Advances in Colloid and Interface Science 123–126 (2006) 369 – 385

www.elsevier.com/locate/cis

Microemulsions as transdermal drug delivery vehicles

Anna Kogan, Nissim Garti ⁎
Casali Institute of Applied Chemistry, The Institute of Chemistry, Givat Ram Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
Available online 14 July 2006

Abstract

Microemulsions are clear, stable, isotropic mixtures of oil, water, and surfactant, frequently in combination with a cosurfactant. Microemulsions
have been intensively studied during the last decades by many scientists and technologists because of their great potential in many food and
pharmaceutical applications. The use of microemulsions is advantageous not only due to the facile and low cost preparation, but also because of the
improved bioavailability. The increased absorption of drugs in topical applications is attributed to enhancement of penetration through the skin by the
carrier. Saturated and unsaturated fatty acids serving as an oil phase are frequently used as penetration enhancers. The most popular enhancer is oleic
acid. Other permeation enhancers commonly used in transdermal formulations are isopropyl myristate, isopropyl palmitate, triacetin, isostearylic
isostearate, R(+)-limonene and medium chain triglycerides. The most popular among the enhancing permeability surfactants are phospholipids that
have been shown to enhance drug permeation in a different mode. L-α-phosphatidylcholine from egg yolk, L-α-phosphatidylcholine 60%, from
soybean and dioleylphosphatidyl ethanolamine which are in a fluid state may diffuse into the stratum corneum and enhance dermal and transdermal
drug penetration, while distearoylphosphatidyl choline which is in a gel-state has no such capability. Other very commonly used surfactants are
Tween 20®, Tween 80®, Span 20®, Azone®, Plurol Isostearique® and Plurol Oleique®. As cosurfactants commonly serve short-chain alkanols such
as ethanol and propylene glycol. Long-chain alcohols, especially 1-butanol, are known for their enhancing activity as well. Decanol was found to be
an optimum enhancer among other saturated fatty alcohols that were examined (from octanol to myristyl alcohol). Many enhancers are concentration-
dependent; therefore, optimal concentration for effective promotion should be determined. The delivery rate is dependent on the type of the drug, the
structure and ingredients of the carrier, and on the character of the membrane in use. Each formulation should be examined very carefully, because
every membrane alters the mechanism of penetration and can turn an enhancer to a retarder.
Various potential mechanisms to enhance drug penetration through the skin include directly affecting the skin and modifying the formulation
so the partition, diffusion, or solubility is altered. The combination of several enhancement techniques such as the use of iontophoresis with fatty
acids leads to synergetic drug penetration and to decrease in skin toxicity.
Selected studies of various microemulsions containing certain drugs including retinoic acid, 5-fluorouracil, triptolide, ascorbic acid, diclofenac,
lidocaine, and prilocaine hydrochloride in transdermal formulations are presented in this review.
In conclusion, microemulsions were found as an effective vehicle of the solubilization of certain drugs and as protecting medium for the
entrapped of drugs from degradation, hydrolysis, and oxidation. It can also provide prolonged release of the drug and prevent irritation despite the
toxicity of the drug. Yet, in spite of all the advantages the present formulations lack several key important characteristics such as cosmetic-
permitted surfactants, free dilution in water capabilities, stability in the digestive tracts and sufficient solubilization capacity.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Microemulsions; Drug delivery system; Transdermal

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
2. Microemulsions as transdermal drug delivery vehicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
2.1. Mechanisms of skin permeation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
2.2. Components of the transdermal formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
2.2.1. Oil phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
2.2.2. Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373

⁎ Corresponding author. Tel.: +972 2 658 6574/5; fax: +972 2 652 0262.
E-mail address: garti@vms.huji.ac.il (N. Garti).

0001-8686/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.cis.2006.05.014
370 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385

2.2.3. Cosurfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

2.2.4. Aqueous phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
2.3. Selected studies on microemulsions as transdermal drug vehicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
2.3.1. Ascorbic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
2.3.2. Diclofenac. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
2.3.3. Lidocaine and prilocaine hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
2.3.4. Triptolide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
2.3.5. 5-Fluorouracil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
2.3.6. Retinoic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
3. Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

1. Introduction the physical or chemical properties of the drug, administrative

Pharmaceutical formulators aim to deliver the active mole-
cule to the target organ at therapeutically relevant levels, with
negligible discomfort and side effects to the patient. This deli-
very is significantly influenced by the physical and chemical
properties of the drug.
The biopharmaceutical classification system of drugs was
defined by Amidon et al. in 1995 [1]. Class I and Class II drugs
demonstrate high gastrointestinal permeability. In contrast to
Class II, Class I covers drugs with high water solubility. Class I
drugs are well absorbed, but their bioavailability can still be low
because of the first pass metabolism [1]. The rate-limiting step
to drug absorption is the drug dissolution. In cases of very rapid
dissolution, the rate-controlling step will be gastric emptying.
Compounds of Class II with solubility below 10 mg/ml present
difficulties related to solubilization during formulation. In these
cases, the rate controlling step to drug absorption is drug
dissolution. The drug dissolution profile can be affected by
many formulation and in vivo variables; therefore, drugs in this
class can be expected to have variable absorption. The absorp-
tion of these drugs is usually slower than for Class I. Class III
and IV drugs are compounds featuring high solubility and low
permeability, and low solubility and low permeability, respec-
tively. Class III drugs feature variability in both the rate and
extent of absorption. However, if the dissolution is rather fast
(i.e., 85% dissolved in less than 15 min) the variability will be
due to the variations in luminal content, gastrointestinal transfer,
and membrane permeability which is the rate-determining step,
and not due to the dosage form factors. Due to their character-
istics, Class IV drugs exhibit many problems in their successful
delivery [1]. In the conventional pharmaceutical industry and in
modern medicine, it is well known that many promising drugs
that are discovered never make it to the market because of
difficulties in delivery. This means that such drugs need to be
formulated with smart drug delivery systems and/or deli-
very technology to make them acceptable for the treatment of
patients. Some of these drugs are insoluble while others are
eliminated by the acidity of the stomach, or are cleared from the
blood too rapidly to be effective. Intravenous delivery may
serve as an alternative in such cases, but may require either very
frequent administration or large a volume of drug injected each
time. The problems that occur with many drugs can be related to
matters such as approval for use, excipients, and engineering
issues [2].
Some of the major challenges of drug delivery are [2] poor
solubility, short in vitro (shelf-life) and in vivo (half-life)
stability, low bioavailability, strong side effects (therefore,
targeted delivery is needed) and regulatory issues. In order to
increase the probability of a drug delivery formulation entering
the pharmaceutical market, it should fulfill (as much as
possible) the main requirements [2]: ease of production, appli-
cability to as many drugs as possible, physical stability, ex-
cipients that are well tolerated and accepted by regulatory
authorities and availability of large scale production allowable
by regulatory authorities.
By many estimates, up to 40% of the new chemical entities
discovered by the pharmaceutical industry today are poorly
soluble or lipophilic compounds. The solubility issue, compli-
cating the delivery of these new drugs, also affects the delivery
of many existing drugs. Researchers are making great efforts to
discover new methods for delivery of poorly soluble drugs that
will be efficient and economically acceptable for drug
manufacturers.
The most common approach to improving the solubility of
drugs possessing a net negative electrical charge is to form salts
(e.g., hydrochlorides, sulfates, nitrates, maleates, citrates, tar-
tarates) of the basic drugs. Yet, other drugs do not form such
salts and this method of improving solubility is not possible.
Another route is to reduce particle size of powdered drug by
new milling technologies or by applying new crystallization
processes to improve dissolution kinetics. Researchers are con-
stantly searching for new and more efficient vehicles to carry
active molecules into the blood stream. One approach to over-
come these problems is to package the drugs into a particulate
carrier system. Microcapsules, micro- and nanospheres, nano-
powders, nanocrystals, and nanodispersions are only some of
the options. Other options include delivery of the nutraceuti-
cals or drugs via liquid vehicles such as liposomes, emulsions,
double emulsions, microemulsions, micellar solutions and lyo-
tropic liquid crystals such as cubosomes and hexosomes. These
last two vehicles are still in an experimental stage. The incor-
poration of the drug into a carrier-system can be envisioned to
protect it against degradation in vitro as well as in vivo; the
release can be controlled, and targeting can also be achieved.
 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385
In 1959, Schulman et al. visualized the existence of small
emulsion-like structures by electron microscopy and subse-
quently coined the term “microemulsions” [3]. The term has
been defined and redefined by many authors. In this review,
however, we will use the most general definition provided by
Danielsson and Lindman in 1981 [4]: a microemulsion is a
single, optically isotropic structured solution of surfactant, oil,
and water.
Microemulsions seem to be ideal liquid vehicles for drug
delivery since they provide all the possible requirements of
a liquid system including thermodynamic stability (long shelf-
life), easy formation (zero interfacial tension and almost
spontaneous formation), low viscosity with Newtonian
behavior, high surface area (high solubilization capacity),
and very small droplet size. The small droplets have better
chance to adhere to membranes and to transport bioactive
molecules in a more controlled fashion. Using the microemul-
sion vehicles, water-insoluble and oil-soluble components
from different plant extracts can be co-solubilized in order to
attain synergistic effect for a specific therapeutic goal.
Microemulsions can be introduced into the body orally,
topically on the skin, or nasally, as an aerosol for direct entry
into the lungs.
Microemulsions have been subjected to numerous studies
during the last decades because of their great potential in many
applications. Due to their rather complicated phase behavior and
the fascinating microstructures encountered in microemulsion
forming systems, many researchers have made significant
efforts to obtain a better understanding of these microstructures.
Comprehensive reviews discussing the microstructures encoun-
tered in microemulsion phases were written [5–8].
In order to investigate the potential of microemulsions as
delivery vehicles, it is necessary to characterize their micro-
structures as well as the locus of the drug in the loaded micro-
emulsion. In some cases, due to molecular interactions between
the loaded drug and the microemulsion, the microstructure of
the system may be altered. Due to the complexity of the mic-
roemulsions and the variety of the structures and components
involved in construction of the microstructure, as well as the
limitation associated with each technique, the characterization
of such structures is a rather difficult task. Some of the major
methods relevant to the characterization of the microemulsions
include viscosity [9–14] and conductivity [9,10,15–25] mea-
surements as well as more advanced methods such as cryo-TEM
[26–34], pulsed gradient spin echo (self-diffusion) NMR
[32,35–42], dynamic light scattering (DLS) [43,44], small
angle X-ray scattering (SAXS) [45–55] and small angle neutron
scattering (SANS) [56–59].
However, microemulsions suffer from high surfactant
concentrations and in most cases from high alcohol, solvent,
and co-solvent contents. High levels of non-active compounds
are always a hazard. Patent search shows that microemulsions
have been heavily patented by researchers, as well as by com-
panies, as delivery systems, but a close examination of formu-
lations that are available in the market place reveals that the
technology is far from being exhausted and applied. The ques-
tion is always why?
371
The aim of this chapter is to review the current literature with
respect to the use of microemulsions for cutaneous drug deli-
very and to discuss the influence of microemulsion composi-
tion, components, and structure on the drug delivery potential as
well as the tolerability of these vehicles both in vitro as well as
in vivo.
Many other potential pharmaceutical applications of micro-
emulsions have been studied such as pulmonary [60–68], intra-
vaginal or intrarectal administration delivery vehicles for
lipophilic drugs such as microcides, steroids, and hormones
[69–77], and intramuscular formulations of peptide or cell-
targeting systems [78], other drugs have been also evaluated. The
review recently written by Garti and Aserin includes among
others the recent progress in microemulsions for oral and intra-
venous delivery [79]. The space limitations that are imposed
on this review prevent us from further elaborating on these
applications.
2. Microemulsions as transdermal drug delivery vehicles
Transdermal drug delivery has many advantages over the
oral route of administration: it avoids hepatic metabolism, the
administration is easier and more convenient for the patient, and
there is the possibility of immediate withdrawal of the treatment
if necessary. Despite the great potential of transdermal delivery
of drugs, only a few drug formulations are available com-
mercially. The main reason is the barrier function of human skin
that is considered to be the most impermeable epithelium to
exogenous substances [80].
2.1. Mechanisms of skin permeation
The skin itself has two main layers: the epidermis, which is
the outermost layer of the skin, covering the dermis that is the
active part of the skin, holding the hair muscles, blood supply,
sebaceous glands, and nerve receptors. There is a fat layer
underneath the dermis. The skin is a very heterogeneous mem-
brane and has a variety of cell types, but the layer that controls
the penetration of drugs is called the stratum corneum and,
despite its thickness of only 15–20 μm, it provides a very
effective barrier to penetration. The permeation of the drug
through the skin has several routes: transcellular, intercellular,
and appendageal (through eccrine (sweat) glands or hair
follicles) (Fig. 1). Since the appendages occupy a very low
surface area, this means of permeation is less significant under
Fig. 1. Schematic representation of the different possible routes of penetration
through the skin. Reprinted with permission from Hadgraft [81].
372 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385
normal conditions [81]. Nevertheless, in iontophoretic delivery
this route is more significant [82].
The intercellular spaces consist of a mixture of lipids–cera-
mides, free fatty acids and their esters, and cholesterol and its
sulphates that are structured in bilayers. Recent developments in
spectroscopic techniques give interesting insights at the
molecular level that may explain the impermeability of the
skin by repeated partition and diffusion across structured bi-
layers [81]. Transdermal drug permeability is influenced mainly
by three factors: the mobility of the drug in the vehicle, the
release of the drug from the vehicle, and drug permeation
through skin [83]. Therefore, the researchers are challenged to
come up with formulations that increase the permeability of the
drug without irreversibly changing the skin barrier function.
Various potential mechanisms to enhance drug penetration
through the skin include directly affecting the skin and modi-
fying the formulation so the partition, diffusion, or solubility are
altered [81,84]. Here we will present briefly these potential
mechanisms that are interconnected with each other.
1. Direct effect on the skin [84]
a. Denaturation of intracellular keratin or modification of its
conformation causes swelling and increased hydration
b. Affection of desmosomes (known as macula adherens-
cell structures specialized for cell to cell adhesion) that
maintain cohesion between corneocytes (dead cells of the
stratum corneum)
c. Modification of lipid bilayers reduces resistance to
penetration
d. Altering the solvent properties of the stratum corneum to
modify drug partitioning
e. Use of solvent that can extract the lipids in the stratum
corneum and decrease its resistance to penetration
2. Modification of the formulation [84]
a. Supersaturation state produced by volatile solvent that
leaves the active substance in a more thermodynamically
active state
b. Choosing the enhancer molecules in the vehicle that are
good solvents for the active ingredient and which enhance
permeation through the skin; this way the partition of the
drug into the stratum corneum will be improved
c. The diffusion of the active ingredient through the skin
may be facilitated by using enhancers that create liquid
pools within the bilayers like oleic acid, or disturb the
bilayers uniformly as do the Azone® molecules (Azone®
(1-dodecylazacycloheptan-2-one or lauro capram) is the
first molecule specifically designed as a skin permeation
enhancer. Azone® serves as surfactant and enhances the
skin transport of a wide variety of drugs including ste-
roids, antibiotics and antiviral agents [84]).
Sometimes the synergy between several enhancement effects
causes a greater enhancement in permeability of the desired
substance. More detailed explanations and various examples of
the enhancement mechanisms can be found in very comprehen-
sive reviews recently written by Handgraft [81] and Williams and
Barry [84].
2.2. Components of the transdermal formulations
A large variety of chemicals were defined as penetration
enhancers, but their use in transdermal formulations is limited
because of toxicity issues or unclear mechanisms of action.
Here, we will briefly discuss the most common penetration
enhancers that are used as the components of topically applied
microemulsions. In the very comprehensive review of Williams
and Barry [84] the reader can find more widely used penetration
enhancers and their possible mechanisms of action.
2.2.1. Oil phase
Saturated and unsaturated fatty acids can be used as effective
penetration enhancer for a variety of drugs (e.g., naloxone,
hydrocortisone, estradiol, and peptides like LHRH, and CCK-8)
[81,85–89]. Aungst et al. [90] studied various fatty acids,
alcohols, sulphoxides, surfactants, and amides as enhancers for
naloxone. It was suggested that enhancers with a saturated alkyl
chain of C10–C12 and a polar head, and enhancers with an
unsaturated C18 alkyl chain such as oleic acid, appeared to be
the optimal ones. The unsaturated cis configuration perturbs the
lipid packing more than does the trans configuration [90]. Since
the tail of the stratum corneum bilayer is hydrophobic, the fatty
acids can enter the bilayer, perturb it by creating separate
domains, and in this way may induce highly permeable path-
ways in the stratum corneum [91].
The most popular enhancer is oleic acid. It increased the flux
of salicylic acid 28-fold and of 5-flourouracil 56-fold through
human skin membrane in vitro [92]. Nevertheless, in examina-
tion of hexyl nicotinate on human skin in vivo, the addition of
oleic acid to propylene glycol (PG) did not improve the
permeation flux achieved with PG alone [93]. It is important to
note that formulators should use oleic acid in their formulations
with great care, since its application may cause changes in the
morphology of the Langerhans cells that are located in the
superbasal layer of the epidermis and play a key role in the
initiation and coordination of the T-cell mediated immune
response. Their depletion from the epidermis can cause skin
immunosuppression [94].
The combination of fatty acids and iontophoretic delivery
resulted in enhanced permeation of many drugs. In iontophoretic
delivery, a small electric current applied between two electrodes
placed on the skin enhances the penetration of ionized, neutral,
or polar molecules in a controlled manner [95,96]. Appendageal
sites are suggested as important sites through which electrotran-
sport occurs; ion and water transport have also been reported to
be associated, at least in part, with stratum corneum lipid lamel-
lae. Jadoul et al. [82] suggested that permeation enhancement by
iontophoresis was related to lipid layer stacking disorganization.
Since fatty acids enhance permeation by selective perturba-
tion in the intercellular lipids of the stratum corneum, and ions
are known to take the path with less resistance: so combining
the use of iontophoresis and fatty acids is an alternative that
researchers have used to increase the permeation of not only
low-molecular-weight drugs, but also high-molecular-weight
proteins such as insulin, and peptides like LHRH, CCK-8 and
AVP [85,86,97–99]. Furthermore, the combination of these two
 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385
methods can decrease skin toxicity and irritation that are
associated with use of high levels of either of them. Rastogi and
Singh [99] investigated the influence of R(+)-limonene and fatty
acids such palmitic (C16:0), palmitoleic (C16:1), stearic (C18:0),
oleic (C18:1), linoleic (C18:2), and linolenic (C18:3) on the
penetration enhancement of insulin. It was shown that iontophor-
esis in combination with chemical enhancers synergistically in-
creased (p < 0.05) the in vitro permeability of insulin. Linolenic
acid enhanced the permeability of insulin through the epidermis
more than other fatty acids did during both passive
(44.45 × 10− 4 cm/h) and iontophoretic (78.03 × 10− 4 cm/h) tran-
sport. The authors claim that by using an iontophoretic patch size
of 10 cm2, they would be able to deliver 50 IU of insulin within
3 h [99].
Nair and Panchagnula [98] assessed in vitro the effect of
oleic, linoleic, and lauric fatty acids alone and in combination
with iontophoresis on the transdermal penetration of arginine
vasopressin (AVP), a cyclic peptide that is used in treatment of
diabetis insipidus, alzheimer, and other diseases. It was found
that all fatty acids increased the AVP flux compared to rat skin
that was not pretreated with enhancer, but their effectiveness in
permeability enhancement was similar. This study provided
direct evidence that oleic acid in mixture of ethanol and water
causes disruption of the stratum cornea lipid lamellae. Never-
theless, this study showed that iontophoresis did not further
increase the permeation of AVP through linoleic pretreated skin
[98]. Other researchers detected similar effects with fatty acids
that increased the permeation of midodrine hydrochloride and
leuprolide acetate [100,101]. Iontophoresis was also effective
for enhancing transdermal penetration from microemulsions as
it was shown for methotrexate [102].
Another compound that is often used as an oil phase and as a
permeation enhancer in transdermal formulations is isopropyl
myristate (IPM), but the mechanism of its action is poorly
understood [13,83,102–112]. In some cases IPM does not show a
significant effect [113]. Other oils commonly used are isopropyl
palmitate [114–116], triacetin [117], isostearylic isostearate
[36,118], R(+)-limonene [118] and Mygliol 812® (medium
chain length triglyceride) [119–122].
2.2.2. Surfactants
More than 15 years ago, Kato et al. [123] proposed the use of
low toxicity substances, e.g., phospholipids, as penetration en-
hancers. The penetration of theophylline was enhanced by 1%
phosphatidylcholine in propylene glycol through hairless mouse
skin. Numerous studies have been conducted using various leci-
thin-based microemulsions as topical formulations for enhancing
the penetration of methotrexate [124], ascorbic acid [115],
diclofenac [116,125], indomethacin [116], ketoprofen [117,119],
hematoporphyrin [106], etc. Absorption of phospholipids on skin
can increase tissue hydration, consequently increasing drug per-
meation. When phospholipids are applied to skin as vehicles due to
their physico-chemical properties and structures they can fuse with
stratum corneum lipids, perturb its structure and facilitate drug
delivery [84,126].
As early as 1990, Friberg and later Atwood et al. published
works on drug delivery systems for skin applications [127,128].
373
The phase properties of systems contained isopropyl myristate
(IPM) as an oil, lecithin from egg or soy as a low toxicity
surfactant, butanol [128] or ethanol as cosurfactant, and water.
The influence of lecithin and butanol or ethanol on the area of
the microemulsion was examined. In the system containing
butanol oil-in-water microemulsion regions were detected at a
surfactant/cosurfactant weight ratio between 1:0.6 and 1:0.33.
In the systems consisting of ethanol, microemulsion area was
obtained in only 60–80% ethanol in water w/w. It was shown
that in order to obtain a microemulsion, the amount of lecithin
required increased as the amount of the ethanol decreased. In
comparison to the systems containing butanol it was found that
at the same amount of IPM more ethanol was required. Larger
amounts of ethanol are required to reduce the rigidity of the
lecithin condensed film, creating the curvature that is needed for
droplet formation. This is explained by the low interface/water
partition coefficient of ethanol because of its hydrophilicity
[128]. It is known that with an increase in the aqueous phase
fraction, the droplet size increases. Atwood et al. [128] found
that at constant aqueous phase content, droplet size increased as
the amount of lecithin decreased. Other authors have investi-
gated formulations based on lecithins [106,116,125]. Different
phospholipids enhance drug permeation differently. Kirjavainen
et al.'s [126] study showed that the reason for this difference
was that different phospholipids had different effects on the
partitioning of drugs into the lipid bilayers. The authors used
stratum corneum lipid liposomes as a model for the lipid matrix
of stratum corneum. Estradiol, progesterone, and propranolol
were studied. They concluded that EPC (L-α-phosphatidylcho-
line from egg yolk), SPC (L-α-phosphatidylcholine 60%, from
soybean), and DOPE (dioleylphosphatidyl ethanolamine)
which are in a fluid state may diffuse into the stratum corneum
and enhance dermal and transdermal drug penetration, while
DSPC (distearoylphosphatidyl choline) which is in a gel-state is
not able to do this [126].
There is wide use of nonionic surfactants in topical formula-
tions as solubilizing agents. Among them, the polysorbates (etho-
xylated sorbitan esters) are very common. Tween 80® was
reported to accelerate hydrocortisone and lidocaine permeation,
and Tween 20® improved the permeation of 5-flourouracil across
hairless mouse skin [129–131].
Some recent results indicate that a nonionic surfactant may
also affect the skin barrier function [132,133]. In the experiments
conducted in vitro on rat skin it was found that Span 20®, Tween
20®, and Azone® have different mechanisms of enhancement.
Span 20® and Azone® affect the intercellular lipids of the stratum
corneum by making them more fluid. This way the diffusion of
lipophilic compounds through the stratum corneum (lipophilic
pathway) is enhanced. Tween 20® enhances penetration by al-
lowing the polar molecule to partition across the barrier more
easily. It is also possible that since the experiments were con-
ducted in aqueous medium, large micelles were formed. These
micelles have the potential to extract lipids from the skin. This
modifies the composition of the membrane and favors permeation
of the hydrophilic compounds [132,133]. Recently, new low-irri-
tant surfactants based on caprylocaproyl macrogolglycerides for
microemulsions as drug delivery vehicles for topical application
374 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385
were studied. In order to facilitate caprylocaproyl macrogolgly-
ceride based microemulsion formation, the surfactants based on
polyglycerol fatty acid esters were used as cosurfactants [13,134–
136]. Other surfactants such as dioctyl sodium sulphosuccinate
[137,138], Plurol Isostearique® [36,102,135,139], and Plurol
Oleique® [13,118,120,121,140] are used very often.
2.2.3. Cosurfactants
Short-chain alkanols are widely used as permeation
enhancers. Ethanol is very common among transdermal
formulations and its addition is known to enhance the flux of
several drugs. Levonorgestrel [141], estradiol [142,143], and an
ionized form of diclofenac were shown to be better transported
through rat skin when ethanol was added [144]. Sometimes
when using ethanol-water-based vehicles, the effect of ethanol
is concentration-dependent, and, therefore, under certain
conditions it can even decrease the permeation [84,145–147].
Various mechanisms have been suggested for the enhancing
activity of ethanol. It can increase the drug solubility in the
vehicle [84,143] or it can alter the structure of the membrane
and increase the permeability of the drug [84,146]. Another
mechanism is based on the fact that ethanol is volatilized from
the applied formulation and, consequently, increases the drug
concentration to a supersaturated state with a greater driving
force for permeation. In addition, ethanol may extract some of
the lipid fraction from the stratum corneum and, thus, can
improve the drug flux through it [84]. In some cases ethanol by
itself does not serve as an enhancer, but needs a co-enhancer as
demonstrated in the case of penetration of morphine hydro-
chloride [113]. In this study, a combination of 1-menthol with
ethanol showed greater penetration enhancement than if ethanol
alone was used as solvent. It was suggested that the high
penetration enhancement was derived from the influence of 1-
menthol on the stratum corneum barrier and the effect of ethanol
against the viable skin layer beneath it [84,113]. Long-chain
alcohols are known for their enhancing activity as well. 1-
Butanol was reported to be an enhancer for levonorgesterol
[141]. Decanol was found to be an optimum enhancer for
melatonin among other saturated fatty alcohols that were
examined (from octanol to myristyl alcohol) [141]. Propylene
glycol (PG) has been found to act as an enhancer by a
mechanism similar to that of ethanol [84], enhancing the
permeability of hexyl nicotinate. The addition of oleic acid to
PG did not show an improvement in permeation [93].
It is important to stress that each formulation should be
examined very carefully, because every membrane alters the
mechanism of penetration and can turn an enhancer to a re-
tarder. In vitro studies on the transdermal absorption of flur-
biprofen (a chiral non-steroidal anti-inflammatory drug that is
used for treatment of gout, osteoarthritis, rheumatoid arthritis,
and sunburn) from cellulose hydrogels were conducted by Fang
et al. [148] using different kinds of additives. The permeation
was studied on different types of skin, such as skin pre-treated
by various additives, stratum corneum stripped skin, and
delipidized skin. Propylene glycol and ethanol did not increase
skin absorption of the drug, and phospholipids even markedly
reduced it. Ethanol reduced the skin reservoir of the drug,
whereas oleic acid increased it. In this work ethanol, propylene
glycol, and phospholipids that are known as enhancers turned
out to be retarders [148].
2.2.4. Aqueous phase
In most of the studies water served as the aqueous phase
[13,36,102–105,107,108,111,114–117,119–122,125,
137,138,140,149,150]. In some of the cases phosphate buffer of
pH 7.4 was used [102,109,112,118,135].
2.3. Selected studies on microemulsions as transdermal drug
vehicles
The application of microemulsion vehicles for cutaneous
drug delivery is becoming increasingly popular due to their high
solubilization potential for both lipophilic and hydrophilic
drugs. It was demonstrated that permeation rates from
microemulsions were significantly higher than from conven-
tional emulsions. In emulsions (creams, lotions, etc.), the strong
interactions between the surfactants that occur in the interfacial
membrane film limit the mobility of the drug between the
internal and external phases within the formulation. In addition,
emulsions are not stable formulations and strong fluctuations in
bioavailability were detected. In microemulsions, the co-
surfactant assists in lowering the interfacial tension of the
surfactant film, resulting in spontaneous formation of a
microemulsion and promoting its thermodynamic stability
[36,137,151]. The thermodynamic process of drug diffusion
across the flexible interfacial surfactant film between the phases
of the microemulsion can increase partitioning and diffusion
into the stratum corneum [114]. The drug may also be retained
in the droplets of the microemulsion formulation resulting in
increased concentration of surfactant in dispersed systems that
will decrease its permeation into the skin [107].
An excellent and comprehensive review on the role of
microemulsions in percutaneous penetration of drugs was recently
published by Kreilgaard [80] in which the author summarized the
main studies published before 2002 in several tables. We have
included the data gathered by this author as well as additional
studies that have been conducted since then in Table 1
[13,36,83,102–112,114–122,124,125,135,137,138,140,149,
150,152–154]. Many studies have been conducted incorporating
many drugs in microemulsions, we decided to describe only those
studies conducted on certain drugs.
2.3.1. Ascorbic acid
Ascorbic acid (vitamin C) is an essential nutrient protecting
living tissues and cells from oxidation processes by free radicals
and reactive oxygen derived species. Gallarate et al. [115]
studied the stability of ascorbic acid in several o/w microemul-
sions, o/w and w/o emulsions, and a w/o/w multiple emulsion.
Isopropyl palmitate or cetearyl octanoate were used as oils,
dodecylglucoside and cocoamide propylbetaine were used as
surfactants, and 2-ethyl-1,3-hexanediol was chosen as cosur-
factant. These emulsifiers are non-ionic, non-ethoxylated, and
skin compatible. The addition of only 1% w/w of phosphati-
dylcholine to formulations allowed a two-fold reduction in the
 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385 375

Table 1
Overview of transdermal drug delivery systems containing microemulsions
Drug Microemulsion Membrane/ References
skin
Oil phase Surfactants/cosurfactants Aqueous phase
[3H]H2O octanol dioctyl sodium sulphosuccinate water human [137,138]
5-Fluorouracil isopropyl myristate AOT water mouse [149]
8-Methoxsalen isopropyl myristate Tween 80®, Span 80®, 1,2-octanediol water pig [103]
Apomorphine isopropyl myristate, Epikuron 200®, 1, water, mouse [104]
hydrochloride decanol 2-propanediol benzyl alcohol Aerosil 200®
Ascorbic acid isopropyl palmitate, dodecylglucoside cocoamide propylbetaine, water – [115]
cetearyl octanoate phosphatidylcholine/2-ethyl-1,3-hexanediol
Ascorbyl Mygliol 812® Labrasol®/Plurol Oleique® water – [121]
palmitate
Diclofenac isopropyl palmitate Lecithin water human [116]
Diclofenac Diclofenac diethylamine Lecithin water human [125]
Diclofenac isopropyl myristate Labrasol®/Plurol Oleique® water – [13]
Diphenhydramine isopropyl myristate Tween 80®, Span 20® water human [108]
hydrochloride
Estradiol Epicuron 200®, oleic acid, Tween 20®, Tween 80®, water human [83]
isopropyl myristate Span 80®/ethanol, isopropanol)
Felodipine isopropyl myristate, Tween 20®, tauro-deoxycholate water, mouse [105]
benzyl alcohol Transcutol®, Carbopol®
Glucose octanol dioctyl sodium sulphosuccinate water human [137]
Hematoporphyrin isopropyl myristate, decanol, lecithin, sodium monohexyl-phosphate, water, PG mouse [106]
hexadecanol, oleic acid, monoolein benzyl alcohol
Indomethacin isopropyl palmitate Lecithin water human [116]
Ketoprofen Miglyol 812 N® lecithin/n-butanol water human [119]
Ketoprofen triacetin, oleic acid Labrasol®, Cremophor RH® water rat [117]
Lidocaine isopropyl palmitate glyceryloleate, polyoxyl 40 fatty water mouse [114]
acid derivatives /tetraglycol
Lidocaine iostearylic isostearate Labrasol®, Plurol Isostearique® water rat [36]
Methotrexate decanol lecithin, benzyl alcohol water, PG mouse [124]
Methotrexate ethyl oleate Labrasol®/Plurol Isostearique® Aq. 154 mM NaCl (pH 7.4) pig [102]
Methotrexate isopropyl myristate Tween 80®, Span 80®, 1,2-octanediol water pig [2]
Nifedipine benzyl alcohol Tween 20®, tauro-deoxycholate water, mouse [152]
Transcutol®, PG
Niflumic acid octyl octanoate sucrose monolaurate sucrose dilaurate/ water human [150]
medium chain alcohol
Piroxicam isopropyl myristate hexadecyltrimethylammonium bromide Aqueous buffer (pH 5.5) rat [109]
Prilocaine isostearylic isostearate Labrasol®, Plurol Isostearique® water rat [36]
hydrochloride
Propranolol isopropyl myristate Tween 80® water artificial [107]
Prostaglandin E1 oleic acid Labrasol®, Plurol Oleique® water a mouse [140]
Prostaglandin E1 Gelucire® Labrafac®, Lauroglycol Transcutol®, water mouse [153]
Retinoic acid isopropyl myristate Epikuron 200®, Oramix® phosphate buffer artificial, pig [112]
NS10/ethanol, 1,2 hexanediol
Sodium ascorbyl Mygliol 812® Labrasol®/Plurol Oleique® water artificial [120]
phosphate
Sodium isostearylic isostearate, oleic acid, Labrasol®/Plurol Oleique® water, buffer pH 7.4 rat, rabbit [118]
diclofenac R(+)-limonene tributyrine
Sodium Mygliol 812®, soybean oil Brij 97® water pig [122]
fluorescein
Sodium salicylate isopropyl myristate Tween 21/81/85®, bis-2-(ethylhexyl) water, gelatin pig [110]
sulphosuccinate
Sucrose ethyl oleate Labrasol®, Plurol Isostearique® water, 154 mM mouse [135]
NaCl
Triptolide isopropyl myristate Tween 80®/1,2-propylene glycol water rat [111]
Triptolide oleic acid Tween 80®/propylene glycol H2O/menthol mouse [154]
Reprinted with permission from Kreilgaard et al. [80].
a
A variety of seven different co-solvents was tested with the basic vehicle.

amount of surfactant. Ascorbic acid stability against oxidation oxidation for ascorbic acid, and therefore its degradation rate
was examined in the prepared systems and compared to the was slower than in aqueous solutions. The degradation rate
aqueous solutions at different pH values. It was found that all increased with increasing pH. The highest protection of the
examined emulsified systems provided protection against ascorbic acid was achieved by solubilizing it in a w/o/w
376 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385
multiple emulsion. From the kinetic studies performed, a
pseudo first-order mechanism for ascorbic acid degradation was
suggested in the experimental conditions where abundant
dissolved oxygen was present (Fig. 2). Despite the fact that
ascorbic acid has many favorable effects, its use in cosmetic and
pharmaceutical products is limited due to its low stability. In
order to solve this problem, derivatives of vitamin C, with
action similar to that of ascorbic acid, but with improved
chemical stability, have been synthesized. Two derivatives that
are widely used in cosmetic products are lipophilic ascorbyl
palmitate and hydrophilic sodium ascorbyl phosphate that differ
in stability (Fig. 3) [121].
W/o microemulsions consisting of caprylic/capric triglycer-
ide 24.75%, PEG-8 caprylic/capric glycerides 47.53%, poly-
glycerol-6 dioleate 11.88% and purified water 15.84%, were
prepared by Špiclin et al. [121]. In parallel, o/w microemulsions
containing caprylic/capric triglyceride 7.43%, PEG-8 caprylic/
capric glycerides 38.02%, polyglycerol-6 dioleate 9.50% and
purified water 45.05% were also prepared. Ascorbic acid
derivatives were incorporated into the two types of microemul-
sions at 0.25–2.00 wt.% concentrations. The influence of
several parameters such as initial concentration, location in
microemulsion, dissolved oxygen, and storage conditions on
the stability of the less stable derivative ascorbyl palmitate was
examined. It was found that incorporation of ascorbyl palmitate
into microemulsions at the highest concentration (2.00 w/w%)
reduced its degradation. In presence of oxygen, ascorbyl
palmitate is more stable in w/o microemulsions; on the contrary
if microemulsions are degassed, the compound is more stable in
the o/w type. Therefore, the location of the active ingredient in
the microemulsion may have a great influence on its stability
against oxidation. In a w/o microemulsion the cyclic ring that is
Fig. 2. Pseudo first-order plot of ascorbic acid degradation at 45 ± 0.1 °C in
emulsified systems at pH 5.0 (ascorbic acid = 1.00 wt.%) Reprinted with
permission from Gallarate et al. [115].
sensitive to oxidation is located in the internal aqueous phase
and, therefore, it is protected by the interface that serves as a
barrier for oxygen diffusion. In o/w microemulsions, the cyclic
ring is located in the external aqueous phase, where it is less
protected, and therefore the degradation process is favored. In
addition, it was found that light also accelerates the oxidative
degradation of ascorbyl palmitate. In order to formulate an
optimal carrier system for this ingredient, other factors influen-
cing the stability have to be considered. The studies on sodium
ascorbyl phosphate revealed that, compared to ascorbyl pal-
mitate, it was equally stable towards oxidation in both types of
microemulsions. Consequently, sodium ascorbyl phosphate has
been found to be convenient for use as an active ingredient in
topical formulations [121]. In subsequent studies different types
of thickening agents, that increase viscosity, were added to the
microemulsions described above, to optimize these topical
formulations. The influence of thickening agents on the stability
of the microemulsions and the release kinetics of the solubilized
sodium ascorbyl phosphate were studied. Magnesium stearate,
colloidal silica, or cetostearyl alcohol was used as thickening
agent for w/o type microemulsions while for o/w microemul-
sions sodium alginate, methyl cellulose, HPMC K4M, HPMC
E4M, and xanthan gum were incorporated. As a suitable thick-
ening agent, colloidal silica was chosen for w/o microemulsions
and xanthan gum for the o/w type. The presence of thickening
agent and the location of sodium ascorbyl phosphate in the
microemulsion influenced the in vitro drug release profiles.
When incorporated in w/o microemulsions, sustained release
profiles were observed from both thickened and non-thickened
systems. This is due to the external oil phase which can act as a
barrier for the diffusion of a hydrophilic compound. In the case
of o/w systems, larger amounts were released due to the incor-
poration of the sodium ascorbyl phosphate in the external phase
that increased the diffusion rate (Fig. 4).
The type of thickening agent added to the examined systems
influenced the rate of drug diffusion. The addition of xanthan gum
(o/w system) increased the viscosity of the system and, therefore,
decreased the amount of released compound. On the contrary, the
amount of released sodium ascorbyl phosphate was higher in the
case of thickened w/o microemulsion with colloidal silica. The
authors assumed that colloidal silica modified the physicochem-
ical characteristics of the external phase; therefore, the diffusion
of sodium ascorbyl phosphate was faster. By evaluating the
release profiles by fitting the experimental data to different orders
kinetic equations, it was concluded that the rate-determining step
for sodium ascorbyl phosphate release from microemulsions was
its transport within the carrier system [120]. One can conclude
that microemulsions are an effective solution to preserving
ascorbic acid stability against oxidation and are effective vehicles
for controlling the release kinetics of the active compound.
2.3.2. Diclofenac
Several groups have selected diclofenac (a nonsteroidal anti-
inflammatory drug) as a model compound that was solubilized
in a microemulsion medium [13,116,118,125]. Kriwet and
Müller-Goymann [125] investigated vehicles containing phos-
pholipids, diclofenac diethylamine, and water. Various colloidal
 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385
Fig. 3. Chemical structures of ascorbyl palmitate (a) and sodium ascorbyl phosphate (b). Reprinted with permission from Špiclin et al. [121].
structures such as liposomal dispersions, microemulsions and
lamellar liquid crystals can be formed by varying the ratios of
the components forming the structures and method of pre-
paration. In vitro studies, using a dialysis membrane impreg-
nated with a silicone polymer, showed that the effective
diffusion coefficient of diclofenac diethylamine changed ra-
pidly with a phase transformation of the vehicle. By examina-
tion of the systems with constant concentration of diclofenac
diethylamine (5% w/w) and variable amounts of phospholipids,
it was found that the diffusion coefficient of the drug decreased
with an increase of the phospholipids content [125] (Fig. 5). The
systems with 6% phospholipids or less are microemulsions with
low viscosity; therefore, the release is fast. Further addition of
the phospholipids leads to isotropic and afterwards anisotropic
gel formation, decreasing the release rate. The decrease in
diffusion coefficient can be explained by the increase of the
viscosity of the systems with the addition of phospholipids. The
authors also investigated the influence of drug concentration in
the vehicle on the effective diffusion coefficient [125] (Fig. 6).
It was found that drug molecules participate in the micro-
structure of the resulting systems. At concentrations up to 4.5%
diclofenac diethylamine, liposomal dispersion, dispersion of
multilamellar vesicles in a microemulsion gel, or an isotropic
gel occurred. The viscosity of these systems is high, therefore
the drug release is slow. Further addition of diclofenac die-
thylamine leads to microemulsion formation with a low vis-
cosity, and the rate of the drug release is increased. With the
Fig. 4. Release profiles of sodium ascorbyl phosphate from o/w and w/o
microemulsions. Reprinted with permission from Špiclin et al. [120].
377
addition of diclofenac diethylamine, the number of vesicles with
multilamellar layers decreases until the system transforms into a
microemulsion. Since the release of the entrapped drug in the
vesicle is hindered, the fewer are the vesicles, the easier is the
drug release. Permeation through human stratum corneum was
also examined. A linear relationship between the drug release
out of the vehicle through the artificial membrane and the rate of
drug permeability through the stratum corneum was observed.
The rate-limiting step for vehicles with a high effective diffusion
coefficient like microemulsions was the diffusional resistance in
the stratum corneum. On the contrary, for vehicles with a low
diffusion coefficient the rate-limiting step was the release from
the vehicle. Only microemulsions showed enhanced perme-
ability of diclofenac diethylamine through the stratum corneum,
since the phospholipids were able to interact with the structures
of the stratum corneum only if they were applied as micro-
emulsion [125]. From these studies it can be concluded that
phospholipid content can alter the structure of the vehicle, hence
influences the drug release. Phospholipids can be used as a
thickening agents since they increase the viscosity of the system.
In addition, the drug itself may participate in the organization of
the vehicle and consequently control its own release [125].
Other authors showed that diclofenac diethylamine partici-
pates in the vehicle structure due to its amphiphilic properties.
Djordjevic et al. [13] investigated microemulsion systems com-
posed of water, isopropyl myristate, PEG-8 caprylic/capric gly-
cerides (Labrasol®), and polyglyceryl-6 dioleate (Plurol
Oleique®), as potential diclofenac diethylamine delivery vehicles.
It was found that in the experimental conditions, conductivity and
rheological properties were influenced significantly by the
incorporation of the drug. Conductivity values for drug loaded
microemulsions were increased by a factor of 2–3 in comparison
to microemulsions without the drug. On the contrary, the drug did
not significantly influence either the pH value of the vehicles, or
the stability and the optical texture of the examined systems [13].
Escribano et al. [118] investigated several ternary solvent
systems and microemulsions in vitro using human skin in order to
find the formulation that enhanced the percutaneous permeability
of sodium diclofenac. In order to compare the effect of the vehicle
on the percutaneous absorption, a fixed concentration of the drug
was used in all examined systems. A 1 wt.% solution of sodium
diclofenac and a commercially available semisolid preparation
served as reference. Commonly known enhancers such as oleic
and lauric acids, R(+)-limonene, and Transcutol® (diethylene
glycol monoethyl ether) were used as the components of the
vehicles. The highest values of permeability coefficient and drug
378 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385

Fig. 5. Effective diffusion coefficient of diclofenac diethylamine from vehicle with 5% diclofenac diethylamine vs. content of phospholipids. Reprinted with
permission from Kriwet and Müller-Goymann [125].

flux, and the amount of drug that permeated and was retained in
the skin at 24 h were observed for 1 wt.% drug formulations
containing Transcutol® 59.2 wt.%, oleic acid 14.9 wt.%, and R
(+)-limonene 5 wt.% as enhancers, and water 19.9 wt.%. This
formulation had greater anti-inflammatory activity, both local and
systemic, than the semisolid preparation. It was found that the
synergistic enhancement effect with Transcutol®/oleic acid/D-
limonene was greater than that of Transcutol®/oleic acid or
Transcutol®/lauric acid. In the comparison of permeation
enhancement between oleic acid and lauric acid, it was shown
that oleic acid provides more penetration capacity due to its cis
double bond at C9, which causes a kink in the alkyl chain and
disrupts the skin lipids more efficiently. Despite the expectation
that the microemulsion would alter the skin lipids and show
enhanced permeation, it behaved like a solution. This may be
attributed to the lower percentage of the enhancing agents (19%)
as compared to 73% in other formulations. Therefore, the com-
ponents of the vehicle are no less important than the structure of
the vehicle [118].
In other studies, diclofenac and indomethacin in a microemul-
sion gel were used as model drugs. The enhancement of drug
penetration was studied. The microemulsion gel consisted of
soybean phosphatidylcholine (lecithin), isopropyl palmitate, and
a small amount of water. Studies using Fourier transform infrared
(FTIR) spectroscopy, differential scanning calorimetry (DSC), as
well as low-temperature scanning electron microscopy, indicated

Fig. 6. Effective diffusion coefficient of diclofenac diethylamine in systems with 6% phospholipids vs. content of diclofenac diethylamine. Reprinted with permission
from Kriwet and Müller-Goymann [125].
 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385 379

Table 2 transdermal flux of lidocaine up to four times, compared to a

Microemulsion compositions conventional oil-in-water emulsion, and increased the transder-
System Water Isostearylic isostearate Labrasol® Plurol Isostearique® mal flux of prilocaine hydrochloride almost 10 times compared
(%) (%) (%) (%) to hydrogels (Table 3). The flux seems to be dependent on drug
A 20 10 35 a 35 a solubility in the microemulsion as well as on drug mobility in
B 20 10 47 b 23 b the individual vehicle. It was found that the solubilities of the
C 20 10 53 c 17 c
drugs in the microemulsions were greater in comparison to the
D 7 70 11.5 a 11.5 a
E 11 26 42 b 21 b solubilities obtained in the components of the microemulsion.
F 55 8 25 b 12 b Due to high solubilization property of microemulsions which
G 65 3 24 c 8c leads to high concentration gradients, the transdermal flux in-
Reprinted with permission from Kreilgaard et al. [36]. creased. Lidocaine showed a 28–62% increase in solubility and
a
Labrasol®/Plurol Isostearique® 1:1 (w/w). prilocaine hydrochloride showed an increase of 24–40%. The
b
Labrasol®/Plurol Isostearique® 2:1 (w/w). large increase in solubility is due to surfactant film interface
c
Labrasol®/Plurol Isostearique® 3:1 (w/w).
between the oil and water phases that leads to additional
solubilization sites for drugs, compared to the molecular or-
that isopropyl palmitate affected the stratum corneum lipid orga- ganization of bulk surfactants. A linear relationship between
nization, but in vivo human skin irritation tests showed no sig- self-diffusion of the drugs in the vehicles and transdermal flux
nificant irritancy [116]. was found. It suggests that with given components, the per-
cutaneous delivery potential of microemulsion vehicles may be
2.3.3. Lidocaine and prilocaine hydrochloride decelerated by hindrance to diffusion due to the internal struc-
Lidocaine is a local anesthetic and cardiac depressant com- ture of the microemulsion [36].
monly used to restore a regular heartbeat in patients with ar- Sintov and Shapiro [114] also chose lidocaine as a lipophilic
rhythmia. Prilocaine hydrochloride is also used as an anesthetic. drug model. To reduce irritation, special types of microemul-
Kreilgaard et al. [36] investigated the influence of the structure sions were suggested. Glycerol oleate and polyoxyl [40 EO]
and composition of microemulsions on their transdermal fatty acid derivatives/tetraglycol (cosurfactant)/isopropyl pal-
delivery potential for a lipophilic (lidocaine) and a hydrophilic mitate/water were used to construct a pseudo-ternary phase
model drug (prilocaine hydrochloride), and compared the drug diagram at fixed cosurfactant/surfactant ratios (Fig. 7). Lido-
delivery potential of microemulsions to conventional vehicles. caine was solubilized and penetration studies using rat skin in
They used self-diffusion coefficients, as determined by the vitro showed that the transdermal flux of lidocaine was signi-
pulsed-gradient spin-echo NMR (PGSE-NMR), to study the ficantly improved by microemulsion composed of glycerol
transdermal flux using Franz-type diffusion cells. The authors oleate-PEG 400 stearate compared with that of glycerol oleate-
prepared phase diagrams where w/o and o/w microemulsions PEG 400 hydroxylated castor oil [114]. Fig. 8 shows a
were formed, and seven formulations for further studies were comparison of in vitro transdermal penetration between micro-
chosen (Table 2). The microemulsions were formulated with emulsion, mixture of surfactants, micellar, and macroemulsion
4.8 wt.% of lidocaine and 2.4 wt.% of prilocaine hydrochloride. systems. Macroemulsion and micellar systems presented a lower
It was demonstrated clearly that microemulsions increased the flux of lidocaine relative to the microemulsion. The authors

Table 3
Steady-state flux (J; 20–28 h) and permeation coefficient (κp) of lidocaine and prilocaine hydrochloride (HCl) through rat skin from microemulsion systems A–G with
near-maximum drug load and comparison with EMLA 5%, xylocain 5% o/w-cream and xylocain 2% hydrogel
Formulation Lipophilic model drug Hydrophilic model drug
[Lidocaine] J κp [Prilocaine HCl] J κp
(%, w/w) (μg × h- 1 × cm− 2) (μg × h− 1 × cm− 2) (%, w/w) (μg × h− 1 × cm− 2) (μg × h− 1 × cm− 2)
A 23 36.2 ± 4.2 1.6 ± 0.2 5 8.1 ± 2.6 1.6 ± 0.5
B 27 41.1 ± 8.9 1.5 ± 0.3 5 6.3 ± 1.3 1.3 ± 0.3
C 24 44.8 ± 4.3 1.9 ± 0.2 5 6.4 ± 2.1 1.3 ± 0.4
D 17 56.5 ± 4.6 3.3 ± 0.3 – – –
E 25 50.8 ± 8.6 2.0 ± 0.3 2.4a 6.2 ± 0.7 2.6 ± 0.3
F 12 44.6 ± 4.3 3.7 ± 0.4 13 24.7 ± 4.3 1.9 ± 0.3
G 9.1 78.3 ± 3.9 8.7 ± 0.4 14 29.7 ± 9.9 2.1 ± 0.7
EMLAb 2.5 52.3 ± 19 20.9 ± 7.6 – – –
EMLAb, c 2.5c 57.8 ± 18.8c 23.1 ± 7.5c – – –
Xylocain 5% 5 22.2 ± 6 4.4 ± 1.2 – – –
Xylocain 2% – – – 2d 3.1 ± 1.0 1.6 ± 0.5
Reprinted with permission from Kreilgaard et al. [36].
a
Near-maximum concentration equals 2.4%.
b
n = 5.
c
Prilocaine-free base.
d
Lidocainehydrochloride.
380 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385

suggested that the presence of droplets of the microemulsion of
only a few nanometers in size had a significant contribution to the
percutaneous penetration of lidocaine.
The use of a patch was also studied in this work. The results
showed that patches based on a microemulsion had almost two-
fold higher fluxes than those obtained after applications of the
corresponding liquid microemulsion and EMLA cream. (EMLA
is a commercial product containing 1:1 eutectic mixture of 2.5 wt.
% lidocaine and 2.5 wt.% prilocaine in a o/w macroemulsion.) It
was concluded that patches were a very effective delivery device.
It was also demonstrated that applying a liquid microemulsion or
a patch based on a microemulsion significantly shortened the time
needed to reach steady-state drug penetration rates (lag time). In
addition, there is an increase in the accumulation of drug
quantities in skin layers. The decrease in lag time is an important
issue, in particular for lidocaine and for topical analgesia in
general, since commercial products require a relatively long ap-
plication time to ease pains [114].
2.3.4. Triptolide
Triptolide is used as an immunosuppressive, anti-fertility, and
anti-cancer drug. In order to decrease the adverse side effects
caused by its toxicity, to prevent hydrolysis that may be caused by
long-term storage of triptolide in an aqueous environment and be

Fig. 7. Pseudo-ternary phase diagrams of (a) microemulsion system made of isopropyl palmitate/water/tetraglycol/glyceryl oleate and PEG-40 hydrogenated castor oil
at three different cosurfactant/surfactant ratios and (b) microemulsion system made of isopropyl palmitate/water/tetraglycol/glyceryl oleate and PEG-40 stearate, at
three different cosurfactant/surfactant ratios. Reprinted with permission from Sintov and Shapiro [114].
 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385
Fig. 8. Percutaneous penetration of lidocaine from a microemulsion liquid
vehicle of system made of isopropyl palmitate/water/tetraglycol/glyceryl oleate
and PEG-40 stearate through rat skin in vitro (n = 5) during 3 h. The transport
kinetics (squares) is compared to the penetration profiles of lidocaine from a
surfactant mixture in tetraglycol (diamonds), oil-free micellar system (circles),
and a macroemulsion (triangles). Reprinted with permission from Sintov and
Shapiro [114].
promoted by pH values less than 3 or more than 8, a micro-
emulsion system with controlled and prolonged percutaneous
delivery of triptolide needs to be developed. The purpose of the
studies by Mei et al. [111]and Chen et al. 154] was to investigate
microemulsions for transdermal delivery of triptolide. Pseudo-
ternary phase diagrams were developed and various microemul-
sion formulations were prepared using oleic acid as an oil, Tween
80® as a surfactant, and propylene glycol as a cosurfactant. The
droplet size of the microemulsions was characterized by photo-
correlation spectroscopy and it varied from 12 to 83 nm. The
microemulsion formulations that were stored at 37 °C did not
show any changes in size or phase separation for 6 months. No
degradation of triptolide was detected either, since the drug was
incorporated in the oily phase, preventing its contact with the
external phase and pH values of the constructed microemulsions
that were in the range of 4–6 inhibited hydrolysis. Permeation
studies from microemulsion vehicles and aqueous solutions
containing 20% propylene glycol using mouse skin were also
performed. A steady increase of triptolide during 24 h was ob-
served. On the contrary, the permeation flux from the aqueous
solution decreased significantly after 10 h, which revealed the
inability of this formulation to provide prolonged delivery of
triptolide. In a microemulsion the drug can be released from the
internal to the external phase and then from the external phase to
the skin. The release from the internal phase supplements the
depletion of the drug in the external phase, supplying sustained
and controlled release of the triptolide into the skin. Zero-order
release kinetics was obtained. Despite the great permeation
enhancing properties of oleic acid, the formulation with higher
oleic acid concentration did not show a significant enhancing
effect. It was concluded that penetration of oleic acid was
perturbed by the encapsulation of the surfactant and the
cosurfactant. Menthol was found to be a suitable permeation
enhancer for triptolide loaded microemulsions. It was also found
381
that the microemulsions containing lower amounts of Tween 80®
and propylene glycol provided higher permeation flux, which
may be attributed to the increased thermodynamic activity of the
drug in these microemulsions. A microemulsion containing
0.025% triptolide, 6% oleic acid, 20% Tween 80®, 10% pro-
pylene glycol, 62.975% water and 1% menthol was found to be
the most suitable for triptolide delivery. The irritation studies on
the skin of rabbits did not show any visible irritation for 7 days. In
comparison, the aqueous solution induced significant erythema
and edema. It may be concluded that a microemulsion is an
effective method for triptolide delivery since it protects it from
degradation, provides prolonged release, and despite the toxicity
of the drug it does not cause irritation [154]. This formulation is
better than the one previously suggested by Mei et al. [111]
consisting of 40% isopropyl myristate, 50% Tween 80®/pro-
pylene glycol (5:1), and water, which was a w/o type of
microemulsion. In the latest formulation, triptolide is solubilized
in the outer oily phase and therefore might directly contact the
surface of the skin. From the safety point of view this is not
suitable for long-term use.
2.3.5. 5-Fluorouracil
5-Fluorouracil is an antineoplastic drug which, on intravenous
administration, produces severe systemic gastrointestinal, hema-
tological, neural, cardiac and dermatological effects. Therefore,
transdermal delivery remains the choice route for administration.
Very recently, Gupta et al. [149] investigated in vitro transdermal
permeation through hairless mouse skin of this hydrophilic drug,
which was encapsulated in AOT/water/isopropylmyristate water-
in-oil microemulsions. Incorporation into microemulsions
increased the flux of the drug 2–6 fold in comparison to the
aqueous solution of the drug. The results revealed that
microemulsions increased the average acyl lipid disorder as
well as hydration of the stratum corneum, thus increasing the drug
flux. The skin flux was dependent on the concentration of water
and AOT. Skin toxicity studies indicate that the AOT/water/
isopropylmyristate ME is safe for the transdermal permeation of
this drug [149].
2.3.6. Retinoic acid
Trotta et al. [112] examined the significance of ion pairing on
the topical permeation of retinoic acid (RA) using microemul-
sions as delivery vehicles. Retinoic acid is used in treating acne
vulgaris. Both oil-in-water (o/w) and water-in-oil (w/o) micro-
emulsion formulations were prepared using water, isopropyl
myristate, lecithin, caprylyl-capryl glucoside and ethanol or 1,2
hexanediol. The mean apparent diameters of these vehicles were
20–30 nm. Phenylalanine methyl ester, phenylalanine ethyl
ester, histidine methyl ester, tryptophan methyl ester, and valine
methyl ester were used as counter ions. The study revealed that
the permeability of the RA from an ethanol–pH 6.4 buffer
mixture through polydimethylsiloxane (PDMS) membrane was
significantly increased in presence of the counter ions. These
results were confirmed by examination of the permeability of
the RA from the ethanol–pH 6.4 buffer mixture through pig
skin. In order to clarify whether the enhancement was due to the
ion pair formation or partly due to direct damage of the skin by
382 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385
the amino esters, the same permeability experiments were done
with a Cortisone, a lipophilic drug that is unable to form an ion
pair. Since its flux was not significantly increased in presence of
phenylalanine ethyl ester hydrochloride, the authors concluded
that RA flux increase might be attributed to the ion pair
formation. Nevertheless, ion pairing in ethanolic solution could
not help in optimizing RA targeting since drug accumulated/
drug delivered ratios of 0.6–0.9 and 0.4 μg h cm− 1 10− 3 were
obtained for ion pair and RA, respectively. In the presence of
counter ions, the permeabilities of RA from microemulsions
using PDMS membranes decreased. These results were also
confirmed using pig skin. w/o microemulsions exhibited the
lowest accumulation of the drug in the skin. In comparison,
o/w microemulsions containing counter ions (amino esters)
showed drug accumulation four to five times higher than the
corresponding counter ion-free microemulsions. These kinds
of o/w microemulsions are very appealing vehicles for treat-
ment of skin diseases and can be used to optimize drug
targeting without a concomitant increase in systemic absorp-
tion. Despite the same components of these formulations,
relative percentages of water, oil, and surfactant lead to different
microstructures that provide different drug permeation and thus
different skin accumulation [112].
3. Summary and conclusions
Microemulsions can be formed by numerous oil, surfactant,
co-surfactant, and aqueous constituents. The main advantages
of microemulsions as vehicles for drug delivery are their high
solubilization capacities for both hydrophilic and hydrophobic
drugs, their thermodynamic stability, the ease of formation, and
the relatively low cost of formulation preparation. In some
cases, the enhanced accumulation of the drug can significantly
help optimize the targeting of the drug without increasing the
systemic side effects.
Microemulsions topically applied were shown to signifi-
cantly increase the cutaneous absorption of the drugs. The
vehicles frequently act as penetration enhancers, depending on
the oil/surfactant constituents, which involves the risk of in-
ducing local irritation. The process of skin permeation is very
complex, but recent studies have improved the knowledge
relative to the permeability process and its controllers. The un-
derstanding at the molecular level will enable the design of
topical formulations with better rationale that will increase the
bioavailability and decrease the side effects.
One of the main problems is that after applying a topical
formulation on the skin, the formulation composition may
change. Accordingly, volatile compounds are promptly evapo-
rated, small molecules can get absorbed by themselves, and others
may interact with the skin in an irreversible manner causing
irritation and possible permanent damage. Therefore, many drugs
that penetrate the skin sufficiently to produce a therapeutic effect
fail due to the incompatibility of the formulation in which they are
entrapped. In addition, the choice of the formulation components
is very complicated. Depending on the structure of the micro-
emulsion, the character of the drug, and the membrane properties,
the same substances can act as enhancers or as retarders. The
components that are well known as enhancers such as ethanol
[141–144], propylene glycol [93] and phospholipids [106,115,
116,119,124,125], turned out to be retarders [145,148]. Thicken-
ing agents can serve as promoters or as retarders too [132]. In
order to enhance the penetration ability of certain drugs one must
modify its solubility, as well as diffusion and partition coefficients
in each membrane.
It is understood that in many cases the presence of a co-
enhancer to an enhancer optimizes the permeability, such as in
the case of 1-menthol addition to ethanol that showed greater
penetration enhancement of morphine hydrochloride [113]. It is
important to note that the combination of several enhancing
components leads to a synergistic effect and a greater enhance-
ment effect than is observed for each component alone. In
addition, the synergy between the iontophoresis and enhancers,
such as fatty acids, has resulted in increase of both low and high
molecular weight drug permeation as well as in decrease of skin
toxicity [85,86,97–99].
Many enhancers are concentration-dependent; therefore
optimal concentration for effective promotion should be
determined. Sometimes when using an ethanol–water vehicle
the effect of ethanol is concentration dependent, and therefore,
can even decrease the permeation [145].
Ion pair creation provides prolonged activity due to the
formation of a reservoir in topical formulations. This delay ef-
fect leads to increased bioavailability which promotes a
decrease in daily intake of the drug and side effects.
Many in vitro and in vivo studies have examined the
relevance of the microemulsions as a transdermal route for
administration. Nevertheless, more in vivo studies should be
conducted to support the in vitro findings. In topical formula-
tions, in many cases the irritation issue is not considered. In
addition, chronic application consequences should be studied.
For instance, for very common enhancers such as oleic acid, the
benefit of penetration enhancement must be considered very
carefully since immunosuppression of the skin might be affected
[94]. Local and systemic toxicity should be further studied to
determine therapeutic benefit/risk ratio and to evaluate the
possible influence on the human body. Since some enhancers
can harm the skin, researchers should examine not only the
immediate influence of the formulations both in vitro and in
vivo, but also examine the skin after chronic application.
Despite all the complexity, it is possible to predict the
appropriate enhancer based on similarity in physicochemical
properties such as molecular weight, hydrophilic/lipophilic
classification, and solubility.
The microemulsion structure facilitates drug solubilization in
greater amounts than in its individual components. A much
better understanding of the relationship between the structure of
the microemulsion droplets and the nature of the solubilized
drug has been gained from the recent studies, but yet many of
the results are strictly empirical and difficult to explain and even
more difficult to predict or to forecast. Attention is being paid to
the quantification of the maximum solubilization of a substance
in the concentrate and on its behavior upon dilution. Attempts
have been made to determine the locus of the quest molecule in
the core of the microemulsion or at the interface. Understanding
 A. Kogan, N. Garti / Advances in Colloid and Interface Science 123–126 (2006) 369–385 383

the locus of solubilization can be useful in protecting the drug
and for its sustained or immediate release. The potential in
controlling the delivery rate has been demonstrated only to
some extent and was demonstrated to be dependent on the
structure and ingredients of the microemulsion.
It should be noted that most of the studies conducted with
topical formulations are done in vitro/in vivo on animal's skin
showing greater permeability than that obtained with the same
formulation in humans. It is obvious that both the type of
examined membrane and the kind of vehicle play significant
roles. The same components with varying concentration can
form different vehicles affecting differently the rate of drug
permeability, and the amount of drug accumulated into the skin.
In most cases, the lower the viscosity of the vehicle the faster is
the release [125,112].
There are some cases where the observations do not coincide
with the expectations. Despite expectation of drug permeation
enhancement due to the formation of a microemulsion vehicle,
in some cases no enhancement occurs due to the lower per-
centage of the enhancing components in the vehicle in com-
parison to other formulations [118]. Therefore, the components,
their concentrations and the form of the vehicle are of great
interest to the pharmaceutical scientist.
Phase transitions are known to occur in microemulsion
microstructures as a result of changes in pH, temperature, dilu-
tion, etc., as well as due to the presence of the guest molecules,
the solubilized drugs. Phase transitions were studied only by
few scientists in past reports, and their effect on drug behavior
in the microemulsion was not fully clarified. Phase equilibria
and structural phase transformations within microemulsions in
the presence of drugs are of high importance in drug delivery.
Drugs tend to precipitate and crystallize as large crystals upon
storage or dilution. These aspects were not considered in the past,
but are relevant issues in relation to sustained or slow delivery.
Therefore, stability examinations of drug-loaded microemulsions
should be performed. In view of the fact that the entrapped drug
may participate in the formation of the vehicle and, consequently,
influence its release, it is very important to investigate the drug
impact on the physicochemical properties of the vehicle.
The dilution effects on the stability of the microemulsions
were in most studies neglected and not considered. However, it
is self-obvious that once the formulation is incorporated into the
digestive tracts dilution occurs and the microemulsion in most
cases decomposes and the drug is released in the uncontrolled
patterns and has the tendency to precipitate.
It was shown by very limited number of studies that micro-
emulsions were efficient drugs protectors from environmental
damages such as oxidative degradation [121], hydrolysis, in-
appropriate pH environment [154]. Many more such studies are
required.
Modeling the microemulsion phase transition behavior and
the permeation process through the different membranes can be
a very useful tool to study the change of physicochemical pro-
perties in case of drug upload. This way, hundreds of ex-
periments will be eliminated automatically and will save
researchers and the pharmaceutical industry a lot of money
and precious time. In this area, there is a huge lack of reliable
mathematical models to predict the behavior of real formula-
tions. Currently, the use of in vitro models and in vivo animal
models is the only way to predict in vivo human behavior.
However, the design of such experiments should be done with
care because human membranes either in vivo or extracted (in
vitro) can behave differently from membranes taken from other
mammals.
During the last decade much progress has been made in
exploring new types of microemulsion vehicles for drug deli-
very. More advanced analytical methods are becoming avail-
able; therefore, it becomes easier to better characterize the
correlation between the nature of the microdroplets and the
bioavailability of the embedded drug. Despite the enormous
amount of information gathered in this field, there are still many
questions left unanswered and good deal of work to be done.
Acknowledgement
We are very grateful to Dr A. Aserin and Ms. E. Oxman for
their helpful remarks.
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