulsification can be
The utility of ionic surfactants is also relatively achieved without the need for cosurfactant [137,139].
limited in pharmaceutical dosage forms, however the However, with one or two exceptions it is clear that
use of ionic surfactants in formulation studies has the majority of oils intended for pharmaceutical use
been reported on a number of occasions [18,33]. are large and semi-polar, and therefore rather differ-
Coformulation of the anionic surfactant AOT with a ent to the alkane oils most commonly reported in the
number of different drugs as a microemulsion dosage scientific literature.
form has been more widely reported. Examples,
which have appeared in the literature, include vita- 4.2. Low viscosity microemulsion systems
min K and steroids such as hydrocortisone, pred-
nisolone and betamethasone [34,106]. The solubilisa- At relatively low dispersed phase volume frac-
tion of pilocarpine and chloramphenicol was looked tions, the microemulsion generally contains
at in both AOT and DDAB w / o microemulsions nanometre-sized droplets of oil or water. If the
[31], whilst the trandermal delivery of glyceryl droplets are non-interacting the resulting microemul-
trinitrate has been tested in vivo from a variety of sion will be low viscosity and may therefore be
related AOT systems [149]. As has been indicated suitable for oral, parenteral, pulmonary or even
previously, the advantage of twin tailed surfactants ocular delivery. The potential of these systems for
like AOT and DDAB is that w / o microemulsions use topically has not been overlooked, however it is
form easily without the aid of cosurfactant. However, recognised that more viscous microemulsion systems
when AOT microemulsions are formulated in combi- are preferred for this application. Suitable systems
nation with non-ionic surfactants, the extent of the would include those containing extended structures
microemulsion region is often markedly increased, such as cylindrical or polymeric worm-like or mi-
and in addition the temperature range over which the celles [52,59] or which have been thickened through
microemulsion is stable is generally improved the addition of a specific gelling agent [90,91]. Cubic
[18,33,43]. Fig. 10 gives an example of the increase or hexagonal mesophases identified in the bicontinu-
in microemulsion area of existence achievable in a ous microemulsion region may also be of sufficiently
mixed AOT-non-ionic surfactant system over that high viscosity to have application as topical delivery
seen when either surfactant is used alone. systems [38,85,142].
Total parenteral nutrition emulsions have provided Oil-in-water microemulsions have been used to
a starting point from which suitable oils might be solubilise steroidal drugs such as prednisolone, hy-
selected for formulation into pharmaceutically ac- drocortisone and betamethasone, testosterone and its
ceptable microemulsions. Medium chain tri- esters and progesterone [34,92,106,127]. Interesting-
glycerides such as Miglyol 812 have been used quite ly, it has been noted that hydrophobic drugs need to
frequently [42,128,148], but fatty acid esters are also have a significant solubility in the dispersed oil phase
a popular choice. Of these, isopropyl myristate for the o / w microemulsion system to offer a marked
(IPM) is the most popular [19,21,34,38,66,67, benefit over the micellar system alone [127]. How-
69,71,74,86, 90,106,115,117 – 120,123,124,141,150 – ever, the oils in which the drug is most soluble do
154], but isopropyl palmitate (IPP) has also found not necessarily form microemulsions with the highest
application [150,155], especially in microemulsion drug solubilisation capacity [92].
Fig. 10. Partial ternary phase diagram for Tween 85 (dot) and AOT (solid) alone, or as a surfactant mixture in combination with
isopropylmyristate (oil) and H 2 O at 298 K. Compositions to the right of the phase boundary are optically clear, single phase, water-in-oil
microemulsions. The weight ratios of Tween 85:AOT employed were 2:1 (dash), 1:1 (dash-dot-dot) and 1:2 (long dash). [S. Kantaria, G.D.
Rees, M.J. Lawrence, unpublished observations.]
The utility of w / o microemulsions for the se- diethylamine with phospholipid, not unexpectedly,
questration of labile peptide drugs was demonstrated gives rise to some complex phase behaviour, and
using an analogue of luteinizing hormone-releasing microemulsion phases have been identified from the
hormone (LHRH) to control testosterone levels in ternary phase diagram [159]. Diclofenac release and
rats [99]. The LHRH was solubilised in a lecithin- permeation through excised human skin was sub-
stabilised system with ethyl oleate as the oil phase sequently reported [112] with the researchers clearly
and hexanoic acid as cosurfactant, and was adminis- demonstrating the importance of the nature of the
tered as an intramuscular injection. phase structure of the amount of drug released (Fig.
The peroral delivery of insulin, cyclosporine A 11). Cholesteryl ester prodrugs of ibuprofen and
and vasopressin from microemulsion formulations flufenamic acid have also been incorporated into
has been reviewed by Ritschel [158]. Interestingly, phospholipid microemulsions. In this case the dis-
some drugs such as diclofenac diethylamine are persed oil phase was modified by the addition of
amphiphiles in their own right and indeed this drug cholesteryl oleate [109].
self assembles under aqueous conditions to yield a An interesting non-aqueous microemulsion formu-
liquid crystal phases. Coformulation of diclofenac lation based on lecithin / glycerol / soybean oil has
microemulsion systems has also been indicated and

the b-blocker levobunolol has been incorporated into
o / w microemulsions with this purpose in mind
[107]. Pilocarpine has also been incorporated into a
microemulsion designed for ocular use, which was
stabilised by sucrose fatty acid ester surfactants
[141]. Poloxamer-stabilised microemulsions contain-
ing triacetin, castor oil, water and propylene glycol
have also been formulated as potential ophthalmics.
Formulations were prepared over a range of com-
positions, and in vitro drug permeation studies were
successfully conducted using indomethacin, diclo-
fenac and chloramphenicol [160].
Antifungals including clotrimazole, cyclopiroxol-
amine and econazole nitrate have been incorporated
into IPM and IPP microemulsions designed for
topical use and stabilised by Tween 80 [150].
Azelaic acid, a drug used in the treatment of
pigmentary disorders, has also been investigated as a
topical microemulsion formulation. In this case the
azelaic acid was solubilised in a viscosised o / w
microemulsion and tested in a hairless mouse model
where flux enhancements were observed [161]. The
local anaesthetic pentacaine has been incorporated
into a w / o microemulsion and subjected to in vivo
testing on rabbits [162].
Interestingly, microemulsions have not only been
used directly as drug delivery vehicles, but have also
been used indirectly as a means of producing solid
Fig. 11. (a) Release of diclofenac diethylamine from vehicle with drug-loaded nanoparticles. In this case, solid lipid
5% diclofenac diethylamine and various concentrations of phos- nanoparticles were synthesised by spraying an o / w
pholipids at 208C. (A,B) Microemulsions with (A) 5% phos- microemulsion into cold water at a temperature
pholipids and (B) 6% phospholipids; (C–E) anisotropic gel with
below the melting point of the oil. The microemul-
(C) 9.3%, (D) 13.8% and (E) 20% phospholipids, respectively.
(b) Effective diffusion coefficient of diclofenac diethylamine from sion itself is typically stabilised by lecithin and uses
vehicle with 5% diclofenac diethylamine vs content of phos- a mixture of capric and palmitic acid as the oil
pholipids. Data represent mean and standard deviation of three phase. The microemulsion in addition may contain
duplicate determinations. Redrawn from [112]. taurodeoxycholate and alkyl phosphates as cosurfac-
tants. The resulting drug loaded particles could be
been reported. The formulation was designed for isolated, washed and freeze dried [163–169]. The
parenteral delivery and contained the octyl ester of properties of w / o microemulsions were similarly
ibuprofen. Modification of the microemulsion formu- exploited by utilising droplets as supermolecular
lation with a poloxamer alters the absorption process templates for the synthesis of drug-loaded poly-
with the result that the drug is targeted to reticuloen- butylcyanoacrylate nanoparticles [170,171].
dothelial system-rich organs [113].
A novel pressurised aerosol system has been 4.3. High viscosity systems and microemulsion gels
devised for the pulmonary delivery of salbutamol
using lecithin-stabilised microemulsions formulated A bicontinuous microemulsion stabilised by a
in trichlorotrifluoroethane [15]. The ocular use of mixture of non-ionic surfactants was designed for the
topical delivery of the local anaesthetic lidocaine through excised human skin were reported compared
[38]. Comparative studies have shown that an o / w to solvent only controls [100,173]. Aromatic tetra-
microemulsion gel containing the analgesic anti-in- amidines with antitumour activity have also been
flammatory flufenamic acid and stabilised by PEG-7 incorporated into lecithin organogels for transdermal
glyceryl coccoate (Cetiol HE) outperforms the corre- drug delivery [151]. The in vivo efficacy was
sponding macroemulsion, hydrogel and cream. The determined in nude mice carrying xenografted
formulation was tested in vitro and in vivo by topical tumour cells and was considered to be encouraging.
administration on rats [172]. Methyl nicotinate has been formulated in a lecithin
The interaction of cylindrical or worm-like mi- IPM organogel and tested in vivo with human
celles in microemulsion formulations tend to gives subjects [174]. The utility of these lecithin or-
rise to high viscosity systems. The proposed struc- ganogels has been supported by a human skin
ture of a worm-like (or spaghetti-like) micelle is irritation study, which showed a very low irritancy
shown in Fig. 12. Lecithin in particular is known to potential for the soybean lecithin / IPP/ water system
form such systems in microemulsions at low water [156,175].
content and the utility of the resulting organogels as
novel matrices for the transdermal transport of drugs 4.4. SMEDDs
has been investigated [100]. Scopolamine, broxaterol
and propranolol have been incorporated into lecithin Self-emulsifying drug delivery systems (SEDDS)
organogels based on either cyclohexane, isooctane or and SMEDDS can be described as isotropic solutions
IPM. Ten-fold enhancements of permeation rates of oil and surfactant, which form o / w (micro)emul-
Fig. 12. Microemulsion-based lecithin gels. (a) schematic representation of the formation of lecithin gels upon addition of water to small
lecithin reverse micelles in apolar solvents. (b) localisation of solubilised ‘guest’ molecules within the lecithin gels. Lipophilic drug (stripped
bar); hydrophilic drug (black circle); and amphiphilic drug (shaded head with attached tail). Redrawn from [209].
sions on mild agitation in the presence of water

[176,177]. The utility of SEDDS has been investi-
gated by Charman and coworkers who, although
unable to show enhanced bioavailability of an in-
vestigational lipophilic drug WIN 54954, were able
to demonstrate greatly improved pharmacodynamics
using systems based on medium chain triglyceride
(MCT) and ethoxylated glyceryl trioleate (Tagat TO)
[178]. More recently, self-emulsifying w / o mi-
croemulsions based on MCTs such as Captex 355
and Captex 8000 have been reported. The systems
contained a mixture of mono and diglycerides (Cap-
mul MCM) in combination with Tween 80 as Fig. 13. Representative cylcosporine blood concentration profiles
surfactant. The bioavailabilities of calcein, a water- from a renal transplant patient given the currently marketed
soluble marker, and an RGD peptide were shown to formulation Sandimmune  (SIM) or the new formulation (Neoral)
without food (a.m.) or with food (p.m.). Redrawn from [184].
be significantly increased using a microemulsion
concentrate and preformulated w / o microemulsions
compared to the control aqueous formulation variability as can be seen in Table 2 and Fig. 13.
[96,97,146]. The bioavailability of a poorly water This variation can be ascribed to the proposed
soluble 5a-reductase inhibitor has similarly been mechanism of uptake in vivo which is considered to
shown to be improved in Beagle dogs [179]. It is be related to the lipolysis of the triglyceride yielding
also notable that the presence of liquid crystalline lower partial glycerides which then act as emulsifiers
phases in the pseudo binary oil / surfactant mixtures and enhance drug uptake [181]. The Neoral  formu-
are claimed to be a feature of the most efficient lation uses an isotropic concentrated blend of surfac-
SEDDS [180]. tant based on medium chain length partial glycerides,
The most notable example of a SMEDDS relates a medium chain length triglyceride oil and drug.
to the oral delivery of cyclosporin A, in particular Exposure of this concentrate to water results in
the commercial Neoral  formulation. Cyclosporin A formation of initially a w / o microemulsion which on
is a cyclic undecapeptide used as an immunosuppres- further mixing with water undergoes phase inversion
sant in transplantation surgery, and in contrast to to yield an o / w microemulsion. The delivery of
most peptide drugs is hydrophobic. The original cyclosporine A via microemulsion formulations has
Sandimmune  formulation was based on a solution been considered in some detail [158,182,183], and
of cyclosporin A in vegetable oil. Although the the superiority of the Neoral  microemulsion pre-
coadministration of triglyceride with the cyclospo- concentrate over the original Sandimmune  formula-
rine A improved its bioavailability, there was consid- tion has been demonstrated on several occasions
erable pharmacodynamic inter- and intra-patient [184–186]. Furthermore, the available data has been
Table 2
Mean (CV%) pharmacokinetic parameters following twice-daily dosing with Sandimmune  (SIM) or Neoral  by 11 stable renal transplant
patients. From [184] a
Parameter SIM fasting SIM non-fasting Neoral fasting Neoral non-fasting
T max (h) 2.1 (33.3) 2.6 (76.9) 1.5 (33.3) 1.2 (33.3)
Cmax (mg / l) 663 (34.5) 528 (40.5) 997 (20.0) 892 (35.8)
Cmin (mg / l) 78 (30.8) 92 (29.3) 94 (22.3) 100 (23.0)
AUC (mg-h / l) 2645 (25.7) 2432 (24.3) 3454 (17.6) 3028 (19.7)
PTF% 261 (23.4) 212 (36.8) 317 (18.0) 309 (31.1)
a
All concentrations measured in whole blood at steady state.
AUC was measured over a dosing interval. PTF%5percentage peak–trough fluctuation.
reviewed by Noble and Markham who confirm the lead to the production or otherwise of additional
conclusion that Neoral  offers more predictable and surfactant species.
more extensive drug absorption than the standard An interesting SMEDD variant has been employed
Sandimmune  formulation [187]. for the dermal delivery of b-blockers in an anhydr-
Interestingly, it has been noted that the bioavail- ous surfactant / IPM vehicle [155]. After topical
ability of vasopressin and insulin from w / o mi- administration with an occlusive patch, water parti-
croemulsions is higher when the oil phase is based tions into the SMEDD forming a microemulsion gel
on straight-chain rather than branched-chain fatty phase. As the extent of hydration increases, the drug
acid esters [182]. It is likely that the observed solubility decreases resulting in a supersaturated
differences in bioavailability are related, at least in system which the authors claim results in enhanced
part, to the large reduction in lipolytic activity drug activity and improved pharmacodynamics
exhibited by lipases toward branched chain fatty acid [192]. In a related report, organogels were prepared
substrates [188]. After administration, the mi- from lecithin and a fatty acid ester oil containing
croemulsion formulated with straight chain fatty acid indomethacin [193]. This pseudo binary system was
esters will undergo rapid enzymatic hydrolysis being effectively anhydrous but in common with the
degraded in the gastrointestinal tract. The breakdown previously mentioned study, water uptake would be
products are surface active and will stabilise any expected to result in the formation of the standard
(micro)emulsion that may form, as well as acting as lecithin microemulsion gel which has been previous-
membrane permeation enhancers [189]. As a conse- ly discussed. As expected, enhanced permeation rates
quence of the important role played by metabolic were reported for the indomethacin gel in a hairless
processes in vivo, formulators should be aware that mouse model.
certain hydrophilic surfactants such as Brij 96 / Brij
97 (C 18:1 E 10 ), Tween 80 and polyoxyethylene 40
hydrogenated castor oil (Cremophor RH40) have 5. Recent developments and future directions
been shown to inhibit lipolysis in vitro. Clearly if
this behaviour is mirrored in vivo one of the For the purposes of this review, recent develop-
principal mechanisms facilitating drug uptake would ments will for the most part constitute an evaluation
be compromised. It is therefore encouraging to of the literature in the area of microemulsions and
observe that co-incubation of these hydrophilic sur- microemulsion-based systems for drug delivery for
factants with lipophilic surfactants such as oleic acid the period beginning 1997 to date.
or medium chain length partial glycerides reverses
the inhibition [181]. 5.1. Component selection
It is also notable that in the case of w / o mi-
croemulsion systems, there is no obvious correlation It is notable that an increasing proportion of new
between droplet size and oral bioavailability. This studies recognise the benefit associated with employ-
contrasts with the known relationship between o / w ing as far as possible, pharmaceutically acceptable
emulsion droplet size and bioavailability [190,191]. surfactants, cosurfactants and oils [194]. Naturally
Ignoring the problems of sizing such concentrated occurring surfactants and oils remain an attractive
systems, this behaviour is expected since the w / o option, and the phase behaviour and microstructure
microemulsion phase inverts or phase separates after of microemulsions based on soybean phosphatidyl-
administration, thereby releasing any drug previously choline and triglycerides has recently been reported,
compartmentalised in the aqueous droplet core. although propanol was used as the cosurfactant [65].
Where differences in bioavailability would be pre- The addition of cosurfactants such as alkanol phos-
dicted for w / o systems are occasions where surfac- phocholines have been shown to increase the extent
tant selection is altered. Alternatively, and as has just of the microemulsion region in lecithin / triglyceride
been discussed, changes in bioavailability may occur systems [120]. However the regulatory status of
where there are significant differences in the biodeg- these particular alkanol phosphocholines, which were
radability of formulation components which might synthesised ‘in house’ is unclear, and once again
short chain alcohols including ethanol, propanol and occur. Microemulsions formulations stabilised by
butanol were used as cosolvents / cosurfactants. The sucrose monolaurate and sucrose dilaurate containing
same group has also reported on the phase behaviour ethyl and cetyl 2-(hexylethyl)-2-hexanoate as the oil
of systems containing lecithin and 2-acyl lysolecithin phase and diethyleneglycol monoethyl ether as
derivatives coformulated with medium chain tri- cosurfactant have also been reported. These systems
glycerides or IPM as the oil phase and ethanol as were characterised using FFEM, SANS and viscosity
cosurfactant / cosolvent. These modified phos- [75]. The formation of microemulsion and liquid
pholipids also increase the extent of the microemul- crystal phases in biocompatible sucrose alkanoate
sion region most probably by increasing the fluidity systems has also been claimed [61]. Very recently, a
of the surfactant film [124]. Significantly, most of the study has appeared examining the water solubilisa-
work investigating the formation of lecithin-based tion capacity of microemulsions stabilised by a
microemulsions has reported an improvement in the variety of sucrose esters including mono, di and
extent of the w / o region. In contrast, relatively little polyesters of lauric, palmitic, stearic and oleic acid.
success has been achieved in the water-rich part of Medium chain triglyceride was employed as the oil
the phase diagram. However a recent study describes phase, however the study employed medium chain
the formation of o / w lecithin-based microemulsions alkanols as cosurfactants [144].
in combination with amine N-oxide surfactants The influence of drug incorporation on the phase
[195]. behaviour and structure of microemulsion system
based on water, propanol, lecithin and medium chain
5.2. Phase behaviour triglyceride has also been investigated [125]. The
preparation of non-toxic microemulsions has been
The phase behaviour of systems stabilised by non- described for mixtures of IPM or orange oil with
ionics other than polyethylene glycol ethers con- lecithin. Notably, alkane diols such as pentane-1,2-
tinues to be a prominent area of research activity. A diol and octane-1,2-diol were employed as possible
number of phase behaviour studies involving derma- non-toxic replacements for propanol and pentanol,
tologically acceptable sugar surfactants such as alkyl respectively [119]. Interestingly in their study in-
glucosides have appeared. As has been indicated volving the use of neural networks to predict mi-
previously, the low solubility of sugar esters in croemulsion phase behaviour Richardson and co-
hydrophobic alkane oils generally necessitates the workers predicted that 1,2 hexanediol would be a
use of a cosurfactant such as a medium chain alcohol suitable surfactant for the production of balanced
in order to facilitate microemulsification. However, lecithin-based microemulsions [196]. In terms of
unlike their polyoxyethylene surfactant counterparts, drug solubilisation capacities, microemulsions should
surfactants based on sugar esters are much less fare better than micelles because of the extra locus
sensitive to temperature [74]. Until recently it was for solubilisation provided by the oil phase. How-
not possible to prepare microemulsions stabilised by ever, a recent phase behaviour study has shown that
alkyl glucosides in the absence of a cosurfactant. whilst polar oils offered better drug solubility, the
However it has recently been reported, that by solubility of the drug in the microemulsion itself was
employing a polar oil phase based on alkyl ethylene also determined by the extent to which low molecu-
glycol ethers, in which the alkyl glucosides are more lar volume oils penetrate the PEO region and destroy
soluble, it is possible to prepare glycoside stabilised drug solubilisation sites [92].
microemulsions in the absence of cosurfactant [137–
139]. An interesting alternative approach in mi- 5.3. Block copolymer micelles and microemulsions
croemulsions stabilised by octyl monoglucoside has
been to employ geraniol, a non-toxic perfume al- It is noticeable from the literature that there has
cohol (C 10 H 17 OH) as a cosurfactant / cosolvent been a significant increase in the number of papers
[140]. As is the case with addition of alcohols or describing the use of block copolymer systems for
alkyl glycerol ethers to alkyl glucosides, the addition drug delivery [197–204]. Given that both block
of geraniol allows phase inversion of the system to copolymers and conventional surfactants are am-
phiphilic, it is unsurprising that there is great simi- of the various systems under test. Nevertheless, the
larity between the self-association and adsorption antitumour drug camptothecin, for example, has been
properties of these two classes of compounds. How- tested in vitro for anti-proliferative activity toward
ever, an advantage of amphiphilic block copolymers cultured human leukaemic K 562 cells as a micellar
over conventional surfactants is the relative ease with solution, a microemulsions and incorporated into
which the physicochemical properties can be ‘tai- liposomes. Activities in all cases were moderately
lored’ to suit a given application. Specific examples enhanced over the control. Isostearyl isostearate was
might include the glass transition temperature (Tg) employed as the oil phase and the microemulsion
of the hydrophobic core and the CMC [197,200]. In stabilised by a mixture of Labrosol  and Plurol
addition, amphiphilic block copolymers may be less isostearate  [208]. The peroral delivery of para-
haemolytic than conventional surfactants [201]. As is sympatholytic trospium chloride has been compared
the case with conventional surfactants, the addition using two w / o microemulsion formulations as well
of oil or water respectively to block copolymer as a cyclodextrin formulation and an aqueous solu-
micelles or reverse micelles can lead to the formation tion control. The trospium carries a quaternary
of o / w or w / o microemulsion systems, respectively. nitrogen and is positively charged which may play a
The physicochemical characterisation of block co- role in its poor peroral bioavailability (3 to 11%).
polymer microemulsions has been reported, and Uptake of trospium may also be inhibited by forma-
some of their potential applications examined tion of insoluble complexes with acidic residues of
[205,206]. However, their formulation and potential mucopolysaccharides. This would be consistent with
application in drug delivery has received little atten- the observation that ion pair formation increases its
tion to date with the exception of a study by lipophilicity and improves bioavailability. Disap-
Siebenbrodt and Keipert which examined the formu- pointingly, in this particular study, bioavailabilities
lation of Poloxamer-stabilised microemulsions con- were either equivalent or lower than aqueous solu-
taining triacetin and castor oil, water and propylene tion control [210]. Bicontinuous microemulsions
glycol over a range of compositions [160]. based on sucrose monolaurate or sucrose dilaurate
Block copolymer microemulsions are likely to have been used for the topical delivery of niflumic
become the focus of more intense research over the acid, a potent anti-inflammatory. The 1% microemul-
next few years, particularly where drug delivery sion was as effective as the 3% commercially
applications are concerned. Mechanistically, the dy- available niflumic acid ointment [85]. An in vitro
namics associated with such systems have much in comparative study of the percutaneous absorption of
common with conventional microemulsion stabilised propranolol from an emulsion, an o / w microemul-
by non-polymeric surfactants. However, the time- sion and a micellar solution stabilised by Tween 80
scales associated with molecular events such as and Span 80 has also been reported. Although the
unimer insertion or exchange can be several orders o / w microemulsion was superior to the emulsion
of magnitude slower in the case of block copolymers system, both of which contained IPM, the micellar
[207]. The aforementioned differences would be delivery system containing propranolol was the most
expected to have considerable impact on microemul- effective [152].
sion stability and the control of drug release in vivo.
5.5. Oral delivery — SEDDs and SMEDDs
5.4. Comparative drug delivery studies
The formulation of w / o microemulsions for use as
A number of comparative reports have appeared in SEDDS or SMEDDS has been investigated using
the literature, some of which have evaluated the blends of low and high HLB surfactants, which were
utility of microemulsion formulations against alter- commercially available and pharmaceutically accept-
native delivery systems including liposomes, mi- able, typically sorbitan esters and Tween 80. The oil
celles, emulsions and creams [208,209]. Regrettably, phase comprised long or medium chain length
the picture is often complicated as the same com- glycerides [73]. The microemulsions were character-
ponents are not always employed in the production ised by a variety of techniques including conduc-
tivity, viscosity and photon correlation spectroscopy

(PCS). In a related study, an optimised o / w mi-
croemulsion formulation for the delivery of cyclo-
sporin A prepared using Cremophor EL  as surfac-
tant, Transcutol  as a cosurfactant and Captex 355 
as the oil phase has been reported. Bioavailability
enhancements of 3.3 and 1.25 were observed relative
to the Sandimmune  and Sandimmune Neoral 
formulations [211].
The formulation of SEDDS has also been recently
reviewed and a number of pertinent observations
made [98]. Concerns have been raised for example
regarding administration of dosage forms containing
high concentrations of surfactant, for example, and
opportunities to evaluate chronic toxicology are Fig. 14. The plasma concentration–time profiles of flurbiprofen
limited in comparison to tablet formulations [95]. As after intravenous administration of flurbiprofen solution, commer-
has been indicated already, the presence of water or cial product (Lipfen  , flurbiprofen axetil-loaded emulsion) and
flurbiprofen-loaded microemulsion (EO: lecithin: DSPE–PEG:
another polar cosolvent in a SEDDS formulation
flurbiprofen58:3:1:2) equivalent to 2.5 mg / kg as flurbiprofen to
may mean that the concentrate is itself a microemul- rats (n55). Redrawn from [122].
sion. In highlighting factors that predispose efficient
microemulsions the authors note that self-emulsifica-
tion requires least energy close to the PIT, which is will also depend on the oil / water partition coefficient
also where the capacity for water solubilisation is and factors such as droplet size and specific drug-
enhanced. Mechanisms of self-emulsification dis- excipient interactions. Compositional variables have
cussed include the dynamic formation of liquid been shown to affect the in vitro release of drug from
crystalline units at the oil / water interface, at least for microemulsion formulations in a number of other
simple SEDDS for example based on Tween 85, a cases [53,71].
medium chain triglyceride and drug [98]. For more A pharmacokinetic study with the Sandimmune
complex SEDDS, a mechanism of ‘diffusion and cyclosporin A Neoral  microemulsion concentrate
stranding’ producing fine emulsions or microemul- exhibited the expected improvements in bioavail-
sions may also operate. The formulation of a abilty and inter / intra-patient variability and was
SMEDDS containing flurbiprofen and based on shown to facilitate the effective management of
phospholipid, ethyl oleate and ethanol has also been psoriaris [212]. Very recently, pharmacokinetic trials
reported. After parenteral administration, significant on microemulsion formulations for the oral adminis-
increases in flurbiprofen half-life and an altered tration of Neoral and a macrolide immunosuppres-
biodistribution pattern were observed [122] as is sant SDZ RAD have been evaluated in non-human
clearly illustrated in Fig. 14. In another highly primates and were shown to have promising efficacy
pertinent study, the influence of phase transformation and tolerability [213]. Valsopdar, a P-glycoprotein
on indomethacin release from microemulsions is modulator and an analogue of cyclosporine, has also
examined [123]. The systems of interest were pre- been tested as an oral SEDDS formulation both free
pared from water (42%), IPM, lecithin, lysolecithin and in gelatin soft-capsules in a clinical trial against
and ethanol. The compositions were selected such an i.v. infusion of the drug. Absolute bioavailability
that emulsions, microemulsions, or liquid crystal was 60% and the rate and extent of drug absorption
were formed on dilution. With the exception of phase comparable to that of the IV infusion [214,215]. The
transformations to liquid crystals, the release rate of formulation and performance of SEDDS containing
indomethacin was considered by the authors to be the anti-malarial halofantrine has also been reported.
too rapid for controlled drug delivery. However, the The SEDDS and SMEDDS were isotropic mixtures
release rate of drugs in general from these systems of medium or long chain triglyceride, monoglyceride
(Capmul MCM), drug and ethanol. Six- to eight-fold been reported [118]. The microemulsions containing
improvements in bioavailability were observed rela- pilocarpine were formulated using lecithin, pro-
tive to tablet formulations [216]. pylene glycol and PEG 200 as cosurfactants, and
IPM as the oil phase. The formulations were low
5.6. Parenteral, pulmonary and ocular delivery viscosity fluids with a refractive index lending
themselves to ophthamological application. The test
The preparation and evaluation of flurbiprofen- microemulsions were non-irritant in rabbit eyes or
loaded o / w microemulsions is one of the few recent hen egg membrane. A prolonged pharmacological
reports of delivery systems designed for parenteral effect was observed in vivo compared to the drug
use. The systems of interest were prepared using administered as a simple aqueous solution. This may
ethyl oleate as the oil phase and Tween 20 as have been related to increased bioavailability or
surfactant. The drug solubility was eight times higher enhanced retention or both. However, prolonged
than in buffer, but there was no significant difference release was not observed in vitro using a cellulose
in the pharmacokinetics after administration in rats membrane as permeability barrier.
[217]. Pharmaceutically acceptable microemulsions
designed for i.v. administration have recently not 5.7. Topical delivery
only been formulated and characterised, but also
tested in vivo for hemodynamic response [68]. The A number of recent reports detail microemulsion
microemulsions comprised Miglyol 810N (MCT), formulations designed for topical or transdermal
soybean phosphatidylcholine (Epicuron 200), PEG application [218,219]. Both o / w and a w / o mi-
400, poly(ethylene glycol)(660)-12-hydroxystearate croemulsions have been evaluated in a hairless
and ethanol. PFG–NMR indicated that the mi- mouse model for the delivery of prostaglandin E1.
croemulsions formed over a range of compositions The microemulsions were based on oleic acid or
were bicontinuous, even at high oil concentrations. Gelucire 44 / 14 as the oil phase and were stabilised
After administration, the bicontinuous microemul- by a mixture of Labrasol (C 8 and C 10 polyglycolysed
sions form o / w emulsions on dilution. In vitro glycerides) and Plurol Oleique CC 497 as surfactant
studies showed the resulting droplets were small, [219]. Although enhanced delivery rates were ob-
with mean radii typically in the range 60–200 nm. served in the case of the o / w microemulsion, the
Solubilisation studies using felodipine (a calcium authors concluded that the penetration rates were
antagonist) and an antioxidant H 290 / 58 were inadequate for practical use from either system. The
conducted, however in vivo studies were performed use of lecithin / IPP/ water microemulsion for the
using the drug-free systems. The i.v. administration transdermal transport of indomethacin and diclofenac
of the microemulsion formulations was performed by has also been reported. Fourier transform infra red
infusion into conscious rats over a 5-min period. (FTIR) spectroscopy and differential scanning
Doses up to 0.5 ml / kg had no significant effect on calorimetry (DSC) showed the IPP organogel had
acid–base balance, blood gases, plasma electrolytes, disrupted the lipid organisation in human stratum
arterial blood pressure or heart rate [68]. corneum after a 1 day incubation [157].
The formulation of a water-in-HFA propellant The transdermal delivery of the hydrophilic drug
microemulsion stabilised by fluorocarbon non-ionic diphenhydramine hydrochloride from a w / o mi-
surfactant and intended for pulmonary delivery has croemulsion into excised human has also been
been described [16]. To date these workers have only investigated. The formulation was based on combi-
presented the phase behaviour of the systems to- nations of Tween 80 and Span 20 with IPM.
gether with some light scattering results to prove the However two additional formulations were tested
formation of a microemulsion. As yet no data has containing cholesterol and oleic acid, respectively.
been reported on the incorporation of drug into these Cholesterol increased drug penetration whereas oleic
systems. acid had no measurable effect, but the authors clearly
The development and characterisation of o / w demonstrated that penetration characteristics can be
microemulsions designed for ocular use has recently modulated by compositional selection [153]. Com-
positional effects have also been investigated for the presence of surfactant-stabilised conducting aqueous
skin permeation of felodipine, a calcium antagonist, channels has been their use in the iontophoretic
from o / w microemulsions stabilised by a surfactant transdermal delivery of a model hydrophilic drug.
mixture containing Tween 20 and taurodeoxycholate. One of the structures proposed for these MBGs is
IPM was used as the oil phase with benzyl alcohol as given in Fig. 15. The MBGs were prepared using a
cosurfactant [90]. Characterisation of lecithin / al- variety of pharmaceutically acceptable surfactants
kanol / dodecane / water systems containing lidocaine and oils including Tween 80 and IPM [91]. Novel
and designed for topical use has shown the presence sorbitan monostearate organogels have also been
of L1 (micelles) and L2 (reverse micelles) isotropic prepared from vegetable oils and IPM. Prepared at
droplet phases and a bicontinuous phase is the elevated temperatures and then cooled, the surfactant
mesophase between L1 and L2 [121]. A combination self-assembles into inverse vesicles and then rod-
of drug delivery strategies has been employed in a shaped tubules. The organogels are opaque and
recent report describing the formulation of an inclu- thermoreversible, and may have been suggested as
sion complex of the anti-inflammatory piroxicam novel delivery vehicles for drugs and antigens [220].
with b-cyclodextrin in an o / w microemulsion. Again The inclusion of a water component allows the
designed for topical use, the microemulsion system formulation of w / o organogels which in common
contained IPM and was stabilised by the cationic with gelatin MBGs, may have percolative electro-
surfactant hexadecyltrimethylammonium bromide conductive channels and can be used to solubilise
[154]. In a related study this time employing an hydrophilic drugs and vaccines as well as hydro-
anionic surfactant, the transdermal permeation of phobic materials in the continuous oil phase [221].
glyceryl trinitrate through mouse skin was found to Prolonged release of bovine serum albumin from a
be enhanced by around a factor of around 10 by sorbitan monooleate w / o organogel injected in-
formulating the drug in AOT micelles and reverse tramuscularly to mice has been observed [100].
micelles and w / o microemulsions. Irritation studies
showed that the normal micelles caused moderate
irritation but that AOT reverse micellar solutions 5.8. New developments
caused little or no erythema [149].
An interesting application of gelatin microemul- Environmentally responsive drug delivery systems
sion-based organogels (MBGs) which exploits the are an interesting development and phase changes
that occur after administration triggered by changes
in temperature, pH or ionic strength can be par-
ticularly useful. One example of such behaviour
involves the phase transformation of a reverse micel-
lar solution of lecithin in IPM to a lamellar liquid
crystal. In this case the transition was triggered by
contact of the reverse micellar solution with a
biological aqueous phase, resulting in the controlled
release of the anti-inflammatory fenoprofen [222].
Very recently, similar behaviour has been exploited
by the use of thermosetting microemulsions as
delivery systems for periodontal anaesthesia. In this
case, a block copolymer liquid microemulsion con-
taining lidocaine and prilocaine was designed to
form a gel after in vivo administration to the
periodontal pocket [223]. Thermoresponsive poly-
meric block copolymer micelles based on poly(N-
Fig. 15. Proposed microemulsion-based gel (MBG) structure isopropylacrylamide) and poly(butylmethacrylate)
based in small angle neutron scattering [237]. and containing adriamycin have also been reported
[202]. The abovementioned fluid–gel transitions conventional hydrocarbon-based surfactants. In this

might be usefully exploited in an injectable fluid context, it is also interesting to note that lipase and
dosage form, which undergoes subcutaneous gelation lipoxygenase have been successfully incorporated
after administration. into a water-in-supercritical CO 2 microemulsions
An interesting phase behaviour study has been stabilised by a fluorosurfactant with retention of
conducted using mixtures of water, glyceryl mono- catalytic activity [230]. The incorporation of peptides
leate and Pluronic F-127, the latter being a triblock and proteins into microemulsion systems stabilised
PEP–PPO–PEO copolymer. A phase resembling a by fluorosurfactants without loss of biological activi-
cubic bicontinuous microemulsion was identified ty has therefore been clearly demonstrated. Fluori-
which could be dispersed in water, and after mi- nated liposomes have been prepared using fluoro-
crofluidisation yielded nanometre-sized ‘cubosomes’. carbon–hydrocarbon diblocks [231,232], and the
The authors suggested these ‘cubosomes’ might be circulation time in mice of fluorinated phospholipid
expected to have interesting properties as novel drug vesicles was prolonged three-fold in comparison to
delivery vehicles [224]. equivalent non-fluorinated vesicles [233]. The ability
Another important development, which in the to use fluorinated amphiphiles in the formulation of
longer term should simplify the process of excipient emulsions, gels, microemulsions and vesicles indi-
selection, is the use of artificial neural networks to cate they have considerable potential as drug deliv-
predict microemulsion phase behaviour [196]. ery systems, although the toxicological and regula-
tory hurdles will need to be overcome.
5.9. Alternative surfactants
Another area of growing interest is the use of 6. Conclusion

fluorinated surfactants for the stabilisation of mi-
croemulsion systems [225]. Fluorosurfactants are To date microemulsions have been shown to be
more surface-active than their hydrocarbon counter- able to protect labile drug, control drug release,
parts, the CMCs are typically two orders of mag- increase drug solubility, increase bioavailability and
nitude lower, and importantly fluorosurfactants are reduce patient variability. Furthermore, it has proven
less haemolytic [225]. The biomedical uses of fluori- possible to formulate preparations suitable for most
nated materials has been recently reviewed routes of administration. There is still however a
[226,227], and the low toxicity of a number of considerable amount of fundamental work charac-
fluorinated solvents noted. Specific applications in- terising the physico-chemical behaviour of mi-
clude blood substitutes such as Oxygent  , which is a croemulsions that needs to be performed before they
low viscosity fluid emulsion comprising 60% fluoro- can live up to their potential as multipurpose drug
carbon, perfluordecyl bromide as stabiliser, egg yolk delivery vehicles.
lecithin as emulsifier and buffer [227]. Microemul- It is of interest to note that the first study
sion formulations have also been described for use as investigating the use of microemulsions as potential
a blood substitute, which employed a fluorocarbon drug delivery vehicles was reported in 1974 by
oil and was stabilised by Montanox 80, a hydro- Attwood et al. [234]. However the field lay virtually
genated surfactant, which the authors claimed was a dormant until a review on the subject was published
biocompatible [228,229]. Pulmonary aerosols based by Bhargava et al. in 1987 [43]. Since then there has
on fluorocarbons have also been indicated. The been a very gradual increase in the number of
toxicological and regulatory status of fluorinated research papers published on the topic until 1994
surfactants has not advanced to the point that they since when about 20 papers detailing the pharma-
may be regarded as safe excipients in pharmaceutical ceutical use of microemulsions have been published
formulations. Nevertheless, it is encouraging to each year. This small number of papers contrasts
observe the increasing number of reports describing very sharply with liposomes where the number of
the formation of microemulsion systems stabilised by publications dealing specifically with their use as
fluorinated surfactants, or as surfactant mixtures with drug delivery vehicles runs into the order of 300 per
year. Interestingly liposomes were first proposed as a [15] R.M. Evans, S.J. Farr, The development of novel, pres-
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Advanced Drug Delivery Reviews 45 (2000) 89–121 L

www.elsevier.com / locate / drugdeliv

Microemulsion-based media as novel drug delivery systems

5.9. Alternative surfactants ...................................................................................................................................................... 113

1. Introduction other words it includes systems that are co-solvents,

solubilisation theories [6–8]: and (iii) thermody-

presence of drug. Although it is considered that the

2.3. The role of surfactant

The single-phase microemulsion systems of inter-

lecithin-based microemulsions [19,26]. Interestingly value of scattering methods is exemplified by the

4. Microemulsion-based systems in drug

Microemulsions have generated considerable inter-

microemulsion systems has also been indicated and

sions on mild agitation in the presence of water

tivity, viscosity and photon correlation spectroscopy

[202]. The abovementioned fluid–gel transitions conventional hydrocarbon-based surfactants. In this

Another area of growing interest is the use of 6. Conclusion

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