3 B7 E26 CDD 01

REVIEWS
Microemulsions—Modern Colloidal Carrier for

Dermal and Transdermal Drug Delivery
SANDRA HEUSCHKEL, ALEXANDRA GOEBEL, REINHARD H.H. NEUBERT

Faculty of Biosciences, Institute for Pharmacy, Pharmaceutics and Biopharmaceutics,
Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle/Saale, Germany
Received 8 February 2007; accepted 1 March 2007

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20995
ABSTRACT: Microemulsions are modern colloidal drug carrier systems. They form
spontaneously combining appropriate amounts of a lipophilic and a hydrophilic ingre-
dient, as well as a surfactant and a co-surfactant. Due to their special features,
microemulsions offer several advantages for pharmaceutical use, such as ease of
preparation, long-term stability, high solubilization capacity for hydrophilic and lipo-
philic drugs, and improved drug delivery. The article summarizes the level of research
with respect to dermal and transdermal application. A large number of in vitro as well as
some in vivo studies demonstrated that drugs incorporated into microemulsions pene-
trate efficiently into the skin. The enhancing activity seems to be attributable to a
variety of factors depending on the composition and the resulting microstructure of the
formulations. However, an extended use in practice depends on the choice of well-
tolerated ingredients, mainly surfactants, and the restriction of their amounts in order
to guarantee skin compatibility. ß 2007 Wiley-Liss, Inc. and the American Pharmacists
Association J Pharm Sci 97:603–631, 2008
Keywords: microemulsion; colloidal carrier; dermal drug delivery; characterization;
microstructure; compatibility; skin; surfactants; solubilization; penetration; permeation
Abbreviations: AOT, sodium bis(2-ethyl hexyl)sulfosucci-

nate; AP, ascorbyl palmitate; APG, alkyl polyglycoside; Cs A,
INTRODUCTION AND DEFINITION
cyclosporine A; DDA, diclofenac diethylamine; DLS, dynamic
light scattering; DMSO, dimethyl sulfoxide; DPH, diphenhy- Human skin is an important target site for the
dramine; DSC, differential scanning calorimetry; FF-TEM,
freeze fracture-transmission electron microscopy; IPM, isopro-
application of drugs. In the treatment of local
pyl myristate; IPP, isopropyl palmitate; ME, microemulsion; diseases topical drug delivery is an appropriate
MCT, medium chain triglycerides; MTX, methotrexate; NMP, strategy to restrict the therapeutic effect to the
N-methyl pyrrolidone; NMR, nuclear magnetic resonance; o/w,
oil-in-water; PEG, polyethylene glycol; PG, propylene glycol;
affected area and to reduce systemic incrimina-
Rh, hydrodynamic radius; SANS, small angle neutron scatter- tion. On the other hand, systemic availability is
ing; S/CoS, surfactant/cosurfactant; SDS, sodium dodecyl sul- the aim in transdermal delivery, which can be
fate; SLN, solid lipid nanoparticle; TEM, transmission electron
microscopy; TEWL, transepidermal water loss; THCl, tetra-
used to minimize the first-pass-effect.
caine hydrochloride; w/o, water-in-oil. In order to reach therapeutic drug concen-
Correspondence to: Reinhard H.H. Neubert (Telephone: trations in certain skin layers or in the blood
þ49-345-5525000; Fax: þ49-345-5527292;
E-mail: reinhard.neubert@pharmazie.uni-halle.de)
circulation, the uppermost barrier, the stratum
Journal of Pharmaceutical Sciences, Vol. 97, 603–631 (2008)
corneum (SC), has to be overcome. This pro-
ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association cess is affected by various factors, e.g., the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008 603

604 HEUSCHKEL, GOEBEL, AND NEUBERT
physicochemical properties of the drug and the interfacial layer. Basically two types of micro-
vehicle used for administration. emulsions are differentiated: bicontinuous ones
Modern drug carriers are microemulsions (ME). and microemulsions with droplet like structure.
These systems form spontaneously combining Bicontinuous means that both water and oil form
appropriate amounts of a lipophilic and a hydro- continuous domains separated by surfactant-rich
philic ingredient, as well as a surfactant and interfaces. They are likely to occur when similar
a co-surfactant. What are the characteristics amounts of oil and water are present. Otherwise,
of microemulsions? They are single optically droplet structures are formed. Depending on the
isotropic, transparent or slightly opalescent major compound water-in-oil (w/o) and oil-in-
solutions of low viscosity. Very special about them water (o/w) microemulsions are described. The
are the thermodynamic properties. Microemul- size of the colloidal phase is typically in the range
sions are thermodynamically stable and form of 10–100 nm.
without any energy input.1–3 According to the The common feature of all the appearing
Gibbs-Helmholtz equation, such spontaneously microstructures in microemulsions is that they
running processes are characterized by a negative are highly dynamic, undergoing continuous and
free energy DG. In our case, the equation can be spontaneous fluctuations. According to Lam et al.
written as: two classes of change are considered: inversions
(fluctuations in which the system reverts locally
DG ¼ gDA TDS; from water to oil continuity and back) and
where DG is the free energy of formation, g the superimposed on that, based on the droplet model:
interfacial tension, DA the change in interfacial variations in droplet size.7 Although microemul-
area during the formation process, DS the change sions do not consist of static phases according to
in entropy, and T is the temperature. the definition of Gibbs, throughout the literature,
The formation of a microemulsion is accompa- occurring water- or oil-rich domains are referred
nied by a significant increase in the interfacial to as ‘‘phases.’’
area A. Since the interfacial tension g decreases The term ‘‘microemulsion’’ itself is sometimes
remarkably (but remains positive all the time), used in a misleading way. On the one hand,
a negative free energy is achieved when the various homogeneous surfactant-containing
interfacial energy (gA) is compensated by a solutions were named like this and on the other
dramatic change in the entropy of the system, hand, the expression itself implies emulsion-like
which is mainly dispersion entropy.4,5 The properties with droplet sizes in the submicron-
required very low interfacial tension cannot be range. Therefore, Danielsson and Lindman sug-
realized by only one surfactant. The additionally gested a definition giving some including and
used co-surfactant penetrates the amphiphilic excluding criteria in order to minimize the
interfacial layer and increases its curvature and confusion.2 For example, the concept does not
fluidity.5,6 For this purpose, short or medium cover aqueous surfactant solutions without added
chain alcohols and, for reasons of compatibility solubilizate, liquid crystalline systems, and nor-
in humans, preferably non-ionic surfactants are mal emulsions. Table 1 summarizes the main
used. differences between micro- and ‘‘macro-’’ emul-
The resulting systems show a number of dif- sions. However, a clear-cut distinction from other
ferent microstructures—submicroscopic regions colloidal structures like solubilized micellar sys-
of either aqueous or oleic nature, separated by the tems is missing since there is no well-defined
Table 1. Differences between Microemulsions and Emulsions
Microemulsion Property Emulsion

Transparent/translucent Appearance Milky
Stable Thermodynamic stability Unstable (kinetically stabilized)
Spontaneous Formation Energy input
Towards 0 mN m1 Interfacial tension 50 mN m1
Dynamic (fluctuating surfaces) Microstructure Static (until coalescence)
Yes Optical isotropy No
10–100 nm Droplet size of the colloidal phase >500 nm (nanoemulsions: >50 nm)
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008 DOI 10.1002/jps
MICROEMULSIONS FOR DERMAL AND TRANSDERMAL DRUG DELIVERY 605
transition point. Hence, some authors use the formation of artifacts during the preparation
term ‘‘swollen micelles’’ to describe droplet like process can not always be excluded. For example,
microemulsions.3 ice decoration is a frequently occurring artifact in
Due to their special features, microemulsions freeze fracture transmission electron microscopy
offer several advantages for pharmaceutical use, (FF-TEM).11 Therefore, high cooling rates, a
such as ease of preparation, long-term stability, limited number of components as well as detailed
high solubilization capacity for hydrophilic and structural knowledge from other experimental
lipophilic drugs, and improved drug delivery. The methods are essential.12
latter provides a wide range of possible applica- According to Alany et al., conductivity measure-
tions. Besides dermal administration, which is ments do not only help to determine the nature
explained in detail below, they are used for of the continuous phase of a microemulsion,
example in oral, parenteral and ocular drug but allow also an estimation of the percolation
delivery. threshold.11 This value corresponds to the trans-
formation from droplet-like to bicontinuous micro-
emulsions as the droplets begin to interconnect.
PHYSICOCHEMICAL CHARACTERIZATION Such alterations are also accompanied by changes
OF MICROEMULSIONS in the viscosity11,13 and do clearly influence
permeation parameters.
As mentioned above, microemulsions exist in Frequently applied for size determination and
various microstructures including droplet like partly controversially discussed is the use of
and bicontinuous characters. Since their drug scattering techniques such as small-angle neu-
delivery properties are related to the inner tron scattering, static and, mainly, dynamic light
structure, there is a need to assign the correct scattering. The latter are based on the interaction
state. An appropriate physicochemical character- of light with matter. Static light scattering (SLS)
ization of colloidal formulations is highly challen- observes interparticle interference patterns of
ging due to their small particle sizes and the scattered light by measuring the time average
fluctuating interfaces. The combination of dif- intensity as a function of angle, whereas dynamic
ferent characterization techniques is strongly light scattering (DLS) monitors fluctuations in
required. Here, one has to consider that dilution scattered light as a function of time. These
of microemulsions continuously changes their fluctuations are due to Brownian motion of the
character towards a micellar solution and would, microemulsion droplets within the continuous
therefore, lead to wrong conclusions. phase and depend on the hydrodynamic proper-
To begin with, polarizing light microscopy is ties of the system. Using Stokes-Einstein equa-
used to decide on optical isotropy, a basic feature tion, the average hydrodynamic radius of the
of microemulsions. scattering droplets can be calculated from the
The influence of kind and/or amount of oil and determined free particle diffusion coefficient.
surfactant on the internal structure can be The principle of neutron scattering can be
studied by rheological measurements. Ktistis understood due to the similarities to light scat-
determined the effect of the composition of a tering. In the case of light, the interaction is
microemulsion on the hydration of the dispersed between the electric field of the radiation and the
droplets.8 Furthermore, viscosity is of practical electronic charges. Neutrons, having no electrical
relevance to the administration on the skin, charge, interact in almost all situations via their
especially if a spray system is taken into account. scattering length with the nuclei exclusively.
Different methods of specimen preparation The typical wavelength associated with thermal
combined with electron microscopy techniques neutrons is in the order of 1 to 10 Å which means
enable the visualization of structural differences an increased resolution. Considering the droplet
between droplet and bicontinuous microemulsion sizes present in colloidal systems, it can be
states as well as other colloidal formulations. Hoar deduced that neutrons are very often the more
and Schulman who first mentioned the formation appropriate way of studying their structure.
of transparent dispersions in 19439 coined the Mostly, the technique of small angle neutron
term ‘‘micro emulsion’’ due to electron microscopic scattering or SANS is employed.
observations of the system’s microstructure.10 The Other methods, e.g., electrokinetic chromato-
methods are high-sophisticated and require care- graphy, infrared spectroscopy, and calorimetry
ful interpretation of the micrographs because are also in use.1,13–15 Very interesting and helpful
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008
results concerning self diffusion in microemul- able molecular size provided) only marginally
sions have been obtained by nuclear magnetic influences the droplet size of a microemulsion.
resonance (NMR) studies.16,17 In contrast, an increased oil content of water
Some pharmaceutical relevant applications of continuous microemulsions is accompanied by an
these characterization techniques are described increase in droplet size as Attwood and Ktistis
as follows. found out by means of static light scattering.24
Since the development of microemulsions is an Similar results obtained Saint Ruth et al. exam-
empirical task, the first step to obtain information ining lecithin-based o/w systems25 as well as
often is to construct pseudoternary phase dia- Shukla et al.26 The latter determined hydrody-
grams from the beforehand chosen ingredients. namic radii of microemulsions having a eutectic
The existence area of microemulsions is deter- mixture of lidocaine and prilocaine as colloidal
mined and by the exchange of compounds, their phase.
influence on the formation of certain microstruc- A set of experimental methods was employed by
tures can be investigated. Podlogar et al. in order to get inside into structural
Fixing water and oil in a phase diagram, several changes of a microemulsion by dilution with
times the surfactant/co-surfactant mass ratio water.27 In differential scanning calorimetry
(S/CoS) was found to be an important factor (DSC)-cooling curves size and position of the
concerning position and size of microemulsion water peak contain information on the state of
regions.16–20 But also the kind of oil plays a water within the formulation, i.e., stronger or
role.21,22 For pragmatic reasons, in most cases weaker interactions with surfactants. This know-
only isotropic phases are further investigated. ledge in conjunction with electrical conductivity,
Alany et al. performed a more extended char- surface tension and density helped to identify
acterization study with systems composed of ethyl transforming substructures from w/o via bicontin-
oleate, water, and a surfactant blend either with uous to o/w microemulsions. Their influence on
or without the co-surfactant 1-butanol.11 In the drug release was focus of further studies.
co-surfactant-free phase diagram a microemul- Whereas in the previous experiments the ratio
sion region and a phase of lamellar liquid crystals between oil and surfactants was kept constant,
were identified, whereas the 1-butanol containing another approach was to use varying oil-to-water
system showed only a microemulsion area, ratios and a constant amount of surfactant blend
although a considerably increased one. The of 30%.28 Again, a transformation from oil- to
authors employed viscosity and conductivity water-continuous microemulsions via a bicontin-
measurements as well as FF-TEM in order to uous state was coincidently found using the
differentiate between liquid crystals, droplet-like mobility parameters conductivity and viscosity
and bicontinuous microemulsions. Furthermore, besides density, surface tension data and DSC.
transitions between the single states could be Furthermore, by small angle X-ray scattering
detected. (SAXS) combined with the model of a polydisperse
Scattering experiments on o/w microemulsions system of hard spheres for data interpretation, in
with different oils (octyl dodecanol and isopropyl w/o systems a conversion from elongated to more
palmitate, respectively) were performed by spherical oil droplets at lower oil-to-water ratios
Shukla et al.23 In a SANS study, a core shell was found. In o/w microemulsions, strong inter-
model was used for a suitable fitting of the data. actions between the droplets were concluded
The size parameters were defined as Rcore (size of which led to gel-like structures at higher water
the oil droplet, i.e., pure oil including surfactant concentrations.
tail that penetrates the oil), and Rshell (distance In dermal drug delivery, a frequently used
between the centre of the particle and a position in combination is Labrasol, Plurol oleique, isopropyl
the surface film where the difference in scattering myristate, and water. For this system a pseudo-
length density has its maximum). As expected, the ternary phase diagram was constructed by
outer radius incorporates looser-bounded surfac- Djordjevic et al. and selected mixtures of a dilution
tant molecules and is substantially bigger than line were characterized by conductivity, which
the hydrodynamic radius Rh, obtained by DLS. Rh indicated occurring percolation phenomenon.29
is supposed to consist of the oil core and a stronger Addition of water was also accompanied by
bounded surfactant film, perhaps containing some changes in viscosity and confirmed a continuous
solvent molecules too. Values of about 10 nm transition of the internal state. Incorporation
for Rh indicated that the kind of oil (compar- of diclofenac diethylamine clearly affected the
physicochemical properties of the systems, and a short or medium chain alcohol can be found
emphasizing the significantly influence of an in the literature. Most frequently surfactants such
amphiphilic drug on the microstructure. as sorbitan fatty acid esters, polysorbates, (peg-
Besides rheological and DLS studies, thermo- ylated) glycerol fatty acid esters, pegylated fatty
dynamical parameters such as free energy, alcohols, and fatty acids, respectively, as well as
enthalpy and entropy were determined by Sub- poloxamers occur in various combinations. More
ramanian et al. for polysorbate-based microemul- recently attempts have been made to use surfac-
sions.30 tants from natural base stocks, mainly alkyl
A completely different characterizing issue was polyglycosides and sucrose esters that are known
addressed by Malcolmson et al.21 They investi- for their good biocompatibility and favorable
gated the effect of varying properties of the oil in ecotoxicological properties. Microemulsions can
water-continuous microemulsions, i.e., size and also be formed using phospholipids. Besides,
polarity, on the solubilization capacity for testos- AOT (sodium bis(2-ethylhexyl)sulfosuccinate)
terone propionate. Solubility is an important and fluorosurfactants were chosen as amphi-
factor for drug delivery because by increased drug philes. Different alcohols act as co-surfactants,
amounts within the vehicle the concentration e.g., ethanol, (iso-)propanol, butanol, propylene
gradient towards the skin increases which is a glycol, tetraglycol, and octanediol.
driving force for diffusion processes. Observing The following chapter is intended to give an
the formation of the microemulsions by means of overview on several approaches in the formulation
light scattering it appeared that decreasing of microemulsions as well as their characteristics
molecular volume of the oil led to an increase in in the performed in vitro and in vivo examina-
the area of microemulsion formation. Interest- tions. Most of the studies are carried out in order
ingly, there was no relationship between solubi- to develop optimized vehicle systems exhibiting
lity of the drug in the microemulsions and the improved permeation properties for several
pure bulk oils. The authors recommended the use (model) drugs, hereby comparing different micro-
of high molecular volume oils because most drugs emulsion compositions or even completely differ-
are believed to be partly solubilized within the ent types of formulations. As in the development
headgroups of the surfactant aggregates and, of microemulsions, the surfactant blend and the
amongst other things, those oils do not impact hydrophilic ingredients (water or buffer) are often
molecular packing in this area very much. fixed beforehand, the lipophilic components and
A highly promising tool for the investigation of the ratio of all the ingredients are the variables.
the correlation between microstructure and pene- The choice of the oil depends mostly on its
tration behavior of microemulsions is NMR solubilization capacity for the drug used and
spectroscopy. Kreilgaard et al.16 as well as Hua known enhancing properties as in the case of oleic
et al.17 applied this method in order to obtain self acid. Other typical lipophilic components are
diffusion coefficients of drugs and other ingredi- esters such as isopropyl myristate (IPM) and
ents of colloidal systems. Partly in combination isopropyl palmitate (IPP) as well as medium chain
with other characterization techniques they triglycerides (MCT).
gained interesting results that can simplify the The structure of the following chapter complies
optimization process in formulation development. with basic compositions of microemulsions for
dermal use in order to summarize their status of
investigation. The corresponding tables (Tabs. 2–
DERMAL AND TRANSDERMAL DRUG 9) are based on Kreilgaard31 and were modified
DELIVERY USING MICROEMULSIONS and extended.
Since microemulsions turned out to enhance

PEGylated (Glycerol) Fatty Acid Ester-Based
dermal and transdermal drug delivery, a lot of
Microemulsions
compositions have been created and tested in vitro
and in vivo. A frequently used combination of surfactants is
A crucial point for the clinical use is the the mixture of Labrasol (caprylocaproyl polyox-
compatibility for which the surfactants, namely ylglycerides) and a Plurol-derivative (polyglyceryl
their type and amount, play the most important fatty acid ester) (see Tab. 2). It was chosen by
role. Mixtures of non-ionic surfactants are pre- Delgado-Charro et al. to form microemulsions
ferred. Occasionally, combinations of a surfactant together with ethyl oleate and water because of
Table 2. Overview of PEGylated (glycerol) Fatty Acid Ester-Based Microemulsions—Composition and Studies
608
Aqueous In Vitro Studies: In Vivo Studies:

Surfactant/Co-surfactant Phase Oil Phase Additives Drug Skin Model/Membrane Species Year Ref.
31
Labrasol/Plurol Isostearique Water Ethyl oleate NaCl (S) Sucrose Hairless mouse Human (I) 1997
skin
16
Labrasol/Plurol Isostearique Water Isostearyl Lidocaine, Excised rat skin 2000
isostearate prilocaine HCl
35
Labrasol/Plurol Isostearique Water Isostearyl Lidocaine, Rat 2001
isostearate prilocaine HCl
36
Labrasol/Plurol Isostearique Water Isostearyl Lidocaine Human 2001
isostearate
32
Labrasol/Plurol Isostearique NaCl Ethyl oleate Methotrexate Pig skin 2001
pH 7.4
37
Labrasol/Plurol Oleique Water MCT Ascorbyl palmitate, 2001
sodium ascorbyl
HEUSCHKEL, GOEBEL, AND NEUBERT
phosphate
40
Labrasol/Plurol Oleique Water MCT Xanthan Ascorbyl palmitate Cellulose 2003
gum, Aerosil (T) acetate
membrane,
porcine skin
38
Labrasol/Plurol Oleique Water MCT Ascorbyl palmitate 2003
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008

29
Labrasol/Plurol Oleique Water IPM Diclofenac Regenerated 2004,
41
diethylamine cellulose membrane 2005
42
Labrasol/Plurol Oleique/ Water Isostearyl Diclofenac sodium Human skin 2003
Transcutol isostearate
18
Polyoxyl-40 fatty acid Water IPP Lidocaine, Excised rat skin Rat 2004
derivates/glyceryl lidocaine HCl
oleate/tetraglycol
48
PEG 40-stearate/glyceryl 0.01 M IPP Lidocaine HCl Porcine skin Rat 2006
oleate/tetraglycol NaCl
49
PEG-40 stearate/glyceryl Water IPM Diclofenac sodium Different types Rat 2006
oleate/tetraglycol of animal skin
75
PEG-20-glycerol monooleate/ Water IPP Bupranolol Rabbit 1992
Tegin 4600 (uptake
from skin)
44
Labrasol/ethanol Water Oleic acid Piroxicam Excised rat skin 2005
43
Labrasol/ethanol Water Lauryl Diclofenac Excised rat skin 2004
alcohol diethylamine
DOI 10.1002/jps
45
Labrasol/Transcutol Water Lauroglycol Azone, SR-38, Fluoxetine HCl Human cadaver skin 2005
ethanol (E);
BHT, Na-
metabisulfite
DOI 10.1002/jps
(A); Na-benzoate
(P)
29
Labrasol/Transcutol Water Oleic acid Vinpocetine Excised rat skin, Mouse (I) 2004
human skin
19
Labrasol/Cremophor Water Oleic acid Terpenes (E) Ketoprofen Excised rat skin 2001
RH 40
46
Cremophor RH 40/ Water Oleic acid Vinpocetine Excised rat skin Mouse (I) 2004
Transcutol
50
Cremophor ELP/ Water Oleyl Terpenes (E) Aceclofenac Excised rat skin 2005
ethanol macrogol-6-
glycerides
54
Cremophor EL/propylene Acetate IPM Carbopol 1342 Different beta- Dialysis 1995
glycol/decanoic acid buffer (T) blockers membrane,
hairless mouse skin
51,52
PEG-20 glycerol monooleate/ Water IPP, oleic DMSO (E) Cyclosporine A Excised human skin Human 2002
Poloxamer/propylene glycol acid
53
PEG-20 glycerol monooleate/ Water Pelemol1 Curcumin Human 2007
Poloxamer/propylene glycol BIP
55
PEG-20 glycerol monooleate/ Water IPP Desmopressin Human skin 2005
Span 80 acetate
94
PEG-20 glycerol monostearate/ Water IPM Hydrocortisone Human, (I) 2001
Plurololeat WL 1173/
propylene glycol
95
PEG-20 glycerol monostearate/ Water IPM Human 2003
Plurololeat WL 1173/
propylene glycol
A, antioxidant; E, enhancer; P, preservative; S, electrolyte; T, thickening agent; I, irritability study.
MICROEMULSIONS FOR DERMAL AND TRANSDERMAL DRUG DELIVERY
609

Year Ref.
the known skin compatibility.31 Varying the
56
57
21
58
59
60
61
62
water-to-oil proportions, systems with different
1980
1993
1998
2004
2005
2004
2005
2002
microstructures (o/w and w/o) resulted. In spite of
the relatively large amount of surfactant (25–
44%), an in vivo study on the forearms of
In Vivo Studies:
volunteers under occlusive conditions confirmed

Species
the tolerability of the systems — at least in single

dose administration — by transepidermal water
loss (TEWL) and skin blood flow measurements.
rat
In contrast, a solution of 5% oleic acid in propylene
glycol, used as comparator besides water and
Skin Model/Membrane
pure propylene glycol, caused erythema and a

In Vitro Studies:
significant increase in TEWL. Kreilgaard et al.

Skin membrane
investigated the potential skin irritancy of a

microemulsion with similar compounds contain-
Human skin
Porcine skin
Rabbit skin
ing an extremely high amount of the surfactant
Mice skin blend (70%). A 20-h treatment of excised rat skin
with the drug-free formulation prior to the
permeation experiment did not perturb the skin
barrier.16
Table 3. Overview of PEGylated Fatty Alcohol-Based Microemulsions—Composition and Studies
Different steroids
The above-mentioned study of Delgado-Charro

Amethocaine
Amethocaine
Testosterone
Tetracycline
et al. dealt with the ability of microemulsions to

Fluconazole
Drug
fluorescein
propionate
Diclofenac
enhance skin permeation.31 In in vitro studies on

Carrageenan Sodium
sodium
hairless mouse skin, the flux of sucrose as a highly

HCl
hydrophilic model drug was investigated. Gen-

erally, the systems with the higher amount of
water showed a larger enhancement compared
Additives
DMSO, PG
to rather oil-continuous ones and an aqueous

sucrose solution. Finally, the authors presented a
model of multiple factors influencing transdermal
(E)
(T)
drug delivery. Main parts are different partition-

ing processes between microemulsion droplets,
Ethyl esters, hydrocarbons,
continuous phase and skin. Resulting penetration

represents the sum of the drug’s relative activities
in these fractions. Additionally, diffusion of single
Oil Phase
MCT, soybean oil
Tributyrin, MCT
constituents into the skin is possible which

(Miglyol 812),
may reduce the barrier function of the stratum

Soybean oil
Soybean oil
soybean oil
corneum by diverse interactions and consequently

Dodecane
Jojoba oil
improves penetration properties. The formulation

Decane
Decane
can also extract some horny layer components and

a new physical entity, realizing drug release now,
may result by losing the original microemulsion
Aqueous
Phase
structure.
Water
Water
Water
Water
Water
Water
Water
Water
E, enhancer; T, thickening agent.
Applying similar ingredients, Kreilgaard

et al.16 developed microemulsions and investi-
Surfactant/Co-surfactant
gated them concerning their transdermal drug

isopropanol or propanol
Brij 96/butanol/mono-/
delivery potential in vitro and in vivo. Prilocaine

di-/triethylene glycol
Lauromacrogol 300
Lauromacrogol 300
HCl and lidocaine acted as hydrophilic and

Brij 58/Span 80/
lipophilic model drug, respectively. In the first

monobutylether
Brij 96/Capmul
Brij 35/decanol
part of the study, a correlation between trans-

dermal flux of the drugs and their self-diffusion
coefficient in the vehicles as determined by spin-
Brij 96
Brij 97
echo NMR was found. Consequently, micro-

emulsions do not per se improve permeation.
DOI 10.1002/jps
Table 4. Overview of Microemulsions with (PEGylated) Sorbitan Fatty Acid Esters—Composition and Studies
In Vitro Studies:
Aqueous Skin Model/ In Vivo Studies:
Surfactant/Co-surfactant Phase Oil Phase Additives Drug Membrane Species Year Ref.
63
Polysorbate Water Silicon fluid Octyl dimethyl Human cadaver 1990
PABA, Cetyl skin, hairless
alcohol mouse skin
64
Polysorbate 20/1-butanol Water Decanol, DMSO, PG (E); Azelaic acid Hairless mouse skin 1991
dodecanol Carbopol 934 (T)
65
Polysorbate 20/1-butanol Water Decanol, DMSO, PG (E); Azelaic acid Hairless mouse skin 1994
dodecanol Carbopol 934 (T)
66
Polysorbate 80/sorbitol Water IPM Propranolol Artificial double 1998
layer membrane
105
Polysorbate 80/sorbitol, Water IPM, benzyl a-Tocopherol Pig skin 2003
Polysorbate 20/Transcutol alcohol
22
Polysorbate 85/ethanol Water IPM Meloxicam Excised rat skin 2006
69
Polysorbate 20/ethanol, Phosphate Oleic acid Estradiol Human cadaver skin 2003
Polysorbate 80/ethanol, buffered saline
Span 80/ethanol
67
Polysorbate 80/propylene Water IPM Triptolide Rat skin Rat 2003
glycol
68
Polysorbate 80/propylene Water Oleic acid Menthol (E) Triptolide Mice skin Rabbit (I) 2004
glycol
20
Polysorbate 80/propylene Water Ethyl Xanthan gum (T) Ibuprofen Porcine skin 2006
glycol oleate
70
Polysorbate 80/propylene Water IPM Hydroxyethyl Different Agar dilution assay 2006
glycol cellulose (T) basil oils
71
Polysorbate 80/glycerol Water IPM Tea tree oil Bovine udder skin 2005
E, enhancer; T, thickening agent; I, irritability study.
611

612
Table 5. Overview of Microemulsions with Polysorbates Combined with Other Non-Ionic Surfactants—Composition and Studies
In Vitro Studies:
Aqueous Skin Model/ In Vivo Studies:
72
Polysorbate 80/Span 20 Water IPM Oleic acid, Diphenhydramine HCl Human skin 1997
cholesterol (E)
73
Polysorbate 80/Span 20 Water IPP Glycolipid (E) Diphenhydramine HCl Human skin 2005
74
Polysorbate 85/Poloxamer 101 Water IPP Different beta-blockers Rabbit 1991
(uptake from skin)
75
Polysorbate 85/Poloxamer 101 Water IPP Bupranolol Rabbit 1992
(uptake from skin)

76
Polysorbate 20/taurodeoxycholate/ Water IPM/benzyl Felodipine Hairless 1997
Transcutol alcohol mouse skin
77
Polysorbate 80/Span 80/ Water IPM 8-Methoxsalen Newborn 2000
1,2-octanediol pig skin
78

Polysorbate 80/Span 80/ Water IPM Methotrexate Pig skin 2001
1,2-octanediol
47
Polysorbate 80/Span 20/ethanol Water IPM NMP, oleyl Lidocaine, Lidocaine Human 2003
alcohol (E) HCl, Estradiol, cadaver skin
Diltiazem HCl
79
Polysorbate 80/mono-/ Water IPM Carbopol Celecoxib Excised rat skin 2005
di-glycerides 934 (T)
27
Polysorbate 40/glyceryl caprylate Water IPM Ketoprofen Cellulose acetate 2005
membrane
100
Polysorbate 85/AOT Water IPM Cyclosporine A Excised rat skin Rabbit (I) 2006
E, enhancer; T, thickening agent; I, irritability study.
DOI 10.1002/jps
Table 6. Overview of Phospholipid-Based Microemulsions—Composition and Studies
DOI 10.1002/jps
In Vitro Studies: In Vivo
Aqueous Skin Model/ Studies:
32
Phospholipon 90 G Water Diclofenac Diclofenac Silicon impregnated 1995
diethylamine diethylamine membrane, human
stratum corneum
80
Soybean lecithin Water IPP Methyl nicotinate Cellulose ester Human 1995
membrane between
silicone membranes
81
Soybean phosphatidylcholine Water IPP Indomethacin, Human skin 1997
Diclofenac
82
Lecithin/n-butanol Water MCT Oleic acid (E) Ketoprofen Human skin Human 2002
(I)
83
Lecithin/n-propanol Water IPM Tetracaine HCl Mice skin 2006
84
Lecithin/n-propanol Water IPM Tetracaine HCl Rat 2006
&(I)
69
Epicuron 200/isopropanol Phosphate IPM Carbopol 940 (T) Estradiol Human cadaver skin 2003
buffered saline
86
Epicuron 200/bile salt/ Water IPM/decanol Aerosil 200 (T); Apomorphine HCl Lipophilic/ 2001
propylene glycol sodium hexanoate hydrophilic
(or octanoate), octanoic acid double membrane,
(C); benzyl alcohol (P); hairless mouse skin
ascorbic acid, a. palmitate (A)
87
Epicuron 200/sodium IPM/decanol Aerosil 200 (T); Apomorphine HCl Human 2004
taurocholate/propylene glycol octanoic acid, sodium
octanoate (C); ascorbic acid,
a. palmitate (A); benzyl alcohol (P)
88
Lecithin/propylene glycol Water Decanol Benzyl alcohol Methotrexate Membrane filter 1996
impregnated with
decanol; hairless
mouse skin
89
Epicuron 200/caprylyl- Phosphate IPM Methyl and ethyl Retinoic acid Siloxan membrane, 2003
capyl glucoside/ethanol or buffer pH 6.4 esters of amino acids (C) pig skin
1,2-hexanediol
A, antioxidant; C, counter ion; E, enhancer; P, preservative; T, thickening agent; I, irritability study.
613

614
Table 7. Overview of Microemulsions with Sugar-Based Surfactants—Composition and Studies

94
Sucrose laurate L595/ Water IPM Hydrocortisone Human, (I) 2001
L1695/propylene glycol
95
Sucrose laurate L595/L1695/ Water IPM Human 2003
propylene glycol
96
Sucrose mono-/di-laurate/ Water Octyl Niflumic acid Human 1998
medium chain alcohol octanoate
39
Dodecylglucoside/cocamide Water IPP, cetearyl Ascorbic acid 1999
propylbetaine/2-ethyl-1,3- octanoate
hexanediol/(phosphatidylcholine)
I, irritability study.

Table 8. Overview of Microemulsions with Ionic Surfactants—Composition and Studies

3 99
AOT Water Octanol [H2O] Human skin 1988
33
AOT Water Octanol Glucose, 3[H2O] Human cadaver skin 1991
97
AOT Water IPM Tetracaine HCl Rat, mouse (I) 2000
98
AOT Water IPM 5-Fluorouracil Hairless mouse skin Mouse (I) 2005
100
Polysorbate 85/AOT Water IPM Cyclosporine A Excised rat skin Rabbit (I) 2006
101
SDS/butyl lactate Water IPM 2005
103
N-Hexadecyl-N,N,N- Phosphate IPM Carbopol Piroxicam Cellulose acetate membrane Rat 2001
trimethylammonium buffer pH 5.5 940 (T) (b-Cyclodextrin)
bromide (HTAB)/ethanol
T, thickening agent; I, irritability study.
DOI 10.1002/jps
Ref.
Depending on the internal structure, drug diffu-
104
85
sion and hence transdermal delivery rate can also
be hampered. These conclusions are supported by
Year
2003
2006
findings of other groups.17,32,33 Additionally to the
mobility of the drug in the vehicle, the increased
solubilization capacity of microemulsions was
In Vivo Studies:
found to be a reason for the enhancing potential.

Species
It provides a larger concentration gradient of the

Mouse
Mouse
drug towards the skin. Similar to Delgado-Charro
et al.,31 it was demonstrated that the transdermal
delivery potential of microemulsions is not due to
a general enhancing effect of the surfactants and
their interaction with the stratum corneum.
Skin Model/Membrane
Increased surfactant contents partly resulted in

In Vitro Studies:
lower fluxes and permeation coefficients.

In a subsequent study, selected microemulsion
systems were compared to commercial products in
rats by means of in vivo microdialysis.35 A
significant benefit of the novel formulations was
obvious due to increased drug flux and in vivo
penetration rate for both model drugs. Applying a
pharmacokinetic model for a reliable estimation of
encoding DNA vaccine
Table 9. Overview of Fluorosurfactant-based Microemulsions—Composition and Studies
cutaneous absorption coefficient and lag time from

antigen (PA) protein-
Anthrax protective
microdialysis data, a good correlation was found

between the obtained in vivo data and previous
Drug
Plasmid DNA
in vitro results using Franz-type diffusion cells.

Further investigations were carried out in order to
estimate dermal drug delivery of lidocaine from
microemulsions and an o/w emulsion based cream
in volunteers, again using minimal invasive
microdialysis technique as well as determination
of the pharmacodynamic effect.36 Applying the
Additives
ME, the mean absorption coefficient of the local

anaesthetic drug was shown to increase about
threefold and the lag time entering the dermis was
reduced considerably compared to the conven-
Perflubron
Perflubron
Oil Phase
tional vehicle. However, the anaesthetic effect did

not diverge significantly between the two for-
mulations.
A completely different issue was addressed by a
Slovenian and an Italian research group. Among
Aqueous
Phase
other carriers, o/w and w/o microemulsions were

Water
Water
examined for their effect on the stability of

ascorbyl palmitate (AP), sodium ascorbyl phos-
phate and ascorbic acid.37–39 It turned out that
Surfactant/Co-surfactant
microemulsions are less suitable to protect a

Zonyl FSN-100/ethanol
Zonyl1 FSN-100/ethanol
pentadecafluorooctanoic
molecule from chemical degradation like oxida-

tion because their liquid, dynamic structure does
not allow encapsulating or immersing the drug
or at least its unstable part in a less reactive
acid/ethanol
environment.
For practical reasons, microemulsions are often
1
thickened, e.g., by Aerosil or xanthan gum. So did

Jurkovic et al. with the above-mentioned ascorbyl
palmitate containing systems.40 The w/o formula- oglycol as oily component were varied by the
tion showed a better in vitro release of the addition of either an oxazolidinone derivative or
antioxidant drug than the o/w one. The latter ethanol as permeation enhancer. Neither of these
delivered AP much better to excised porcine skin, colloidal carriers was able to exceed the high flux
which was concluded from its higher effectiveness rates obtained by ethanolic solutions.
in scavenging UV-induced free radicals. The An interesting study on the relationship
authors suggested that the microemulsions led between structure and permeation behavior was
to a different partitioning behavior of the drug conducted by Hua et al.17 Similar to Kreilgaard
within the skin. The o/w formulation was sup- et al.,16 they determined self diffusion coefficients
posed to accumulate AP in stratum corneum and of several microemulsion components by a NMR-
epidermis whereas the w/o system delivered it technique. The systems, essentially comparable to
primarily into deeper skin regions which were the ones used for fluoxetine, varied in the S/CoS
removed prior to the measurement. ratio, water and oil content and hence in their
Microemulsions composed of similar ingredi- viscosity. Permeation testing took place in vitro on
ents were characterized and tested for the in vitro rat and human skin. Remarkable correlations
release of the amphiphilic diclofenac diethylamine were found, e.g., between the self diffusion
(DDA) by Djordjevic et al.29,41 Dependent on the coefficient of the drug vinpocetine and its flux,
internal structure, different releasing profiles viscosity of the formulation and permeability as
were obtained—linear drug diffusion for droplet well as water diffusivity and permeability.
like microemulsions and non-linear profiles Although vinpocetine was supposed to be located
for bicontinuous systems. This was explained in the inner phase, high water contents of the o/w
by differences in drug/vehicle interactions and microemulsions and therefore lower amounts of
the water content of the formulations. Those surfactants favored the permeation. This finding
having high water contents showed a higher was explained by the hydration effect of the
flux, whereas in the bicontinuous microemul- stratum corneum by water and the increased
sions the microstructure seemed to hamper drug thermodynamic activity of the drug in these
diffusion. formulations due to a poor solubility in water-
In order to improve transdermal permeation of rich surroundings. Moreover, a low S/CoS ratio
diclofenac sodium salt, three ternary solvent exerted a positive influence.
systems, a solution, and a microemulsion were Using a combination of Cremophor RH 40
tested in vitro on human skin.42 In addition to the (PEG-40 hydrogenated castor oil) and Transcutol,
typical ingredients of the already mentioned and oleic acid as lipophilic ingredient for the
microemulsions, Escribano et al. incorporated preparation of microemulsions for vinpocetine,
19% Transcutol (diethylene glycol monoethyl the authors also found an influence of the internal
ether) because of its intrinsic enhancing effect. structure on the drug delivery potential.46 Once
Nonetheless, the colloidal carrier did not provide more, main parameters were S/CoS amount and
convincing permeation parameters. The finding ratio as well as water content. An irritation test on
was attributed to the lower content of enhancers mouse ear pointed towards skin compatibility of
compared to the other formulations. Even the the favored vehicle systems in both studies.
solution of the drug in a Transcutol/buffer mixture Sintov and Shapiro established new microemul-
showed slightly better results. sions for dermal delivery of lidocaine.18 They were
Labrasol combined with ethanol as cosurfactant using a combination of PEG-40 hydrogenated
was used by a Korean group. They developed castor oil/glyceryl oleate or PEG-40 stearate/
optimized o/w microemulsions for transdermal glyceryl oleate as surfactant and tetraglycol as
delivery of the anti-inflammatory drugs diclofenac cosurfactant. Similar to Lee et al.47 a significantly
diethylamine and piroxicam as proved in vitro higher flux for the base form of the drug than for
using rat skin.43,44 Criteria in this process were the salt (lidocaine HCl) was found in vitro on rat
solubilization capacity of the oil phase and skin. It turned out that PEG-40 stearate contain-
surfactant/co-surfactant (S/CoS) ratio. However, ing formulations are more effective than those
ethanol content was in some formulations rela- with PEG-40 hydrogenated castor oil. As principle
tively high—up to 50%. factors influencing lidocaine penetration water
Attempts were made to apply fluoxetine trans- content and S/CoS ratio were identified. Corre-
dermally.45 Basic o/w microemulsions containing sponding to the results of other groups,33,41 higher
Labrasol/Transcutol as S/CoS mixture and laur- amounts of water led to increased drug fluxes.
Furthermore, the superiority of a selected micro- weight of 1202 g mol1. In the past, several
emulsion over a micellar system and a crude conventional topical Cs A-formulations failed in
emulsion, which derived from the colloidal carrier, the treatment of psoriasis compared to systemic or
was demonstrated. An enhancing effect of the intradermal application. Mostly, an accumulation
pure surfactants was ruled out since this of the drug in the stratum corneum took place. But
mixture showed the worst lidocaine flux. In a T-cells as target structures are localized mainly in
second study, the authors combined the advan- the upper dermis layer. In ex vivo penetration
tages of the vehicle microemulsion with physical studies on human breast skin, higher concentra-
enhancement by short-term iontophoresis and tions of Cs A in viable epidermis and dermis
succeeded in the improvement of lidocaine HCl following the application of an o/w cream were
skin penetration.48 detected, whereas 20–30% of the applied dose
Sintov et al. also investigated the delivery from the o/w microemulsions reached the accep-
potential for diclofenac sodium from the micro- tor. This amount of drug is assumed to be
emulsion compared to a commercial formulation, responsible for a pharmacological effect.
Voltaren Emulgel1.49 In in vitro experiments Clinical relevance of these colloidal systems was
using several types of animal skin the microemul- confirmed by a clinical trial including patients
sion was superior to Voltaren Emulgel1. How- suffering from chronic plaque-type psoriasis. A Cs
ever, different flux rates were obtained dependent A-microemulsion was shown to be comparable to
on the skin type. In another approach, both therapeutic standards containing calcipotriol and
formulations were administered transdermally to bethamethasone-17-valerate. The slight advan-
rats in vivo. Eightfold higher drug plasma levels tage of a system with dimethyl sulfoxide (DMSO)
were achieved using the colloidal formulation. as enhancer in addition to oleic acid as lipophilic
Compared to a subcutaneous administration ingredient in preceding penetration studies could
of diclofenac with fast occurring, but rapidly not be established in vivo. Application of this
decreasing plasma peaks, the microemulsion formulation on chronic-inflammatory skin caused
maintained constant drug levels for at least 8 h. irritant effects and is, therefore, concluded not to
Rhee et al. developed an optimized o/w micro- be suited for the treatment of damaged skin.
emulsion for ketoprofen.19 The authors carried Information about depth profiling of a lipophilic
out permeation experiments on rat skin and dye, curcumin, within the stratum corneum follow-
examined the dependence of oil and surfactant ing topical administration of a similar composed
content on transdermal transport. With increas- microemulsion and a cream were obtained in
ing surfactant content a significant decrease in another in vivo study.53 Penetration of curcumin
permeation rate was detected which was probably from the colloidal carrier into both the stratum
due to a lower thermodynamic activity at higher corneum and the hair follicles was improved
surfactant amounts. For certain surfactant con- compared to the cream. Lipid layers and, pre-
centrations optimum oil contents were found. sumably, the follicles seemed to be the preferred
Incorporating several terpenes as enhancer, only pathways for the dye applied in the microemulsion
limonene exhibited the wanted effect. as indicated by microscopic observations.
In contrast to the current results, investigations Pattarino et al. solubilized eight beta-blockers
of Lee et al. did not show different permeation in an o/w microemulsion to achieve systemic
parameters for aceclofenac following application effects.54 Loading capacity depended on physico-
of three different o/w microemulsions.50 They chemical properties of the drugs. Their distribu-
were prepared with constant ratios between tion between the phases of the microemulsion was
S/CoS and oil, and increasing amounts of water evaluated by an apparent partition coefficient
(60–80%). In this case, only the addition of and the permeation coefficient through a dialysis
terpenes led to a more or less intense increase membrane. Transdermal absorption through
in drug flux. However, all the investigated hairless mouse skin using thickened microemul-
systems exhibited significantly higher aceclofenac sions resulted in pseudo-zero order kinetics for all
fluxes than an ethanolic solution. the beta-blockers. The authors found a linear
The development of an effective vehicle for correlation between the distribution parameters
dermal application of a drug with challenging and drug flux, which offered the possibility to
physicochemical properties was successfully done predict permeation of similar substances and led
by Jahn51 and Wohlrab et al.52 Cyclosporine A to the conclusion that the flux depends on drug
(Cs A) is a lipophilic drug with a high molecular concentration in the external phase.
Getie et al. used a w/o microemulsion and an In another study Malcolmson et al. investigated
amphiphilic cream to examine the penetration of the effect varying properties of the oil, i.e., size
the hydrophilic peptide desmopressin by analyz- and polarity on the solubilization of testosterone
ing the amount of the model drug in different skin propionate.21 Again, o/w MEs were prepared of
layers.55 Although there was no difference in the Brij1 96, water, and the lipophilic phase. The
total amount penetrated from the two vehicles, latter was represented by a set of different oils
the kind of formulation evidently influenced the (ethyl esters, hydrocarbons, MCT, and soybean
deposition of the drug in the skin. Higher amounts oil). The solubilization capacity for testosterone
of desmopressin were obtained in the upper propionate also showed an increase as a result of
layers, mainly in the stratum corneum when higher surfactant contents up to 20% (w/w). Only
the cream was applied, whereas a significantly some microemulsions exhibited a significant
larger quantity in the deeper skin layers and the increase in drug solubilization over an equivalent
acceptor compartment of the Franz diffusion cells micellar solution. Furthermore, the increase in
resulted using the microemulsion. drug load observed in the MEs was not related to
the drug’s solubility in the pure bulk oil. These
findings were explained by individual changes in
the internal structure depending on the molecular
PEGylated Fatty Alcohol-based Microemulsions
volume of the oil and its interaction with the
PEGylated fatty alcohols (e.g., Brij1), another surfactant layer.
important class of non-ionic surfactants, offer the As already mentioned, the low viscosity of
useful possibility of forming co-surfactant free microemulsions might be restricting in clinical
microemulsions. use. Therefore, thickening agents are sometimes
They were part of microemulsion formulations added. Since these ingredients change not only
created by Ziegenmeyer and Fuehrer.56 In the the rheological behavior but might also influence
1980s, the authors performed in vitro experiments the skin permeation, the effect of such a gelating
with skin membranes, comparing the penetration agent, the polysaccharide carrageenan, was
behavior of tetracycline HCl incorporated in a studied by Valenta and Schultz.58 Addition of
cream, a gel, and a microemulsion. The systems carrageenan transformed the liquid micro-
consisting of the same water and dodecane emulsions into stable semisolid gels exhibiting
content differed only in the amount of decanol. measurable increased thixotropy. Regarding the
Penetration enhancing activity of the ME was permeation, an enhancing effect of carrageenan
shown by the distinct increase in diffusion rate for the model drug sodium fluorescein was found
compared to the conventional vehicles. from all the thickened formulations compared to
Malcolmson et al. suggested that important the fluid ones as studied by Franz diffusion cells.
variables using an o/w microemulsion as potential The good adhesiveness on the skin due to the
delivery system are the percentage of dispersed polysaccharide was given as possible explanation.
hydrophobic phase and the solubility of the drug In vitro permeability coefficients and flux rates
in this phase.57 Several poorly water soluble of the anaesthetic drug amethocaine applied in an
model steroids were incorporated in an o/w o/w microemulsion and a commercially available
microemulsion and micellar solutions. All formu- Ametop1 Gel were compared by Escribano et al.59
lations contained Brij1 96 as surfactant. Increas- They found enhanced permeation parameters
ing its content, an increased drug load resulted. using the lauromacrogol-based colloidal formula-
However, at low surfactant concentrations the tion where the drug was totally solubilized. In
superior solubilization capacity of the microemul- contrast, amethocaine is partially precipitated in
sions was most obvious compared to the micellar the gel, which could influence the permeation.
solution. With stronger lipophilicity of the model A preclinical trial with the mentioned ametho-
steroids an increasing solubility mainly in the caine microemulsion compared with EMLA cream
unpolar core of microemulsions (consisting of and Ametop1 Gel was carried out by Arevalo
soybean oil and the hydrocarbon moiety of the et al.60 Firstly, analgesic activity was tested in
surfactant) and micelles (without oil) was rats made hyperalgesic or allodynic by carragee-
assumed. The authors concluded that the higher nan-induced inflammation. The microemulsion
the solubility of a drug in the soybean oil the more produced the fastest antihyperalgesic effect and
the microemulsion could improve the drug carry- was the only topical formulation with an anti-
ing capabilities. allodynic effect. Drug release from the micro-
emulsion was supposed to be more easily than (Tween1) and Span1, respectively, having either
from gel or cream. The second experiment was no co-surfactant or a short or medium chain
conducted on healthy, selected heat- or touch- alcohol (Tab. 4).
hypersensitive rats. Paw withdrawal time from a A w/o microemulsion composed of polysorbate,
heat and a mechanical stimulus was used as pain silicon fluid as oil phase, and water was developed
index. Here, all formulations were effective in by Linn et al. in order to investigate dermal
reducing heat-induced pain in both the treated delivery of the model drugs octyl dimethyl PABA
and the non-treated paw. However, touch induced and cetyl alcohol in vitro.63 The authors quantified
withdrawal time of both paws increased only rate and depth of penetration. The results were
following application of the microemulsion and compared with two macroemulsions—a cream
amethocaine infiltration. All in all a rapid pain and a lotion. The microemulsion delivered cetyl
relief due to improved drug penetration using the alcohol into the skin faster and at least twice as
micro-emulsion was concluded. much as cream and lotion. Interestingly, the
Kantarci et al. were interested in the enhance- absorption of cetyl alcohol from the macroemul-
ment of topical penetration of diclofenac sodium sions was enhanced if the skin had been pre-
and its modulation by DMSO and propylene treated with the microemulsion prior to product
glycol.61 Two microemulsions were prepared from application.
soybean oil, water, and Brij158/Span180 as Gasco et al. examined the transport of azelaic
surfactant blend. Either propanol or isopropyl acid through mice skin from a viscosized micro-
alcohol were added as co-surfactant. The permea- emulsion and a gel.64 A lag time was observed
tion behavior was determined by Franz diffusion with both systems. It was rather longer for the
cells equipped with rabbit skin and analyzed by a colloidal vehicle than for the gel. However, the
factorial randomized design. Different effects of amount permeated from the microemulsion was
the enhancers depending on the formulation were sevenfold higher than from the gel. Lag time
obvious. Propylene glycol had a stronger influence disappeared when the enhancer DMSO was added
in the microemulsion prepared with isopropyl to the ME and a further increase in drug diffusion
alcohol, whereas DMSO was superior when was reached.
incorporated into the propanol-containing vehicle. Since drugs are able to enter the skin only in a
Nonetheless, both additives led to an improved dissolved state and microemulsions offer high
permeation. Histopathological changes of the solubilization capacity and maximum thermody-
treated skin, mainly swelling, as observed by namic activity, drug load usually has its limit at
light microscopy could not be related to the saturation level. In spite of this fact, Pattarino
different microemulsions since they also occurred et al. increased the amount of azelaic acid in the
in the saline treated control samples. According microemulsion (6.4%, 10%, 15%) to achieve a
to the literature, they were supposed to be a result higher drug permeation.65 In the system with the
of the exposure of the skin to humidity and lowest content of azelaic acid the drug was totally
temperature of the Franz cell experiment. dissolved. It showed the lowest permeation rate.
El laithy and El-Shaboury compared Cutina Enhanced drug diffusion was obtained by the
lipogels and microemulsion gels as possible saturated vehicle including a small amount of
vehicles for the topical use of the antifungal drug suspended drug. This trend did not continue by
fluconazole.62 Although they focused the different further addition of azelaic acid. The presence of a
Cutina based lipogels, it turned out that the larger amount of suspended drug probably
microemulsion showed the highest in vitro drug obstructed the skin.
release and the best in vitro percutaneous Ktistis et al. examined the effect of polysorbate
absorption on mice skin. 80 concentration on the permeation of propranolol
In Table 3 Brij1-containing colloidal carriers in different vehicles (emulsion, microemulsion
are listed. and micellar system) through an artificial double
layer membrane.66 Basically, emulsion and micro-
emulsion were made of propranolol, water, IPM,
and polysorbate 80. For each system the apparent
Microemulsions With (PEGylated) Sorbitan
permeation coefficient decreased with increasing
Fatty Acid Esters
surfactant content. For a specific polysorbate
The following chapter includes colloidal drug 80 concentration, the parameter increased when
carrier systems prepared with polysorbates the disperse system changed from emulsion to
microemulsion and further to a dissolved system. explained by the higher concentration gradient
The authors argued that a larger interfacial area of the drug due to the solubilizing capacity of
of the dispersed phase enables a faster drug MEs and the droplet like microstructure of the
transfer, which is reflected in the increased formulations. Further aim of the work was to
transdermal permeation in the above-mentioned obtain microemulsion-based hydrogels that are
order. A similar approach was applied by Sintov more suitable for topical application. Therefore,
and Shapiro.18 But in their study, conducted with Chen et al. added xanthan gum and created stable
rat skin, drug fluxes decreased in the order of formulations. Unfortunately, no permeation stu-
ME — micellar system — macroemulsion. Since dies were carried out in order to evaluate the in-
they used higher surfactant amounts for the fluence of the viscosity on the permeation profile.
micellar solution, drug flux might have been For cosmetic purpose, Viyoch et al. incorporated
hampered due to interfacial interactions. Thai basil oils into o/w microemulsions.70 The
Mei et al. developed several solid lipid nano- in vitro activity against Propionibacterium acnes
particles (SLNs) and microemulsions as vehicles was tested by means of an agar dilution assay.
for the anti-inflammatory drug triptolide.67 Drug Application of the pure basil oils resulted in a
release from both systems was examined using rat higher inhibition compared to the loaded micro-
skin. The microemulsions demonstrated a higher emulsions, which was due to the higher oil
and constant flux having no burst release like contents when they were used in pure form. In
SLNs. Furthermore, the authors tested the spite of this, the microemulsions resulted good
pharmacodynamic effect of triptolide in vivo. inhibition effects and would be an effective carrier
Carrageenan-induced rat paw edema could be in acne skin care. Thickening of the vehicles
inhibited by all the formulations. In this case, by hydroxyethyl cellulose led to slightly lower
SLNs were superior to the microemulsions. antibacterial activities.
However, treating edema as a result of a chronic Different oils and non-ionic surfactants were
inflammation, the strongest chronic anti-inflam- screened by Yuan et al. in order to develop an
matory activity was observed applying the w/o optimized microemulsion for meloxicam.22 Sim-
microemulsion. ilar to Rhee et al.19 the authors observed an
Based on this work, Chen et al. modified increased skin permeation rate with decreased
microemulsion systems for triptolide.68 Physico- surfactant content, but also with decreased oil
chemical properties, transdermal ability of the concentration.
drug, and skin irritation were evaluated. Com- Transdermal administration of estradiol is a
pared to a propylene glycol containing aqueous frequently used way for increasing systemic
solution, the microemulsions showed a controlled, bioavailability by avoiding the first pass metabo-
sustained and prolonged delivery in the in vitro lism that occurs after oral treatment. Peltola et al.
test. Moreover, microemulsions with lower used various o/w microemulsions to deliver the
amounts of surfactant exhibited increased per- drug across human skin in vitro.69 The flux from
meation and, therefore, were supposed to be the microemulsions was 200–700-fold higher than
suitable for long-term use in contrast to the from control, whereas the permeation coefficient
microemulsions of Mei et al.67 having a surfactant decreased 5–18-fold. This result was assumed to
content of 50%. The optimized vehicle containing be due to the improved solubility of the lipophilic
triptolide did not show any visible irritation on drug in the microemulsions and the correspond-
rabbit skin. Thus, the incorporation of triptolide ingly increased concentration gradient towards
seemed to protect the skin from the toxic potential the skin. Finally, it was concluded that micro-
of the drug. emulsions might be appropriate vehicles for the
The same group developed microemulsions for above-mentioned purpose.
topical delivery of ibuprofen.20 Screening several For a drug entering the stratum corneum, the
oils to find an optimum, ethyl oleate was chosen intercellular route is known to be the most
because of the best ibuprofen solubility and its important. However, the follicular route may
properties as effective permeation enhancer. be involved to a greater extent and could be
Permeation profiles of several microemulsions, potentially more useful than previously assumed.
determined by Franz diffusion cells equipped with Therefore, Biju et al. determined the follicular
porcine ear skin, showed zero order kinetics and concentration of tea tree oil after topical applica-
higher fluxes than a saturated aqueous ibuprofen tion of several formulations (e.g., microemulsion,
solution. According to Peltola et al.,69 it was liposomal dispersion, and multiple emulsion)
in vitro using a perfused bovine udder model.71 concentration, and drug lipophilicity because of
Interestingly, microemulsion and liposomal for- many interactions occurring between drug, micro-
mulation exhibited about a twofold increased emulsion and skin. The authors also found a
transfollicular penetration compared to the multi- relationship between pharmacodynamic effect
ple emulsion. Hence, a kind of follicular targeting and solubility as studied with bupranolol in
is conceivable which can be useful in the treat- different water-free microemulsion bases.75
ment of acne vulgaris. Increasing amounts of water were added to the
formulations and the corresponding solubility was
determined. The rise of the pharmacodynamic
Microemulsions With Polysorbates Combined With effects in vivo correlated with the decline of the
Other Non-ionic Surfactants solubility-versus-water content curves in vitro.
The oil phase composition as a further para-
Polysorbates are also often found in combination meter influencing the skin permeation of o/w
with other types of non-ionic surfactants. Inves- microemulsions was presented by Trotta et al.76
tigations with those systems are summarized As lipophilic ingredients, benzyl alcohol or differ-
below (Tab. 5). ent ratios of benzyl alcohol and IPM were incor-
Schmalfuss et al. described the possibility of porated into the systems, keeping the amount of
controlling the penetration behavior of a hydro- the other phases nearly constant. The in vitro
philic model drug (diphenhydramine HCl) by permeation of felodipine increased with the ratio
means of additives. Ex vivo penetration studies of benzyl alcohol/IPM and, therefore, with the
on human skin were performed, analyzing the solubility of the drug in the internal phase. In
drug concentration in different skin layers.72 contrast, permeation rate of the comparator, a
Administration of a standard w/o microemulsion felodipine suspension in the apparent external
resulted in an accumulation of diphenhydramine phase, decreased over time.
HCl (DPH) in the dermis layer. Addition of Baroli et al. incorporated 8-methoxsalen in o/w
cholesterol as penetration enhancer caused a and w/o microemulsions made of the same
generally higher penetration rate and a shift of compounds but combined in different ratios.77
the drug towards the epidermis. Cholesterol was Cutaneous accumulation and percutaneous deliv-
assumed to loosen the stratum corneum lipid ery of the photoactive drug in saturated micro-
bilayers enabling an increased hydration of the emulsions were studied using vertical diffusion
polar headgroups and, therefore, facilitating cells. All microemulsions exhibited an increase in
penetration of DPH along the polar route. This both parameters compared to a saturated IPM
mechanism is proposed for hydrophilic sub- solution, which was the oil phase of the formula-
stances. Unlike this, incorporation of oleic acid tions, and a clinical used aqueous solution on
as enhancer changed neither penetration rate nor newborn pig skin. Since 8-methoxsalen is effective
concentration profile, probably because it influ- in psoriasis therapy, retaining of the drug in the
ences only the lipophilic pathway by altering the skin is required. The quotient of accumulated to
ceramide chains mobility. In a further study, a delivered drug could be modified by changing the
glycolipid was found to slightly facilitate DPH ratio of the ingredients.
permeation from the microemulsion.73 In vitro investigations on pig skin regarding
Kemken et al. tested water-free microemulsion transdermal delivery of methotrexate (MTX) were
pre-formulations nearly saturated with different carried out by Alvarez-Figueroa and Blanco-
beta-blockers.74 Pharmacodynamic effects after Mendez.78 Topical application of this drug is
dermal administration of the model drugs were problematic because of its hydrophilic character,
evaluated in vivo using rabbits. The pre-formula- the high molecular weight, and the high dissocia-
tions were applied on an occlusive patch. This tion degree at physiological pH. The authors found
should lead to water uptake from the skin and, incorporation of MTX in microemulsions, mainly
hence, to a change of the formulations into water of the o/w type, to be more effective compared to
containing supersaturated microemulsions. The simple solutions. Iontophoretic delivery from
observed high pharmacodynamic responses were solutions exceeded the ME results, probably due
assumed to be due to rising thermodynamic to the lower solubility of MTX in microemulsions
activity as driving force for enhanced dermal than in aqueous solutions.
drug uptake. However, not all effects could be Transdermal transport of hydrophilic and
described by dose dependency, influence of drug lipophilic drugs such as lidocaine base, lidocaine
HCl, estradiol, and diltiazem HCl from w/o and systems showed higher fluxes and were the
o/w microemulsions composed of IPM, polysorbate superior structure in this work.
80, water, ethanol as well as n-methyl pyrrolidone
(NMP) and oleyl alcohol as enhancer was studied
by Lee et al.47 For all the drugs a considerable
Phospholipid-based Microemulsions
improved transport by microemulsions com-
pared to the solution in either water or IPM Natural lecithin is one of the most promising and
was observed, with a significantly better flux useful pharmaceutical agents in topical formula-
from the o/w system than from the w/o. The tions. It is non-toxic even in high concentrations
enhancement from the o/w formulation was 17- and does not lead to skin irritation. Furthermore,
fold for lidocaine base, 30-fold for lidocaine HCl, it is able to increase skin permeation.80 Due to
58-fold for estradiol, and 520-fold for diltiazem their amphiphilic lipid structure, phospholipids
HCl. Moreover, the simultaneous delivery of both are able to form liposomes, but also microemul-
a hydrophilic and a hydrophobic drug from the sions—either on their own in narrow composition
microemulsion was indistinguishable from either ranges or with co-surfactants like short chain
drug alone. The results suggest that transport alcohols. During the past several years, phospho-
from the aqueous phase is the most important lipids have been used in different approaches as
factor for both kinds of drugs whereas the oil amphiphile for dermal drug delivery by micro-
phase serves as a drug depot. This could be con- emulsions (Tab. 6).
firmed by removing surfactant and oil from the A meaningful study was conducted by Kriwet
system. The flux from the remaining water phase and Mueller-Goymann.32 They investigated the
components was comparable to that from the o/w relationship between the colloidal structure of
ME. It was concluded that presence of NMP ternary phospholipid-containing formulations
increases the partition of the lipophilic drugs into and kinetics of drug release as well as stratum
the water phase, hence making them available for corneum permeability. The amphiphilic molecule
the transport across the skin. diclofenac diethylamine was chosen as model drug
Subramanian et al. developed a stable micro- and represented also the oil phase of the systems.
emulsion system for celecoxib and found out that Depending on the ratio of the components, various
the droplet size of the vehicles increased with drug colloidal structures from liposomal dispersions via
addition.79 Caused by a higher amount of mono- microemulsions to lamellar liquid crystals could
and di-glycerides as co-surfactant, droplet size be generated. Drug release through a silicon-
and viscosity increased. These changes were impregnated membrane strongly depended on
accompanied by lower drug permeation rates the vehicle’s microstructure—Just as stratum
through rat skin. Comparing the permeation corneum permeation. Whereas in liposomes
obtained with microemulsions, a viscosized ME and lamellar phases strongly bound drug and
and a cream, the microemulsions were superior to phospholipids hamper the interaction with the
the other formulations. horny layer, incorporation into microemulsions
Podlogar et al. identified different types and enhances permeability.
structures of microemulsions along a dilution line Different colloidal structures were also com-
within the phase diagram by a combination of pared by Bonina et al., who examined the percu-
experimental methods.27 Addition of water to a taneous absorption of methyl nicotinate.80 The
surfactant/oil mixture led to changes in the drug elicits a distinctive erythema and generates
internal structure from w/o to bicontinuous and a vasodilatory effect in vivo. The corresponding
further to o/w microemulsions. Gel-like structures measurements showed that liposomes could in
were formed at a water content of more than 45%. fact lead to a good skin partitioning of bioactive
Ketoprofen was incorporated into selected for- compounds, improving their topical activity,
mulations. Its release was tested by Franz diffu- compared to conventional formulations like
sion cells with an artificial hydrophilic membrane. creams and gels. The lecithin microemulsion gel
Although release rates for all systems followed a showed an activity profile characterized by a
zero order kinetic, different microstructures strong initial vasodilatory response followed by a
caused different profiles. The slowest release rapid decline. The fast passage of the drug seemed
was observed from the w/o microemulsion. In this to be caused by a disruption of the stratum
region, strong interactions between ketoprofen, corneum, but the microemulsion could not further
oil and the surfactants were assumed. O/w penetrate in the skin.
Dreher et al.81 investigated different micro- facilitating drug uptake. CLSM results showed
emulsion gels containing indomethacin and diclo- that sweat glands and hair follicles also provide
fenac, respectively, dissolved in lecithin, IPP and the path for transdermal permeation of micro-
water with saturated solutions of the drugs, each emulsions. Further conducted in vivo studies on
dissolved in the pure oil. In permeation studies, rats demonstrated increased local analgesic
higher drug fluxes were obtained by the ME responses of THCl by elevating drug concentra-
gels compared to the solution in IPP. However, tion and water content.84 The advantage of o/w
permeability coefficients acted vice versa. This microemulsions was explained by the hydrophilic
was assumed to be due to the higher solubilization nature of THCl which provides a better avail-
capacity of the microemulsion on the one hand, ability in the system. Histopathological investiga-
and an unfavorable partitioning of the drugs tions and biochemical findings indicated that the
between ME and stratum corneum compared to developed vehicles are safe for transdermal drug
IPP solution/stratum corneum on the other hand. delivery.
The role of lecithin as enhancer could not finally Peira et al. evaluated the capability of the
be clarified by interaction studies on human internal phase of w/o microemulsions to act as
stratum corneum by means of Fourier Transform drug reservoir.86 Among other ingredients, the
Infrared spectroscopy and DSC. Low-temperature colloidal systems contained apomorphine HCl,
scanning electron microscopy showed in some first Epicuron 200 (soybean lecithin) and bile salts.
results a change in the ultrastructure of the Antioxidants were added to avoid the oxidation of
intercellular lipid regions after incubation with the drug. The lipophilicity of apomorphine was
lecithin microemulsion gel. increased by forming ion pairs with octanoic acid,
Good human skin tolerability of a lecithin-based which was found to be the main reason for the
o/w microemulsion compared to conventional obtained facilitated drug transport through hair-
vehicles (o/w and w/o cream, and gel) was observed less mouse skin in vitro. It was concluded, that
by Paolino et al.82 It could be demonstrated that apomorphine concentration in plasma following
incorporation of 1% of the enhancer oleic acid transdermal administration might reach a ther-
into the microemulsion was significantly less apeutic effect. Later on, one of Peira’s microemul-
irritant than an oleic acid dispersion of the same sions was employed within a clinical trial on the
concentration. This effect was supposed to be due treatment of Parkinson’s disease.87 The pharma-
to the incorporation of oleic acid into the colloidal cokinetic analysis of human blood samples showed
microstructure and the impossibility to strongly that apomorphine HCl was indeed absorbed by the
perturb the stratum corneum lipids. For the same transdermal route. The formulation was able to
reason, the oleic acid containing microemulsions provide a sustained drug release and therapeutic
exhibited poor additional enhancing activity on plasma levels for a prolonged period of time.
skin permeation of the model drug ketoprofen, but However, it needed 1 h to reach therapeutic
both vehicles clearly improved transdermal deliv- concentrations.
ery with respect to the conventional vehicles. The concept of ion pairing in order to increase
Changez et al. did not only compare transder- drug lipophilicity was also successfully used by
mal delivery potential of microemulsions and an Trotta et al.88 They studied the permeation of
aqueous solution.83 They also studied the effect of methotrexate in vitro from w/o microemulsions in
the composition of microemulsions on barrier absence and presence of counter ions at different
properties of the skin. W/o and o/w microemul- pH values.
sions were made of tetracaine HCl (THCl), Topical delivery of retinoic acid ion paired with
lecithin, n-propanol, IPM, and water. Both types amino esters was also investigated.89 Permeation
of colloidal formulations showed an increased behavior through a siloxan membrane depended
THCl flux by elevating the water concentration. on the type of microemulsion. Systems having the
Additionally, amount and ratio of S/CoS influ- drug pure or formed as ion pair in the continuous
enced steady state flux, probably by swelling and phase, exhibited higher permeability coefficients
extraction of stratum corneum lipids. From DSC, than those showing a favored drug partitioning
TEM and confocal laser scanning microscopy towards the internal phase. In diffusion experi-
(CLSM) studies, the authors suggested that the ments on pig skin, very low flux rates resulted
colloidal formulations generate a hydration gra- following administration of microemulsions com-
dient across the skin accompanied by an increased pared to aqueous solutions. However, since the
intercellular space in epidermis and dermis drug is used in the treatment of acne vulgaris, the
observed retinoic acid accumulation in pig skin The authors also employed a pharmacodynamic
using o/w microemulsions indicated optimized assessment and found that the effect of the
drug targeting without increased systemic side novel formulation, saturated with the drug (1%),
effects. was as efficient as a commercially available 3%
o/w emulsion. The accumulation of niflumic acid
in the interfacial film of the microemulsion
Microemulsions with Sugar-Based Surfactants
was considered to be responsible for the occur-
In the 1990s a promising class of non-ionic ring lag time, which could control the drug
surfactants came up in the development of release.
colloidal carriers. Based on the renewable raw
materials starch and natural oils, alkyl polyglyco-
sides (APGs) show excellent environmental and Microemulsions With Ionic Surfactants
skin compatibility.90,91 In contrast to the use of
ethoxylated fatty alcohols, APG-based microemul- AOT (sodium bis(2-ethyl hexyl)sulfosuccinate) is a
sions are temperature-stable. Their phase beha- frequently used anionic surfactant that forms
vior can only be varied by the combination with a stable w/o microemulsions without the addition of
suitable co-surfactant and the oil to water cosurfactants. In the literature, it can be found
ratio.92,93 Qualitative composition as well as combined with IPM or octanol and water as a
corresponding in vitro and in vivo studies are carrier for hydrophilic drugs. Several formula-
presented in Table 7. tions were classified to be safe for dermal
Glycolipids are able to penetrate the stratum application.97,98
corneum and have a slightly enhancing effect on Investigating the transdermal permeation of
the permeation of hydrophilic drugs as studied glucose as hydrophilic model drug from micro-
with diphenhydramine HCl which was incor- emulsions through human cadaver skin, Osborne
porated into a w/o microemulsion.73 It was et al. found a relationship between drug flux and
assumed that the glycolipid increases the space water content in the formulation.33 Presence of
between the polar headgroups of the stratum free water was shown to be essential for glucose
corneum lipids, thus, enabling an increased transport. At lower water contents, all molecules
hydration. are used for hydrating the surfactant headgroups,
Besides APGs, sucrose esters are in use, e.g., thus being not available for partitioning into the
in studies of Lehmann et al.94 They tested an skin.
o/w and a w/o microemulsion for their suitability Already in a previous study, the authors
in dermatological use. In hen’s egg test on hypothesized that a hydrophilic drug would not
chorioallantoic membrane (HET-CAM) both be available for percutaneous transport unless
vehicles were classified as non-irritant. But water from the microemulsion is freely trans-
from an in vivo skin blanching test on humans ported into the skin.99
arose, that despite the enhanced hydrocortisone Changez and Varshney used AOT microemul-
penetration from the colloidal systems, neither sions for topical application of the local anaes-
microemulsion conferred benefit in this therapy thetic drug tetracaine HCl.97 Local analgesic
because irritant effects of the formulations response as a measure for the therapeutic
outbalanced the improved penetration of the potential was evaluated on rats. The optimum
anti-irritant drug. The authors concluded that formulation exhibited an eightfold enhancement
use of microemulsions as drug delivery systems of this parameter compared to an aqueous solution
is more valuable when irritant effects are of the drug. It was assumed that AOT is able to
negligible. A study of Gloor et al. gave an soften the stratum corneum, but it did not alter
example for such a case.95 They demonstrated the structure as observed microscopically. More-
that the above mentioned drug-free microemul- over, application of the microemulsions did not
sions exhibit a keratolytic activity and are, induce oxidative stress in mice skin.
therefore, suitable for elimination or prevention In further experiments, the water-soluble drug
of plantar desquamative and hyperkeratotic 5-fluorouracil was used.98 Permeation studies on
skin changes. depilated mouse skin resulted in water and AOT
Sucrose fatty acid ester-stabilized bicontinu- concentration as enhancing factors. Deeper
ous microemulsions were applied as carrier insides into the effect of the ME on the stratum
system for niflumic acid by Bolzinger et al.96 corneum structure were given by Fourier Trans-
form Infrared-Attenuated Total Reflectance Spec- biologically inert. A stable ethanol-in-fluorocar-

troscopy (FTIR-ATR) examinations of untreated bon formulation was selected for in vivo studies in
and treated skin. The frequency shifts of specific mice (Tab. 9). Compared to ‘‘naked’’ plasmid DNA
IR-bands provided useful information. Main find- in saline or ethanol, the novel system led to
ings were the increased disordering of the significant enhancements in immune response
hydrocarbon chains of the stratum corneum lipids against the encoded model antigen. For example,
as well as the increased hydration of the skin by a 45-fold and over 1000-fold increase in the
both, water and AOT, which explained the specific serum IgG and IgA titers, respectively,
enhancing properties of the tested formulations. was detected.
Liu et al. formulated a bicontinuous microemul- The same vehicle was used to incorporate an
sion system for transdermal delivery of the anthrax protective antigen (PA) protein-encoding
oligopeptide cyclosporine A.97,100 Subsequently plasmid (pGPA).85 The anti-PA immune
to the physicochemical characterization, in vitro responses following topical application on mice
permeation studies through rat skin were con- were measured. In contrast to pGPA alone, pGPA
ducted and showed an up to 10 times increased applied in the microemulsion induced a significant
transdermal delivery of the drug by the micro- level of anti-PA IgG in the serum of the mice. This
emulsion compared to a suspension. The extent of titer was still lower than the one reached by
the enhancing effect depended on water content subcutaneous injection of the current anthrax
and microstructure of the formulations. vaccine in the United States. However, the
Another anionic, sodium dodecyl sulfate con- microemulsion was successfully used for topical
taining microemulsion system was investigated boosting of mice primed with PA protein, which
by Park et al.101 Their objective was to introduce offers a simplified dosing schedule.
butyl lactate as a new skin compatible co-
surfactant. However, up to now there have not
been conducted any dermal drug delivery studies. FACTORS INFLUENCING THE PENETRATION
Cationic microemulsions containing piroxicam BEHAVIOR OF MICROEMULSIONS
and a piroxicam-ß-cyclodextrin inclusion complex,
respectively, were developed by Dalmora Although the drug delivery potential of micro-
et al.102,103 These systems, exhibiting a remark- emulsions is widely accepted, up to now its
ably increased solubility of the drug compared to mechanism is not yet well understood. Most likely
simple solutions, demonstrated in in vitro drug it is attributable to a variety of factors depending
release studies a reservoir effect for piroxicam. on the composition and the resulting microstruc-
The following in vivo assessment of anti-inflam- ture of the formulation.
matory activity on rats resulted in significantly Influence of surfactant content on drug flux
inhibited inflammatory reactions after topical has been studied several times. It turned out
application relative to control and an improved that the more surfactant is not the bet-
effect of the microemulsions after subcutaneous ter.16,18,19,22,31,46,66,68 Indeed within formulation
administration compared to a buffered solution of specific limits, an inverse correlation arises. Some
the drug. Moreover, a prolonged pharmacological authors suggested that the thermodynamic activ-
activity after subcutaneous application confirmed ity of the drugs got lower due to increasing
the potential of modifying dermal drug delivery by surfactant amounts.22,68 Therefore, a general
ME systems. enhancement by alteration of the stratum cor-
An overview of the microemulsions under neum barrier properties due to this class of
investigation is given in Table 8. excipients can be ruled out.
Furthermore, an optimum surfactant/co-surfac-
tant mass ratio exists. Regarding a large micro-
emulsion area in the phase diagram, in the case of
Fluorosurfactant-based Microemulsions
non-ionic surfactants combined with glycols or
Cui et al. are working in the highly challenging Transcutol as co-surfactant, higher S/CoS ratios
field of topical immunization. As carrier systems are beneficial.18,20,46 However, higher drug fluxes
for plasmid DNA they used w/o microemul- were obtained at lower S/CoS values.17,18
sions.104 A non-ionic fluorosurfactant was chosen Another important factor concerning drug
and combined with perflubron, which is safe for delivery potential is the amount of water in a
pharmaceutical use as well as chemically and microemulsion. Osborne et al. found a correlation
to the glucose flux in their permeation studies. However, flux through rat skin was about five
Presence of free water was shown to be essential times higher than through human one.
for glucose transport into skin. At lower water Besides the mobility parameters, the high
contents, all molecules are used for hydrating the solubilization capacity of microemulsions for
surfactant headgroups, thus being not available hydrophilic and lipophilic substances is an impor-
for partitioning into the skin.33 Sintov and tant feature. If maximum thermodynamic activity
Shapiro reported on similar effects for lidocaine is used by incorporating the drug at saturation
flux18 as well as Changez et al. which were using level or even supersaturated, it leads to a large
lecithin-containing microemulsions for dermal concentration gradient towards the skin which is
delivery of tetracaine HCl.83 Also drug release a driving force for drug transport.69,74–76
is a function of water content. Djordjevic et al. Concerning the pathway of a drug entering the
found drug fluxes proportionally increasing to the stratum corneum, the intercellular route is
amount of water in their microemulsions.41 accepted as the preferred one. However, a
In general, continuously and spontaneously participation of follicles and sweat glands has to
fluctuating interfaces of microemulsions enable be taken into consideration as indicated by several
high drug mobility and might enhance the drug authors.53,71,83 This finding might be attributable
diffusion process.31 Yet, NMR-studies of Kreil- to the low surface tension that ensures an excel-
gaard et al.16 and Hua et al.17 on dynamics within lent contact to the skin, where the good spreading
the colloidal formulations could give an explana- is additionally supported by the low viscosity.
tion that comprises all the above mentioned facts. Hence, the formulation is capable to enter the skin
Both groups found a correlation between drug easily.
mobility resulting from a certain microstructure Interestingly, even pretreatment with a micro-
and drug flux. An optimum extent of hydration of emulsion can increase the percutaneous absorp-
the surfactant headgroups seems to be essential tion of a subsequently applied drug (cetyl alcohol)
where enough free water is additionally present to included in a cream and a lotion as presented by
enable fast drug diffusion. The necessary amount Linn et al.63
of water is specific for each quaternary system and More or less successful in further increasing
probably depends on the kind of surfactant and co- permeation rate was the incorporation of pene-
surfactant, mainly size and water binding capa- tration enhancer like oleic acid, DMSO, choles-
city of the polar moiety. This principle seems to terol, and terpenes. Remarkably, using a
concern not only hydrophilic drugs as described hydrophilic drug, it has been shown that the
by Osborne et al.33 Permeability of lipophilic enhancer effect of the constituents depends also
drugs is also correlated to water diffusivity.36 on the drug’s preferred route through the stratum
In this context it was suggested that the corneum.72
hydration of the stratum corneum by the vehicle In summary, a number of influencing factors on
plays a role. the penetration behavior of microemulsions could
Consequently, full drug diffusivity potential of be found. A strong relationship between micro-
microemulsions can also be hampered by their structure and drug delivery potential exists.
composition and microstructure, e.g., due to Nevertheless, more systematic research work is
adsorption of drug molecules to the surfactant, required for a detailed clarification of the pene-
encapsulation or unfavorable partitioning of the tration mechanism.
drug between formulation and skin.17,32,33 The
probability is obviously higher in the case of
amphiphilic drugs and when high amounts of CURRENT FIELDS OF TOPICAL
surfactants are employed. O/w type microemul- ADMINISTRATION AND FUTURE PROSPECTS
sions were convincing in most studies, even if
hydrophilic drugs were applied. Since skin is the body’s largest organ, it does not
Incidentally, Hua et al. used two types of skin only fulfill physiological functions but is also an
for their permeation studies and obtained a linear important target site for the administration of
relationship between the mentioned parameters drugs. Cutaneous drug delivery is gaining ground
across human skin as well as across rat skin. This because it possesses advantages in relation to
is an important information considering that a lot other administration routes in several aspects. As
of permeation studies throughout the literature it is well known, the main challenge is to overcome
are conducted with other than human skin. the barrier function of the stratum corneum,
which hampers the achievement of therapeutic to first pass metabolism. Hence, for patients
drug levels in either skin or systemic circulation. suffering from tendinopathy, rheumatoid arthri-
Due to their penetration enhancing properties, tis or osteoarthritis transdermal delivery might be
microemulsions can find application in a number an option.20,79,82
of clinical areas as summarized below. Topical administration of drugs can provide
Site-specific treatment of dermatological dis- therapeutic plasma levels, i.e., transdermal
eases is a classical field of topical administration. absorption. Significant advantages are the
For example, several anti-acne drugs were incor- increase in bioavailability by avoiding first pass
porated into colloidal carriers, e.g., antimicrobial metabolism and minimization of adverse effects
agents like basil oil,70 tea tree oil,71 retinoic acid,89 such as gastrointestinal ones. Microemulsions
and azelaic acid64,65 as well as antibiotics (tetra- offer a high solubilization capacity even for poorly
cycline HCl56). Since acne concerns sebaceous soluble drugs and combined with their permeation
glands, the proposed follicular uptake by micro- enhancing effect high flux rates can be obtained.
emulsions might be advantageous. For example for steroids like estradiol69 and
Dermal delivery of antioxidants plays a role in testosterone,21,57 but also for beta-blockers54,74,75
prophylaxis and treatment of ultraviolet-induced they are conceivable vehicles. In vitro experi-
damage of the skin like photoaging and photo- ments as well as a clinical trial concerning the use
carcinogenesis. They are related to increased of topically applied apomorphine in the treatment
levels of free radicals. An effective skin protection of Parkinson’s disease were successfully per-
by ascorbyl palmitate, incorporated into a micro- formed.86,87
emulsion, has been demonstrated,40 but also a- A growing field in therapeutics is the applica-
tocopherol is in use.105 tion of peptides or peptide-like drugs. Because of
Application of microemulsions for local anaes- their low oral bioavailability caused by extensive
thetics like lidocaine and prilocaine appears to proteolytic degradation in the gastrointestinal
be useful as well since a fast penetration and, tract as well as weak permeability due to high
hence, a fast occurring anaesthetic effect can be molecular weight and hydrophilic character they
reached. Besides their use in minimal invasive are mostly applied parenterally. Therefore, alter-
operations, performing of other painful treat- native administration routes have to be found.
ments might be more comfortable, especially in First attempts to incorporate peptides into micro-
paediatrics. Several investigations dealt with this emulsion were made by Getie et al. who used
topic.18,35,36,60,83,84 desmopressin as model drug.55
One of the most significant skin diseases is Topical genetic immunization using fluorosur-
psoriasis vulgaris. Immunosuppressives like factant-based microemulsions is a highly innova-
methotrexate (MTX) and the oligopeptide cyclos- tive approach. In contrast to intramuscular
porine A (Cs A) belong to the standard treatment injection, the standard method, immunization
and are usually applied orally or parenterally. But through intact skin seems to be ideal because the
systemic administration is accompanied by severe skin represents the body’s front line for immuno-
side effects such as hepatotoxicity and nephro- survelliance.102 There is a need for optimized
toxicity, respectively. Physicochemical properties vehicles, which can improve the potency of DNA
of both high molecular weight drugs do not vaccines since it was very limited and variable by
privilege them for transdermal delivery. MTX is intramuscular injection as studied on primates
highly dissociated at physiological pH whereas in and humans.107
the case of Cs A its lipophilicity leads to an accu- However, topical application of microemulsions
mulation in the stratum corneum with slow trans- might not be convenient for all patients because of
port into deeper skin layers. However, a number of the low viscosity. Therefore, in several studies
encouraging in vitro and in vivo studies on the thickening agents like carrageenan,58 carbo-
enhanced dermal drug uptake by microemulsion pols54,69,79 or Aerosil40 were added. Another
systems have been published.51,52,78,88,100,106 possibility was given by Sintov and Shapiro.18
Investigations were carried out aiming the They created patches from pure microemulsions
development of optimized formulations for non- by adding a polymer. Compared to a commercial
steroidal anti-inflammatory drugs. Percutaneous product, this adapted formulation showed
penetration by microemulsions is appropriate increased drug fluxes similar to the fluid micro-
since these drugs are mostly sparingly soluble, emulsion and improved the drug disposition into
induce gastrointestinal side effects and are liable the dermis layer.
In summary, the utilization of microemulsion 12. Jahn W, Strey R. 1988. Microstructure of micro-
systems offers a number of advantages. How- emulsions by freeze fracture electron microscopy.
ever, they did not find broad use in practice up to J Phys Chem 92:2294–2301.
now. Main point of criticism is the necessity of 13. Kumar P, Mittal KL, editors. 1999. Handbook of
large amounts of surfactants to form micro- microemulsion science and technology. New York:
Marcel Dekker.
emulsions. Throughout the literature this pro-
14. Mrestani Y, Neubert RH, Krause A. 1998. Parti-
blem occurs as most microemulsions contain tion behaviour of drugs in microemulsions mea-
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REVIEWS

Microemulsions—Modern Colloidal Carrier for

SANDRA HEUSCHKEL, ALEXANDRA GOEBEL, REINHARD H.H. NEUBERT

Received 8 February 2007; accepted 1 March 2007

Abbreviations: AOT, sodium bis(2-ethyl hexyl)sulfosucci-

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008 603

Table 1. Differences between Microemulsions and Emulsions

Microemulsion Property Emulsion

Since microemulsions turned out to enhance

Aqueous In Vitro Studies: In Vivo Studies:

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008

volunteers under occlusive conditions confirmed

the tolerability of the systems — at least in single

pure propylene glycol, caused erythema and a

significant increase in TEWL. Kreilgaard et al.

investigated the potential skin irritancy of a

The above-mentioned study of Delgado-Charro

et al. dealt with the ability of microemulsions to

enhance skin permeation.31 In in vitro studies on

hairless mouse skin, the flux of sucrose as a highly

hydrophilic model drug was investigated. Gen-

to rather oil-continuous ones and an aqueous

drug delivery. Main parts are different partition-

continuous phase and skin. Resulting penetration

MCT, soybean oil

constituents into the skin is possible which

may reduce the barrier function of the stratum

corneum by diverse interactions and consequently

improves penetration properties. The formulation

can also extract some horny layer components and

E, enhancer; T, thickening agent.

Applying similar ingredients, Kreilgaard

gated them concerning their transdermal drug

delivery potential in vitro and in vivo. Prilocaine

HCl and lidocaine acted as hydrophilic and

lipophilic model drug, respectively. In the first

part of the study, a correlation between trans-

echo NMR was found. Consequently, micro-

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008

(uptake from skin)

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008

Table 7. Overview of Microemulsions with Sugar-Based Surfactants—Composition and Studies

Aqueous In Vitro Studies: In Vivo Studies:

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008

Aqueous In Vitro Studies: In Vivo Studies:

found to be a reason for the enhancing potential.

It provides a larger concentration gradient of the

Increased surfactant contents partly resulted in

lower fluxes and permeation coefficients.

cutaneous absorption coefficient and lag time from

microdialysis data, a good correlation was found

in vitro results using Franz-type diffusion cells.

ME, the mean absorption coefficient of the local

tional vehicle. However, the anaesthetic effect did

other carriers, o/w and w/o microemulsions were

examined for their effect on the stability of

microemulsions are less suitable to protect a

molecule from chemical degradation like oxida-

thickened, e.g., by Aerosil or xanthan gum. So did

form Infrared-Attenuated Total Reflectance Spec- biologically inert. A stable ethanol-in-fluorocar-