3b7e26cdd01

REVIEWS

Microemulsions—Modern Colloidal Carrier forDermal 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

Abbreviationnate; AP, ascorbcyclosporine A;light scatteringdramine; DSC,freeze fracture-tpyl myristate; IMCT, medium cN-methyl pyrroloil-in-water; PERh, hydrodynaming; S/CoS, surffate; SLN, solidmicroscopy; TEcaine hydrochlo

Correspondeþ49-345-552500E-mail: reinhar

Journal of Pharm

� 2007 Wiley-Liss

ABSTRACT: Microemulsions are modern colloidal drug carrier systems. They formspontaneously 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 ofpreparation, long-term stability, high solubilization capacity for hydrophilic and lipo-philic drugs, and improved drug delivery. The article summarizes the level of researchwith respect to dermal and transdermal application. A large number of in vitro as well assome in vivo studies demonstrated that drugs incorporated into microemulsions pene-trate efficiently into the skin. The enhancing activity seems to be attributable to avariety of factors depending on the composition and the resulting microstructure of theformulations. However, an extended use in practice depends on the choice of well-tolerated ingredients, mainly surfactants, and the restriction of their amounts in orderto guarantee skin compatibility. � 2007 Wiley-Liss, Inc. and the American Pharmacists

Association J Pharm Sci 97:603–631, 2008

Keywords: microemulsion; colloidal ca
rrier; dermal drug delivery; characterization;microstructure; compatibility; skin; surfactants; solubilization; penetration; permeation
s: AOT, sodium bis(2-ethyl hexyl)sulfosucci-yl palmitate; APG, alkyl polyglycoside; Cs A,

DDA, diclofenac diethylamine; DLS, dynamic; DMSO, dimethyl sulfoxide; DPH, diphenhy-differential scanning calorimetry; FF-TEM,ransmission electron microscopy; IPM, isopro-PP, isopropyl palmitate; ME, microemulsion;hain triglycerides; MTX, methotrexate; NMP,idone; NMR, nuclear magnetic resonance; o/w,G, polyethylene glycol; PG, propylene glycol;ic radius; SANS, small angle neutron scatter-

actant/cosurfactant; SDS, sodium dodecyl sul-lipid nanoparticle; TEM, transmission electronWL, transepidermal water loss; THCl, tetra-ride; w/o, water-in-oil.nce to: Reinhard H.H. Neubert (Telephone:0; Fax: þ49-345-5527292;

[email protected])

aceutical Sciences, Vol. 97, 603–631 (2008)

, Inc. and the American Pharmacists Association

JOURNAL OF PH

INTRODUCTION AND DEFINITION

Human skin is an important target site for theapplication of drugs. In the treatment of localdiseases topical drug delivery is an appropriatestrategy to restrict the therapeutic effect to theaffected area and to reduce systemic incrimina-tion. On the other hand, systemic availability isthe aim in transdermal delivery, which can beused to minimize the first-pass-effect.

In order to reach therapeutic drug concen-trations in certain skin layers or in the bloodcirculation, the uppermost barrier, the stratumcorneum (SC), has to be overcome. This pro-cess is affected by various factors, e.g., the

ARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008 603

604 HEUSCHKEL, GOEBEL, AND NEUBERT

physicochemical properties of the drug and thevehicle used for administration.

Modern drug carriers are microemulsions (ME).These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydro-philic ingredient, as well as a surfactant anda co-surfactant. What are the characteristicsof microemulsions? They are single opticallyisotropic, transparent or slightly opalescentsolutions of low viscosity. Very special about themare the thermodynamic properties. Microemul-sions are thermodynamically stable and formwithout any energy input.1–3 According to theGibbs-Helmholtz equation, such spontaneouslyrunning processes are characterized by a negativefree energy DG. In our case, the equation can bewritten as:

Table 1. Diffe

Microemulsion

Transparent/traStableSpontaneousTowards 0 mNDynamic (fluctuYes10–100 nm

JOURNAL OF PHAR

DG ¼ gDA � TDS;

where DG is the free energy of formation, g theinterfacial tension, DA the change in interfacialarea during the formation process, DS the changein entropy, and T is the temperature.

The formation of a microemulsion is accompa-nied by a significant increase in the interfacialarea A. Since the interfacial tension g decreasesremarkably (but remains positive all the time),a negative free energy is achieved when theinterfacial energy (gA) is compensated by adramatic change in the entropy of the system,which is mainly dispersion entropy.4,5 Therequired very low interfacial tension cannot berealized by only one surfactant. The additionallyused co-surfactant penetrates the amphiphilicinterfacial layer and increases its curvature andfluidity.5,6 For this purpose, short or mediumchain alcohols and, for reasons of compatibilityin humans, preferably non-ionic surfactants areused.

The resulting systems show a number of dif-ferent microstructures—submicroscopic regionsof either aqueous or oleic nature, separated by the

rences between Microemulsions and Emulsi

Property

nslucent AppearanceThermodynamic stabiFormation

m�1 Interfacial tensionating surfaces) Microstructure

Optical isotropyDroplet size of the col

MACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008

interfacial layer. Basically two types of micro-emulsions are differentiated: bicontinuous onesand microemulsions with droplet like structure.Bicontinuous means that both water and oil formcontinuous domains separated by surfactant-richinterfaces. They are likely to occur when similaramounts of oil and water are present. Otherwise,droplet structures are formed. Depending on themajor compound water-in-oil (w/o) and oil-in-water (o/w) microemulsions are described. Thesize of the colloidal phase is typically in the rangeof 10–100 nm.

The common feature of all the appearingmicrostructures in microemulsions is that theyare highly dynamic, undergoing continuous andspontaneous fluctuations. According to Lam et al.two classes of change are considered: inversions(fluctuations in which the system reverts locallyfrom water to oil continuity and back) andsuperimposed on that, based on the droplet model:variations in droplet size.7 Although microemul-sions do not consist of static phases according tothe definition of Gibbs, throughout the literature,occurring water- or oil-rich domains are referredto as ‘‘phases.’’

The term ‘‘microemulsion’’ itself is sometimesused in a misleading way. On the one hand,various homogeneous surfactant-containingsolutions were named like this and on the otherhand, the expression itself implies emulsion-likeproperties with droplet sizes in the submicron-range. Therefore, Danielsson and Lindman sug-gested a definition giving some including andexcluding criteria in order to minimize theconfusion.2 For example, the concept does notcover aqueous surfactant solutions without addedsolubilizate, liquid crystalline systems, and nor-mal emulsions. Table 1 summarizes the maindifferences between micro- and ‘‘macro-’’ emul-sions. However, a clear-cut distinction from othercolloidal structures like solubilized micellar sys-tems is missing since there is no well-defined

ons

Emulsion

Milkylity Unstable (kinetically stabilized)

Energy input�50 mN m�1

Static (until coalescence)No

loidal phase >500 nm (nanoemulsions: >50 nm)

DOI 10.1002/jps

MICROEMULSIONS FOR DERMAL AND TRANSDERMAL DRUG DELIVERY 605

transition point. Hence, some authors use theterm ‘‘swollen micelles’’ to describe droplet likemicroemulsions.3

Due to their special features, microemulsionsoffer several advantages for pharmaceutical use,such as ease of preparation, long-term stability,high solubilization capacity for hydrophilic andlipophilic drugs, and improved drug delivery. Thelatter provides a wide range of possible applica-tions. Besides dermal administration, which isexplained in detail below, they are used forexample in oral, parenteral and ocular drugdelivery.

PHYSICOCHEMICAL CHARACTERIZATIONOF MICROEMULSIONS

As mentioned above, microemulsions exist invarious microstructures including droplet likeand bicontinuous characters. Since their drugdelivery properties are related to the innerstructure, there is a need to assign the correctstate. An appropriate physicochemical character-ization of colloidal formulations is highly challen-ging due to their small particle sizes and thefluctuating interfaces. The combination of dif-ferent characterization techniques is stronglyrequired. Here, one has to consider that dilutionof microemulsions continuously changes theircharacter towards a micellar solution and would,therefore, lead to wrong conclusions.

To begin with, polarizing light microscopy isused to decide on optical isotropy, a basic featureof microemulsions.

The influence of kind and/or amount of oil andsurfactant on the internal structure can bestudied by rheological measurements. Ktistisdetermined the effect of the composition of amicroemulsion on the hydration of the disperseddroplets.8 Furthermore, viscosity is of practicalrelevance to the administration on the skin,especially if a spray system is taken into account.

Different methods of specimen preparationcombined with electron microscopy techniquesenable the visualization of structural differencesbetween droplet and bicontinuous microemulsionstates as well as other colloidal formulations. Hoarand Schulman who first mentioned the formationof transparent dispersions in 19439 coined theterm ‘‘micro emulsion’’ due to electron microscopicobservations of the system’s microstructure.10 Themethods are high-sophisticated and require care-ful interpretation of the micrographs because

DOI 10.1002/jps JOURN

formation of artifacts during the preparationprocess can not always be excluded. For example,ice decoration is a frequently occurring artifact infreeze fracture transmission electron microscopy(FF-TEM).11 Therefore, high cooling rates, alimited number of components as well as detailedstructural knowledge from other experimentalmethods are essential.12

According to Alany et al., conductivity measure-ments do not only help to determine the natureof the continuous phase of a microemulsion,but allow also an estimation of the percolationthreshold.11 This value corresponds to the trans-formation from droplet-like to bicontinuous micro-emulsions as the droplets begin to interconnect.Such alterations are also accompanied by changesin the viscosity11,13 and do clearly influencepermeation parameters.

Frequently applied for size determination andpartly controversially discussed is the use ofscattering techniques such as small-angle neu-tron scattering, static and, mainly, dynamic lightscattering. The latter are based on the interactionof light with matter. Static light scattering (SLS)observes interparticle interference patterns ofscattered light by measuring the time averageintensity as a function of angle, whereas dynamiclight scattering (DLS) monitors fluctuations inscattered light as a function of time. Thesefluctuations are due to Brownian motion of themicroemulsion droplets within the continuousphase and depend on the hydrodynamic proper-ties of the system. Using Stokes-Einstein equa-tion, the average hydrodynamic radius of thescattering droplets can be calculated from thedetermined free particle diffusion coefficient.

The principle of neutron scattering can beunderstood due to the similarities to light scat-tering. In the case of light, the interaction isbetween the electric field of the radiation and theelectronic charges. Neutrons, having no electricalcharge, interact in almost all situations via theirscattering length with the nuclei exclusively.The typical wavelength associated with thermalneutrons is in the order of 1 to 10 A which meansan increased resolution. Considering the dropletsizes present in colloidal systems, it can bededuced that neutrons are very often the moreappropriate way of studying their structure.Mostly, the technique of small angle neutronscattering or SANS is employed.

Other methods, e.g., electrokinetic chromato-graphy, infrared spectroscopy, and calorimetryare also in use.1,13–15 Very interesting and helpful

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


results concerning self diffusion in microemul-sions have been obtained by nuclear magneticresonance (NMR) studies.16,17

Some pharmaceutical relevant applications ofthese characterization techniques are describedas follows.

Since the development of microemulsions is anempirical task, the first step to obtain informationoften is to construct pseudoternary phase dia-grams from the beforehand chosen ingredients.The existence area of microemulsions is deter-mined and by the exchange of compounds, theirinfluence on the formation of certain microstruc-tures can be investigated.

Fixing water and oil in a phase diagram, severaltimes the surfactant/co-surfactant mass ratio(S/CoS) was found to be an important factorconcerning position and size of microemulsionregions.16–20 But also the kind of oil plays arole.21,22 For pragmatic reasons, in most casesonly isotropic phases are further investigated.Alany et al. performed a more extended char-acterization study with systems composed of ethyloleate, water, and a surfactant blend either withor without the co-surfactant 1-butanol.11 In theco-surfactant-free phase diagram a microemul-sion region and a phase of lamellar liquid crystalswere identified, whereas the 1-butanol containingsystem showed only a microemulsion area,although a considerably increased one. Theauthors employed viscosity and conductivitymeasurements as well as FF-TEM in order todifferentiate between liquid crystals, droplet-likeand bicontinuous microemulsions. Furthermore,transitions between the single states could bedetected.

Scattering experiments on o/w microemulsionswith different oils (octyl dodecanol and isopropylpalmitate, respectively) were performed byShukla et al.23 In a SANS study, a core shellmodel was used for a suitable fitting of the data.The size parameters were defined as Rcore (size ofthe oil droplet, i.e., pure oil including surfactanttail that penetrates the oil), and Rshell (distancebetween the centre of the particle and a position inthe surface film where the difference in scatteringlength density has its maximum). As expected, theouter radius incorporates looser-bounded surfac-tant molecules and is substantially bigger thanthe hydrodynamic radius Rh, obtained by DLS. Rh

is supposed to consist of the oil core and a strongerbounded surfactant film, perhaps containing somesolvent molecules too. Values of about 10 nmfor Rh indicated that the kind of oil (compar-

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

able molecular size provided) only marginallyinfluences the droplet size of a microemulsion.

In contrast, an increased oil content of watercontinuous microemulsions is accompanied by anincrease in droplet size as Attwood and Ktistisfound out by means of static light scattering.24

Similar results obtained Saint Ruth et al. exam-ining lecithin-based o/w systems25 as well asShukla et al.26 The latter determined hydrody-namic radii of microemulsions having a eutecticmixture of lidocaine and prilocaine as colloidalphase.

A set of experimental methods was employed byPodlogar et al. in order to get inside into structuralchanges of a microemulsion by dilution withwater.27 In differential scanning calorimetry(DSC)-cooling curves size and position of thewater peak contain information on the state ofwater within the formulation, i.e., stronger orweaker interactions with surfactants. This know-ledge in conjunction with electrical conductivity,surface tension and density helped to identifytransforming substructures from w/o via bicontin-uous to o/w microemulsions. Their influence ondrug release was focus of further studies.

Whereas in the previous experiments the ratiobetween oil and surfactants was kept constant,another approach was to use varying oil-to-waterratios and a constant amount of surfactant blendof 30%.28 Again, a transformation from oil- towater-continuous microemulsions via a bicontin-uous state was coincidently found using themobility parameters conductivity and viscositybesides density, surface tension data and DSC.Furthermore, by small angle X-ray scattering(SAXS) combined with the model of a polydispersesystem of hard spheres for data interpretation, inw/o systems a conversion from elongated to morespherical oil droplets at lower oil-to-water ratioswas found. In o/w microemulsions, strong inter-actions between the droplets were concludedwhich led to gel-like structures at higher waterconcentrations.

In dermal drug delivery, a frequently usedcombination is Labrasol, Plurol oleique, isopropylmyristate, and water. For this system a pseudo-ternary phase diagram was constructed byDjordjevic et al. and selected mixtures of a dilutionline were characterized by conductivity, whichindicated occurring percolation phenomenon.29

Addition of water was also accompanied bychanges in viscosity and confirmed a continuoustransition of the internal state. Incorporationof diclofenac diethylamine clearly affected the

DOI 10.1002/jps


physicochemical properties of the systems,emphasizing the significantly influence of anamphiphilic drug on the microstructure.

Besides rheological and DLS studies, thermo-dynamical parameters such as free energy,enthalpy and entropy were determined by Sub-ramanian et al. for polysorbate-based microemul-sions.30

A completely different characterizing issue wasaddressed by Malcolmson et al.21 They investi-gated the effect of varying properties of the oil inwater-continuous microemulsions, i.e., size andpolarity, on the solubilization capacity for testos-terone propionate. Solubility is an importantfactor for drug delivery because by increased drugamounts within the vehicle the concentrationgradient towards the skin increases which is adriving force for diffusion processes. Observingthe formation of the microemulsions by means oflight scattering it appeared that decreasingmolecular volume of the oil led to an increase inthe area of microemulsion formation. Interest-ingly, there was no relationship between solubi-lity of the drug in the microemulsions and thepure bulk oils. The authors recommended the useof high molecular volume oils because most drugsare believed to be partly solubilized within theheadgroups of the surfactant aggregates and,amongst other things, those oils do not impactmolecular packing in this area very much.

A highly promising tool for the investigation ofthe correlation between microstructure and pene-tration behavior of microemulsions is NMRspectroscopy. Kreilgaard et al.16 as well as Huaet al.17 applied this method in order to obtain selfdiffusion coefficients of drugs and other ingredi-ents of colloidal systems. Partly in combinationwith other characterization techniques theygained interesting results that can simplify theoptimization process in formulation development.

DERMAL AND TRANSDERMAL DRUGDELIVERY USING MICROEMULSIONS

Since microemulsions turned out to enhancedermal and transdermal drug delivery, a lot ofcompositions have been created and tested in vitroand in vivo.

A crucial point for the clinical use is thecompatibility for which the surfactants, namelytheir type and amount, play the most importantrole. Mixtures of non-ionic surfactants are pre-ferred. Occasionally, combinations of a surfactant


and a short or medium chain alcohol can be foundin the literature. Most frequently surfactants suchas sorbitan fatty acid esters, polysorbates, (peg-ylated) glycerol fatty acid esters, pegylated fattyalcohols, and fatty acids, respectively, as well aspoloxamers occur in various combinations. Morerecently attempts have been made to use surfac-tants from natural base stocks, mainly alkylpolyglycosides and sucrose esters that are knownfor their good biocompatibility and favorableecotoxicological properties. Microemulsions canalso be formed using phospholipids. Besides,AOT (sodium bis(2-ethylhexyl)sulfosuccinate)and fluorosurfactants were chosen as amphi-philes. Different alcohols act as co-surfactants,e.g., ethanol, (iso-)propanol, butanol, propyleneglycol, tetraglycol, and octanediol.

The following chapter is intended to give anoverview on several approaches in the formulationof microemulsions as well as their characteristicsin the performed in vitro and in vivo examina-tions. Most of the studies are carried out in orderto develop optimized vehicle systems exhibitingimproved permeation properties for several(model) drugs, hereby comparing different micro-emulsion compositions or even completely differ-ent types of formulations. As in the developmentof microemulsions, the surfactant blend and thehydrophilic ingredients (water or buffer) are oftenfixed beforehand, the lipophilic components andthe ratio of all the ingredients are the variables.The choice of the oil depends mostly on itssolubilization capacity for the drug used andknown enhancing properties as in the case of oleicacid. Other typical lipophilic components areesters such as isopropyl myristate (IPM) andisopropyl palmitate (IPP) as well as medium chaintriglycerides (MCT).

The structure of the following chapter complieswith basic compositions of microemulsions fordermal use in order to summarize their status ofinvestigation. The corresponding tables (Tabs. 2–9) are based on Kreilgaard31 and were modifiedand extended.

PEGylated (Glycerol) Fatty Acid Ester-BasedMicroemulsions

A frequently used combination of surfactants isthe mixture of Labrasol (caprylocaproyl polyox-ylglycerides) and a Plurol-derivative (polyglycerylfatty acid ester) (see Tab. 2). It was chosen byDelgado-Charro et al. to form microemulsionstogether with ethyl oleate and water because of


Ta

ble

2.

Over

vie

wof

PE

Gyla

ted

(gly

cero

l)F

att

yA

cid

Est

er-B

ase

dM

icro

emu

lsio

ns—

Com

pos

itio

nan

dS

tud

ies

Su

rfact

an

t/C

o-su

rfact

an

tA

qu

eou

sP

hase

Oil

Ph

ase

Ad

dit

ives

Dru

gIn

Vit

roS

tud

ies:

Sk

inM

odel

/Mem

bra

ne

InV

ivo

Stu

die

s:S

pec

ies

Yea

rR

ef.

Labra

sol/

Plu

rol

Isos

teari

qu

eW

ate

rE

thyl

olea

teN

aC

l(S

)S

ucr

ose

Hair

less

mou

sesk

inH

um

an

(I)

1997

31

Labra

sol/

Plu

rol

Isos

teari

qu

eW

ate

rIs

oste

ary

lis

oste

ara

teL

idoc

ain

e,p

rilo

cain

eH

Cl

Exci

sed

rat

skin

2000

16

Labra

sol/

Plu

rol

Isos

teari

qu

eW

ate

rIs

oste

ary

lis

oste

ara

teL

idoc

ain

e,p

rilo

cain

eH

Cl

Rat

2001

35

Labra

sol/

Plu

rol

Isos

teari

qu

eW

ate

rIs

oste

ary

lis

oste

ara

teL

idoc

ain

eH

um

an

2001

36

Labra

sol/

Plu

rol

Isos

teari

qu

eN

aC

lp

H7.4

Eth

yl

olea

teM

eth

otre

xate

Pig

skin

2001

32

Labra

sol/

Plu

rol

Ole

iqu

eW

ate

rM

CT

Asc

orbyl

palm

itate

,so

diu

masc

orbyl

ph

osp

hate

2001

37

Labra

sol/

Plu

rol

Ole

iqu

eW

ate

rM

CT

Xan

than

gu

m,

Aer

osil

(T)

Asc

orbyl

palm

itate

Cel

lulo

seace

tate

mem

bra

ne,

por

cin

esk

in

2003

40

Labra

sol/

Plu

rol

Ole

iqu

eW

ate

rM

CT

Asc

orbyl

palm

itate

2003

38

Labra

sol/

Plu

rol

Ole

iqu

eW

ate

rIP

MD

iclo

fen

ac

die

thyla

min

eR

egen

erate

dce

llu

lose

mem

bra

ne

2004,

2005

29

41

Labra

sol/

Plu

rol

Ole

iqu

e/T

ran

scu

tol

Wate

rIs

oste

ary

lis

oste

ara

teD

iclo

fen

ac

sod

ium

Hu

man

skin

2003

42

Pol

yox

yl-

40

fatt

yaci

dd

eriv

ate

s/gly

cery

lol

eate

/tet

ragly

col

Wate

rIP

PL

idoc

ain

e,li

doc

ain

eH

Cl

Exci

sed

rat

skin

Rat

2004

18

PE

G40-s

teara

te/g

lyce

ryl

olea

te/t

etra

gly

col

0.0

1M

NaC

lIP

PL

idoc

ain

eH

Cl

Por

cin

esk

inR

at

2006

48

PE

G-4

0st

eara

te/g

lyce

ryl

olea

te/t

etra

gly

col

Wate

rIP

MD

iclo

fen

ac

sod

ium

Dif

fere

nt

typ

esof

an

imal

skin

Rat

2006

49

PE

G-2

0-g

lyce

rol

mon

oole

ate

/T

egin

4600

Wate

r(u

pta

ke

from

skin

)

IPP

Bu

pra

nol

olR

abbit

1992

75

Labra

sol/

eth

an

olW

ate

rO

leic

aci

dP

irox

icam

Exci

sed

rat

skin

2005

44

Labra

sol/

eth

an

olW

ate

rL

au

ryl

alc

ohol

Dic

lofe

nac

die

thyla

min

eE

xci

sed

rat

skin

2004

43

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008 DOI 10.1002/jp


s

Labra

sol/

Tra

nsc

uto

lW

ate

rL

au

rogly

col

Azo

ne,

SR

-38,

eth

an

ol(E

);B

HT

,N

a-

met

abis

ulfi

te(A

);N

a-b

enzo

ate

(P)

Flu

oxet

ine

HC

lH

um

an

cad

aver

skin

2005

45

Labra

sol/

Tra

nsc

uto

lW

ate

rO

leic

aci

dV

inp

ocet

ine

Exci

sed

rat

skin

,h

um

an

skin

Mou

se(I

)2004

29

Labra

sol/

Cre

mop

hor

RH

40

Wate

rO

leic

aci

dT

erp

enes

(E)

Ket

opro

fen

Exci

sed

rat

skin

2001

19

Cre

mop

hor

RH

40/

Tra

nsc

uto

lW

ate

rO

leic

aci

dV

inp

ocet

ine

Exci

sed

rat

skin

Mou

se(I

)2004

46

Cre

mop

hor

EL

P/

eth

an

olW

ate

rO

leyl

macr

ogol

-6-

gly

ceri

des

Ter

pen

es(E

)A

cecl

ofen

ac

Exci

sed

rat

skin

2005

50

Cre

mop

hor

EL

/pro

pyle

ne

gly

col/

dec

an

oic

aci

dA

ceta

tebu

ffer

IPM

Carb

opol

1342

(T)

Dif

fere

nt

bet

a-

blo

cker

sD

ialy

sis

mem

bra

ne,

hair

less

mou

sesk

in

1995

54

PE

G-2

0gly

cero

lm

onoo

leate

/P

olox

am

er/p

rop

yle

ne

gly

col

Wate

rIP

P,

olei

caci

dD

MS

O(E

)C

ycl

osp

orin

eA

Exci

sed

hu

man

skin

Hu

man

2002

51,5

2

PE

G-2

0gly

cero

lm

onoo

leate

/P

olox

am

er/p

rop

yle

ne

gly

col

Wate

rP

elem

ol1

BIP

Cu

rcu

min

Hu

man

2007

53

PE

G-2

0gly

cero

lm

onoo

leate

/S

pan

80

Wate

rIP

PD

esm

opre

ssin

ace

tate

Hu

man

skin

2005

55

PE

G-2

0gly

cero

lm

onos

teara

te/

Plu

rolo

leat

WL

1173/

pro

pyle

ne

gly

col

Wate

rIP

MH

yd

roco

rtis

one

Hu

man

,(I

)2001

94

PE

G-2

0gly

cero

lm

onos

teara

te/

Plu

rolo

leat

WL

1173/

pro

pyle

ne

gly

col

Wate

rIP

MH

um

an

2003

95

A,

an

tiox

idan

t;E

,en

han

cer;

P,

pre

serv

ati

ve;

S,

elec

trol

yte

;T

,th

ick

enin

gagen

t;I,

irri

tabil

ity

stu

dy.

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008


Ta

ble

3.

Over

vie

wof

PE

Gyla

ted

Fatt

yA

lcoh

ol-B

ase

dM

icro

emu

lsio

ns—

Com

pos

itio

nan

dS

tud

ies

Su

rfact

an

t/C

o-su

rfact

an

tA

qu

eou

sP

hase

Oil

Ph

ase

Ad

dit

ives

Dru

gIn

Vit

roS

tud

ies:

Sk

inM

odel

/Mem

bra

ne

InV

ivo

Stu

die

s:S

pec

ies

Yea

rR

ef.

Bri

j35/d

ecan

olW

ate

rD

odec

an

eT

etra

cycl

ine

HC

lS

kin

mem

bra

ne

1980

56

Bri

j96

Wate

rS

oybea

noi

lD

iffe

ren

tst

eroi

ds

1993

57

Bri

j96/b

uta

nol

/mon

o-/

di-

/tri

eth

yle

ne

gly

col

mon

obu

tyle

ther

Wate

rE

thyl

este

rs,

hyd

roca

rbon

s,M

CT

,so

ybea

noi

lT

esto

ster

one

pro

pio

nate

1998

21

Bri

j97

Wate

rT

ribu

tyri

n,

MC

T(M

igly

ol812),

soybea

noi

l

Carr

agee

nan

(T)

Sod

ium

flu

ores

cein

Por

cin

esk

in2004

58

Lau

rom

acr

ogol

300

Wate

rD

ecan

eA

met

hoc

ain

eH

um

an

skin

2005

59

Lau

rom

acr

ogol

300

Wate

rD

ecan

eA

met

hoc

ain

era

t2004

60

Bri

j58/S

pan

80/

isop

rop

an

olor

pro

pan

olW

ate

rS

oybea

noi

lD

MS

O,

PG

(E)

Dic

lofe

nac

sod

ium

Rabbit

skin

2005

61

Bri

j96/C

ap

mu

lW

ate

rJoj

oba

oil

Flu

con

azo

leM

ice

skin

2002

62

E,

enh

an

cer;

T,

thic

ken

ing

agen

t.



the known skin compatibility.31 Varying thewater-to-oil proportions, systems with differentmicrostructures (o/w and w/o) resulted. In spite ofthe relatively large amount of surfactant (25–44%), an in vivo study on the forearms ofvolunteers under occlusive conditions confirmedthe tolerability of the systems — at least in singledose administration — by transepidermal waterloss (TEWL) and skin blood flow measurements.In contrast, a solution of 5% oleic acid in propyleneglycol, used as comparator besides water andpure propylene glycol, caused erythema and asignificant increase in TEWL. Kreilgaard et al.investigated the potential skin irritancy of amicroemulsion with similar compounds contain-ing an extremely high amount of the surfactantblend (70%). A 20-h treatment of excised rat skinwith the drug-free formulation prior to thepermeation experiment did not perturb the skinbarrier.16

The above-mentioned study of Delgado-Charroet al. dealt with the ability of microemulsions toenhance skin permeation.31 In in vitro studies onhairless mouse skin, the flux of sucrose as a highlyhydrophilic model drug was investigated. Gen-erally, the systems with the higher amount ofwater showed a larger enhancement comparedto rather oil-continuous ones and an aqueoussucrose solution. Finally, the authors presented amodel of multiple factors influencing transdermaldrug delivery. Main parts are different partition-ing processes between microemulsion droplets,continuous phase and skin. Resulting penetrationrepresents the sum of the drug’s relative activitiesin these fractions. Additionally, diffusion of singleconstituents into the skin is possible whichmay reduce the barrier function of the stratumcorneum by diverse interactions and consequentlyimproves penetration properties. The formulationcan also extract some horny layer components anda new physical entity, realizing drug release now,may result by losing the original microemulsionstructure.

Applying similar ingredients, Kreilgaardet al.16 developed microemulsions and investi-gated them concerning their transdermal drugdelivery potential in vitro and in vivo. PrilocaineHCl and lidocaine acted as hydrophilic andlipophilic model drug, respectively. In the firstpart of the study, a correlation between trans-dermal flux of the drugs and their self-diffusioncoefficient in the vehicles as determined by spin-echo NMR was found. Consequently, micro-emulsions do not per se improve permeation.

DOI 10.1002/jps

Ta

ble

4.

Over

vie

wof

Mic

roem

uls

ion

sw

ith

(PE

Gyla

ted

)S

orbit

an

Fatt

yA

cid

Est

ers—

Com

pos

itio

nan

dS

tud

ies

Su

rfact

an

t/C

o-su

rfact

an

tA

qu

eou

sP

hase

Oil

Ph

ase

Ad

dit

ives

Dru

g

InV

itro

Stu

die

s:S

kin

Mod

el/

Mem

bra

ne

InV

ivo

Stu

die

s:S

pec

ies

Yea

rR

ef.

Pol

yso

rbate

Wate

rS

ilic

onfl

uid

Oct

yl

dim

eth

yl

PA

BA

,C

etyl

alc

ohol

Hu

man

cad

aver

skin

,h

air

less

mou

sesk

in

1990

63

Pol

yso

rbate

20/1

-bu

tan

olW

ate

rD

ecan

ol,

dod

ecan

olD

MS

O,

PG

(E);

Carb

opol

934

(T)

Aze

laic

aci

dH

air

less

mou

sesk

in1991

64

Pol

yso

rbate

20/1

-bu

tan

olW

ate

rD

ecan

ol,

dod

ecan

olD

MS

O,

PG

(E);

Carb

opol

934

(T)

Aze

laic

aci

dH

air

less

mou

sesk

in1994

65

Pol

yso

rbate

80/s

orbit

olW

ate

rIP

MP

rop

ran

olol

Art

ifici

al

dou

ble

layer

mem

bra

ne

1998

66

Pol

yso

rbate

80/s

orbit

ol,

Pol

yso

rbate

20/T

ran

scu

tol

Wate

rIP

M,

ben

zyl

alc

ohol

a-T

ocop

her

olP

igsk

in2003

105

Pol

yso

rbate

85/e

than

olW

ate

rIP

MM

elox

icam

Exci

sed

rat

skin

2006

22

Pol

yso

rbate

20/e

than

ol,

Pol

yso

rbate

80/e

than

ol,

Sp

an

80/e

than

ol

Ph

osp

hate

bu

ffer

edsa

lin

eO

leic

aci

dE

stra

dio

lH

um

an

cad

aver

skin

2003

69

Pol

yso

rbate

80/p

rop

yle

ne

gly

col

Wate

rIP

MT

rip

toli

de

Rat

skin

Rat

2003

67

Pol

yso

rbate

80/p

rop

yle

ne

gly

col

Wate

rO

leic

aci

dM

enth

ol(E

)T

rip

toli

de

Mic

esk

inR

abbit

(I)

2004

68

Pol

yso

rbate

80/p

rop

yle

ne

gly

col

Wate

rE

thyl

olea

teX

an

than

gu

m(T

)Ib

up

rofe

nP

orci

ne

skin

2006

20

Pol

yso

rbate

80/p

rop

yle

ne

gly

col

Wate

rIP

MH

yd

roxyet

hyl

cell

ulo

se(T

)D

iffe

ren

tbasi

loi

lsA

gar

dil

uti

onass

ay

2006

70

Pol

yso

rbate

80/g

lyce

rol

Wate

rIP

MT

eatr

eeoi

lB

ovin

eu

dd

ersk

in2005

71

E,

enh

an

cer;

T,

thic

ken

ing

agen

t;I,

irri

tabil

ity

stu

dy.



Ta

ble

5.

Over

vie

wof

Mic

roem

uls

ion

sw

ith

Pol

yso

rbate

sC

ombin

edw

ith

Oth

erN

on-I

onic

Su

rfact

an

ts—

Com

pos

itio

nan

dS

tud

ies

Su

rfact

an

t/C

o-su

rfact

an

tA

qu

eou

sP

hase

Oil

Ph

ase

Ad

dit

ives

Dru

g

InV

itro

Stu

die

s:S

kin

Mod

el/

Mem

bra

ne

InV

ivo

Stu

die

s:S

pec

ies

Yea

rR

ef.

Pol

yso

rbate

80/S

pan

20

Wate

rIP

MO

leic

aci

d,

chol

este

rol

(E)

Dip

hen

hyd

ram

ine

HC

lH

um

an

skin

1997

72

Pol

yso

rbate

80/S

pan

20

Wate

rIP

PG

lyco

lip

id(E

)D

iph

enh

yd

ram

ine

HC

lH

um

an

skin

2005

73

Pol

yso

rbate

85/P

olox

am

er101

Wate

r(u

pta

ke

from

skin

)IP

PD

iffe

ren

tbet

a-b

lock

ers

Rabbit

1991

74

Pol

yso

rbate

85/P

olox

am

er101

Wate

r(u

pta

ke

from

skin

)IP

PB

up

ran

olol

Rabbit

1992

75

Pol

yso

rbate

20/t

au

rod

eoxych

olate

/T

ran

scu

tol

Wate

rIP

M/b

enzy

lalc

ohol

Fel

odip

ine

Hair

less

mou

sesk

in1997

76

Pol

yso

rbate

80/S

pan

80/

1,2

-oct

an

edio

lW

ate

rIP

M8-M

eth

oxsa

len

New

bor

np

igsk

in2000

77

Pol

yso

rbate

80/S

pan

80/

1,2

-oct

an

edio

lW

ate

rIP

MM

eth

otre

xate

Pig

skin

2001

78

Pol

yso

rbate

80/S

pan

20/e

than

olW

ate

rIP

MN

MP

,ol

eyl

alc

ohol

(E)

Lid

ocain

e,L

idoc

ain

eH

Cl,

Est

rad

iol,

Dil

tiaze

mH

Cl

Hu

man

cad

aver

skin

2003

47

Pol

yso

rbate

80/m

ono-

/d

i-gly

ceri

des

Wate

rIP

MC

arb

opol

934

(T)

Cel

ecox

ibE

xci

sed

rat

skin

2005

79

Pol

yso

rbate

40/g

lyce

ryl

cap

ryla

teW

ate

rIP

MK

etop

rofe

nC

ellu

lose

ace

tate

mem

bra

ne

2005

27

Pol

yso

rbate

85/A

OT

Wate

rIP

MC

ycl

osp

orin

eA

Exci

sed

rat

skin

Rabbit

(I)

2006

100

E,

enh

an

cer;

T,

thic

ken

ing

agen

t;I,

irri

tabil

ity

stu

dy.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008 DOI 10.1002/jps


Ta

ble

6.

Over

vie

wof

Ph

osp

hol

ipid

-Base

dM

icro

emu

lsio

ns—

Com

pos

itio

nan

dS

tud

ies

Su

rfact

an

t/C

o-su

rfact

an

tA

qu

eou

sP

hase

Oil

Ph

ase

Ad

dit

ives

Dru

g

InV

itro

Stu

die

s:S

kin

Mod

el/

Mem

bra

ne

InV

ivo

Stu

die

s:S

pec

ies

Yea

rR

ef.

Ph

osp

hol

ipon

90

GW

ate

rD

iclo

fen

ac

die

thyla

min

eD

iclo

fen

ac

die

thyla

min

eS

ilic

onim

pre

gn

ate

dm

embra

ne,

hu

man

stra

tum

corn

eum

1995

32

Soy

bea

nle

cith

inW

ate

rIP

PM

eth

yl

nic

otin

ate

Cel

lulo

sees

ter

mem

bra

ne

bet

wee

nsi

lico

ne

mem

bra

nes

Hu

man

1995

80

Soy

bea

np

hos

ph

ati

dylc

hol

ine

Wate

rIP

PIn

dom

eth

aci

n,

Dic

lofe

nac

Hu

man

skin

1997

81

Lec

ith

in/n

-bu

tan

olW

ate

rM

CT

Ole

icaci

d(E

)K

etop

rofe

nH

um

an

skin

Hu

man

(I)

2002

82

Lec

ith

in/n

-pro

pan

olW

ate

rIP

MT

etra

cain

eH

Cl

Mic

esk

in2006

83

Lec

ith

in/n

-pro

pan

olW

ate

rIP

MT

etra

cain

eH

Cl

Rat

&(I

)2006

84

Ep

icu

ron

200/i

sop

rop

an

olP

hos

ph

ate

bu

ffer

edsa

lin

eIP

MC

arb

opol

940

(T)

Est

rad

iol

Hu

man

cad

aver

skin

2003

69

Ep

icu

ron

200/b

ile

salt

/p

rop

yle

ne

gly

col

Wate

rIP

M/d

ecan

olA

eros

il200

(T);

sod

ium

hex

an

oate

(or

octa

noa

te),

octa

noi

caci

d(C

);ben

zyl

alc

ohol

(P);

asc

orbic

aci

d,

a.

palm

itate

(A)

Ap

omor

ph

ine

HC

lL

ipop

hil

ic/

hyd

rop

hil

icd

ouble

mem

bra

ne,

hair

less

mou

sesk

in

2001

86

Ep

icu

ron

200/s

odiu

mta

uro

chol

ate

/pro

pyle

ne

gly

col

IPM

/dec

an

olA

eros

il200

(T);

octa

noi

caci

d,

sod

ium

octa

noa

te(C

);asc

orbic

aci

d,

a.

palm

itate

(A);

ben

zyl

alc

ohol

(P)

Ap

omor

ph

ine

HC

lH

um

an

2004

87

Lec

ith

in/p

rop

yle

ne

gly

col

Wate

rD

ecan

olB

enzy

lalc

ohol

Met

hot

rexate

Mem

bra

ne

filt

erim

pre

gn

ate

dw

ith

dec

an

ol;

hair

less

mou

sesk

in

1996

88

Ep

icu

ron

200/c

ap

ryly

l-ca

pyl

glu

cosi

de/

eth

an

olor

1,2

-hex

an

edio

l

Ph

osp

hate

bu

ffer

pH

6.4

IPM

Met

hyl

an

det

hyl

este

rsof

am

ino

aci

ds

(C)

Ret

inoi

caci

dS

ilox

an

mem

bra

ne,

pig

skin

2003

89

A,

an

tiox

idan

t;C

,co

un

ter

ion

;E

,en

han

cer;

P,

pre

serv

ati

ve;

T,

thic

ken

ing

agen

t;I,

irri

tabil

ity

stu

dy.



Ta

ble

7.

Over

vie

wof

Mic

roem

uls

ion

sw

ith

Su

gar-

Base

dS

urf

act

an

ts—

Com

pos

itio

nan

dS

tud

ies

Su

rfact

an

t/C

o-su

rfact

an

tA

qu

eou

sP

hase

Oil

Ph

ase

Ad

dit

ives

Dru

gIn

Vit

roS

tud

ies:

Sk

inM

odel

/Mem

bra

ne

InV

ivo

Stu

die

s:S

pec

ies

Yea

rR

ef.

Su

cros

ela

ura

teL

595/

L1695/p

rop

yle

ne

gly

col

Wate

rIP

MH

yd

roco

rtis

one

Hu

man

,(I

)2001

94

Su

cros

ela

ura

teL

595/L

1695/

pro

pyle

ne

gly

col

Wate

rIP

MH

um

an

2003

95

Su

cros

em

ono-

/di-

lau

rate

/m

ediu

mch

ain

alc

ohol

Wate

rO

ctyl

octa

noa

teN

iflu

mic

aci

dH

um

an

1998

96

Dod

ecylg

luco

sid

e/co

cam

ide

pro

pylb

etain

e/2-e

thyl-

1,3

-h

exan

edio

l/(p

hos

ph

ati

dylc

hol

ine)

Wate

rIP

P,

cete

ary

loc

tan

oate

Asc

orbic

aci

d1999

39

I,ir

rita

bil

ity

stu

dy.

Ta

ble

8.

Over

vie

wof

Mic

roem

uls

ion

sw

ith

Ion

icS

urf

act

an

ts—

Com

pos

itio

nan

dS

tud

ies

Su

rfact

an

t/C

o-su

rfact

an

tA

qu

eou

sP

hase

Oil

Ph

ase

Ad

dit

ives

Dru

gIn

Vit

roS

tud

ies:

Sk

inM

odel

/Mem

bra

ne

InV

ivo

Stu

die

s:S

pec

ies

Yea

rR

ef.

AO

TW

ate

rO

ctan

ol3[H

2O

]H

um

an

skin

1988

99

AO

TW

ate

rO

ctan

olG

luco

se,

3[H

2O

]H

um

an

cad

aver

skin

1991

33

AO

TW

ate

rIP

MT

etra

cain

eH

Cl

Rat,

mou

se(I

)2000

97

AO

TW

ate

rIP

M5-F

luor

oura

cil

Hair

less

mou

sesk

inM

ouse

(I)

2005

98

Pol

yso

rbate

85/A

OT

Wate

rIP

MC

ycl

osp

orin

eA

Exci

sed

rat

skin

Rabbit

(I)

2006

100

SD

S/b

uty

lla

ctate

Wate

rIP

M2005

101

N-H

exad

ecyl-

N,N

,N-

trim

eth

yla

mm

oniu

mbro

mid

e(H

TA

B)/

eth

an

ol

Ph

osp

hate

bu

ffer

pH

5.5

IPM

Carb

opol

940

(T)

Pir

oxic

am

(b-C

ycl

odex

trin

)C

ellu

lose

ace

tate

mem

bra

ne

Rat

2001

103

T,

thic

ken

ing

agen

t;I,

irri

tabil

ity

stu

dy.


JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008 DOI 10.1002/jp
s

Ta

ble

9.

Over

vie

wof

Flu

oros

urf

act

an

t-base

dM

icro

emu

lsio

ns—

Com

pos

itio

nan

dS

tud

ies

Su

rfact

an

t/C

o-su

rfact

an

tA

qu

eou

sP

hase

Oil

Ph

ase

Ad

dit

ives

Dru

gIn

Vit

roS

tud

ies:

Sk

inM

odel

/Mem

bra

ne

InV

ivo

Stu

die

s:S

pec

ies

Yea

rR

ef.

Zon

yl1

FS

N-1

00/e

than

olp

enta

dec

afl

uor

ooct

an

oic

aci

d/e

than

ol

Wate

rP

erfl

ubro

nP

lasm

idD

NA

Mou

se2003

104

Zon

yl1

FS

N-1

00/e

than

olW

ate

rP

erfl

ubro

nA

nth

rax

pro

tect

ive

an

tigen

(PA

)p

rote

in-

enco

din

gD

NA

vacc

ine

Mou

se2006

85



Depending on the internal structure, drug diffu-sion and hence transdermal delivery rate can alsobe hampered. These conclusions are supported byfindings of other groups.17,32,33 Additionally to themobility of the drug in the vehicle, the increasedsolubilization capacity of microemulsions wasfound to be a reason for the enhancing potential.It provides a larger concentration gradient of thedrug towards the skin. Similar to Delgado-Charroet al.,31 it was demonstrated that the transdermaldelivery potential of microemulsions is not due toa general enhancing effect of the surfactants andtheir interaction with the stratum corneum.Increased surfactant contents partly resulted inlower fluxes and permeation coefficients.

In a subsequent study, selected microemulsionsystems were compared to commercial products inrats by means of in vivo microdialysis.35 Asignificant benefit of the novel formulations wasobvious due to increased drug flux and in vivopenetration rate for both model drugs. Applying apharmacokinetic model for a reliable estimation ofcutaneous absorption coefficient and lag time frommicrodialysis data, a good correlation was foundbetween the obtained in vivo data and previousin vitro results using Franz-type diffusion cells.Further investigations were carried out in order toestimate dermal drug delivery of lidocaine frommicroemulsions and an o/w emulsion based creamin volunteers, again using minimal invasivemicrodialysis technique as well as determinationof the pharmacodynamic effect.36 Applying theME, the mean absorption coefficient of the localanaesthetic drug was shown to increase aboutthreefold and the lag time entering the dermis wasreduced considerably compared to the conven-tional vehicle. However, the anaesthetic effect didnot diverge significantly between the two for-mulations.

A completely different issue was addressed by aSlovenian and an Italian research group. Amongother carriers, o/w and w/o microemulsions wereexamined for their effect on the stability ofascorbyl palmitate (AP), sodium ascorbyl phos-phate and ascorbic acid.37–39 It turned out thatmicroemulsions are less suitable to protect amolecule from chemical degradation like oxida-tion because their liquid, dynamic structure doesnot allow encapsulating or immersing the drugor at least its unstable part in a less reactiveenvironment.

For practical reasons, microemulsions are oftenthickened, e.g., by Aerosil or xanthan gum. So didJurkovic et al. with the above-mentioned ascorbyl



palmitate containing systems.40 The w/o formula-tion showed a better in vitro release of theantioxidant drug than the o/w one. The latterdelivered AP much better to excised porcine skin,which was concluded from its higher effectivenessin scavenging UV-induced free radicals. Theauthors suggested that the microemulsions ledto a different partitioning behavior of the drugwithin the skin. The o/w formulation was sup-posed to accumulate AP in stratum corneum andepidermis whereas the w/o system delivered itprimarily into deeper skin regions which wereremoved prior to the measurement.

Microemulsions composed of similar ingredi-ents were characterized and tested for the in vitrorelease of the amphiphilic diclofenac diethylamine(DDA) by Djordjevic et al.29,41 Dependent on theinternal structure, different releasing profileswere obtained—linear drug diffusion for dropletlike microemulsions and non-linear profilesfor bicontinuous systems. This was explainedby differences in drug/vehicle interactions andthe water content of the formulations. Thosehaving high water contents showed a higherflux, whereas in the bicontinuous microemul-sions the microstructure seemed to hamper drugdiffusion.

In order to improve transdermal permeation ofdiclofenac sodium salt, three ternary solventsystems, a solution, and a microemulsion weretested in vitro on human skin.42 In addition to thetypical ingredients of the already mentionedmicroemulsions, Escribano et al. incorporated19% Transcutol (diethylene glycol monoethylether) because of its intrinsic enhancing effect.Nonetheless, the colloidal carrier did not provideconvincing permeation parameters. The findingwas attributed to the lower content of enhancerscompared to the other formulations. Even thesolution of the drug in a Transcutol/buffer mixtureshowed slightly better results.

Labrasol combined with ethanol as cosurfactantwas used by a Korean group. They developedoptimized o/w microemulsions for transdermaldelivery of the anti-inflammatory drugs diclofenacdiethylamine and piroxicam as proved in vitrousing rat skin.43,44 Criteria in this process weresolubilization capacity of the oil phase andsurfactant/co-surfactant (S/CoS) ratio. However,ethanol content was in some formulations rela-tively high—up to 50%.

Attempts were made to apply fluoxetine trans-dermally.45 Basic o/w microemulsions containingLabrasol/Transcutol as S/CoS mixture and laur-


oglycol as oily component were varied by theaddition of either an oxazolidinone derivative orethanol as permeation enhancer. Neither of thesecolloidal carriers was able to exceed the high fluxrates obtained by ethanolic solutions.

An interesting study on the relationshipbetween structure and permeation behavior wasconducted by Hua et al.17 Similar to Kreilgaardet al.,16 they determined self diffusion coefficientsof several microemulsion components by a NMR-technique. The systems, essentially comparable tothe ones used for fluoxetine, varied in the S/CoSratio, water and oil content and hence in theirviscosity. Permeation testing took place in vitro onrat and human skin. Remarkable correlationswere found, e.g., between the self diffusioncoefficient of the drug vinpocetine and its flux,viscosity of the formulation and permeability aswell as water diffusivity and permeability.Although vinpocetine was supposed to be locatedin the inner phase, high water contents of the o/wmicroemulsions and therefore lower amounts ofsurfactants favored the permeation. This findingwas explained by the hydration effect of thestratum corneum by water and the increasedthermodynamic activity of the drug in theseformulations due to a poor solubility in water-rich surroundings. Moreover, a low S/CoS ratioexerted a positive influence.

Using a combination of Cremophor RH 40(PEG-40 hydrogenated castor oil) and Transcutol,and oleic acid as lipophilic ingredient for thepreparation of microemulsions for vinpocetine,the authors also found an influence of the internalstructure on the drug delivery potential.46 Oncemore, main parameters were S/CoS amount andratio as well as water content. An irritation test onmouse ear pointed towards skin compatibility ofthe favored vehicle systems in both studies.

Sintov and Shapiro established new microemul-sions for dermal delivery of lidocaine.18 They wereusing a combination of PEG-40 hydrogenatedcastor oil/glyceryl oleate or PEG-40 stearate/glyceryl oleate as surfactant and tetraglycol ascosurfactant. Similar to Lee et al.47 a significantlyhigher flux for the base form of the drug than forthe salt (lidocaine HCl) was found in vitro on ratskin. It turned out that PEG-40 stearate contain-ing formulations are more effective than thosewith PEG-40 hydrogenated castor oil. As principlefactors influencing lidocaine penetration watercontent and S/CoS ratio were identified. Corre-sponding to the results of other groups,33,41 higheramounts of water led to increased drug fluxes.

DOI 10.1002/jps


Furthermore, the superiority of a selected micro-emulsion over a micellar system and a crudeemulsion, which derived from the colloidal carrier,was demonstrated. An enhancing effect of thepure surfactants was ruled out since thismixture showed the worst lidocaine flux. In asecond study, the authors combined the advan-tages of the vehicle microemulsion with physicalenhancement by short-term iontophoresis andsucceeded in the improvement of lidocaine HClskin penetration.48

Sintov et al. also investigated the deliverypotential for diclofenac sodium from the micro-emulsion compared to a commercial formulation,Voltaren Emulgel1.49 In in vitro experimentsusing several types of animal skin the microemul-sion was superior to Voltaren Emulgel1. How-ever, different flux rates were obtained dependenton the skin type. In another approach, bothformulations were administered transdermally torats in vivo. Eightfold higher drug plasma levelswere achieved using the colloidal formulation.Compared to a subcutaneous administrationof diclofenac with fast occurring, but rapidlydecreasing plasma peaks, the microemulsionmaintained constant drug levels for at least 8 h.

Rhee et al. developed an optimized o/w micro-emulsion for ketoprofen.19 The authors carriedout permeation experiments on rat skin andexamined the dependence of oil and surfactantcontent on transdermal transport. With increas-ing surfactant content a significant decrease inpermeation rate was detected which was probablydue to a lower thermodynamic activity at highersurfactant amounts. For certain surfactant con-centrations optimum oil contents were found.Incorporating several terpenes as enhancer, onlylimonene exhibited the wanted effect.

In contrast to the current results, investigationsof Lee et al. did not show different permeationparameters for aceclofenac following applicationof three different o/w microemulsions.50 Theywere prepared with constant ratios betweenS/CoS and oil, and increasing amounts of water(60–80%). In this case, only the addition ofterpenes led to a more or less intense increasein drug flux. However, all the investigatedsystems exhibited significantly higher aceclofenacfluxes than an ethanolic solution.

The development of an effective vehicle fordermal application of a drug with challengingphysicochemical properties was successfully doneby Jahn51 and Wohlrab et al.52 Cyclosporine A(Cs A) is a lipophilic drug with a high molecular


weight of 1202 g �mol�1. In the past, severalconventional topical Cs A-formulations failed inthe treatment of psoriasis compared to systemic orintradermal application. Mostly, an accumulationof the drug in the stratum corneum took place. ButT-cells as target structures are localized mainly inthe upper dermis layer. In ex vivo penetrationstudies on human breast skin, higher concentra-tions of Cs A in viable epidermis and dermisfollowing the application of an o/w cream weredetected, whereas 20–30% of the applied dosefrom the o/w microemulsions reached the accep-tor. This amount of drug is assumed to beresponsible for a pharmacological effect.

Clinical relevance of these colloidal systems wasconfirmed by a clinical trial including patientssuffering from chronic plaque-type psoriasis. A CsA-microemulsion was shown to be comparable totherapeutic standards containing calcipotriol andbethamethasone-17-valerate. The slight advan-tage of a system with dimethyl sulfoxide (DMSO)as enhancer in addition to oleic acid as lipophilicingredient in preceding penetration studies couldnot be established in vivo. Application of thisformulation on chronic-inflammatory skin causedirritant effects and is, therefore, concluded not tobe suited for the treatment of damaged skin.

Information about depth profiling of a lipophilicdye, curcumin, within the stratum corneum follow-ing topical administration of a similar composedmicroemulsion and a cream were obtained inanother in vivo study.53 Penetration of curcuminfrom the colloidal carrier into both the stratumcorneum and the hair follicles was improvedcompared to the cream. Lipid layers and, pre-sumably, the follicles seemed to be the preferredpathways for the dye applied in the microemulsionas indicated by microscopic observations.

Pattarino et al. solubilized eight beta-blockersin an o/w microemulsion to achieve systemiceffects.54 Loading capacity depended on physico-chemical properties of the drugs. Their distribu-tion between the phases of the microemulsion wasevaluated by an apparent partition coefficientand the permeation coefficient through a dialysismembrane. Transdermal absorption throughhairless mouse skin using thickened microemul-sions resulted in pseudo-zero order kinetics for allthe beta-blockers. The authors found a linearcorrelation between the distribution parametersand drug flux, which offered the possibility topredict permeation of similar substances and ledto the conclusion that the flux depends on drugconcentration in the external phase.



Getie et al. used a w/o microemulsion and anamphiphilic cream to examine the penetration ofthe hydrophilic peptide desmopressin by analyz-ing the amount of the model drug in different skinlayers.55 Although there was no difference in thetotal amount penetrated from the two vehicles,the kind of formulation evidently influenced thedeposition of the drug in the skin. Higher amountsof desmopressin were obtained in the upperlayers, mainly in the stratum corneum whenthe cream was applied, whereas a significantlylarger quantity in the deeper skin layers and theacceptor compartment of the Franz diffusion cellsresulted using the microemulsion.

PEGylated Fatty Alcohol-based Microemulsions

PEGylated fatty alcohols (e.g., Brij1), anotherimportant class of non-ionic surfactants, offer theuseful possibility of forming co-surfactant freemicroemulsions.

They were part of microemulsion formulationscreated by Ziegenmeyer and Fuehrer.56 In the1980s, the authors performed in vitro experimentswith skin membranes, comparing the penetrationbehavior of tetracycline HCl incorporated in acream, a gel, and a microemulsion. The systemsconsisting of the same water and dodecanecontent differed only in the amount of decanol.Penetration enhancing activity of the ME wasshown by the distinct increase in diffusion ratecompared to the conventional vehicles.

Malcolmson et al. suggested that importantvariables using an o/w microemulsion as potentialdelivery system are the percentage of dispersedhydrophobic phase and the solubility of the drugin this phase.57 Several poorly water solublemodel steroids were incorporated in an o/wmicroemulsion and micellar solutions. All formu-lations contained Brij1 96 as surfactant. Increas-ing its content, an increased drug load resulted.However, at low surfactant concentrations thesuperior solubilization capacity of the microemul-sions was most obvious compared to the micellarsolution. With stronger lipophilicity of the modelsteroids an increasing solubility mainly in theunpolar core of microemulsions (consisting ofsoybean oil and the hydrocarbon moiety of thesurfactant) and micelles (without oil) wasassumed. The authors concluded that the higherthe solubility of a drug in the soybean oil the morethe microemulsion could improve the drug carry-ing capabilities.


In another study Malcolmson et al. investigatedthe effect varying properties of the oil, i.e., sizeand polarity on the solubilization of testosteronepropionate.21 Again, o/w MEs were prepared ofBrij1 96, water, and the lipophilic phase. Thelatter was represented by a set of different oils(ethyl esters, hydrocarbons, MCT, and soybeanoil). The solubilization capacity for testosteronepropionate also showed an increase as a result ofhigher surfactant contents up to 20% (w/w). Onlysome microemulsions exhibited a significantincrease in drug solubilization over an equivalentmicellar solution. Furthermore, the increase indrug load observed in the MEs was not related tothe drug’s solubility in the pure bulk oil. Thesefindings were explained by individual changes inthe internal structure depending on the molecularvolume of the oil and its interaction with thesurfactant layer.

As already mentioned, the low viscosity ofmicroemulsions might be restricting in clinicaluse. Therefore, thickening agents are sometimesadded. Since these ingredients change not onlythe rheological behavior but might also influencethe skin permeation, the effect of such a gelatingagent, the polysaccharide carrageenan, wasstudied by Valenta and Schultz.58 Addition ofcarrageenan transformed the liquid micro-emulsions into stable semisolid gels exhibitingmeasurable increased thixotropy. Regarding thepermeation, an enhancing effect of carrageenanfor the model drug sodium fluorescein was foundfrom all the thickened formulations compared tothe fluid ones as studied by Franz diffusion cells.The good adhesiveness on the skin due to thepolysaccharide was given as possible explanation.

In vitro permeability coefficients and flux ratesof the anaesthetic drug amethocaine applied in ano/w microemulsion and a commercially availableAmetop1 Gel were compared by Escribano et al.59

They found enhanced permeation parametersusing the lauromacrogol-based colloidal formula-tion where the drug was totally solubilized. Incontrast, amethocaine is partially precipitated inthe gel, which could influence the permeation.

A preclinical trial with the mentioned ametho-caine microemulsion compared with EMLA creamand Ametop1 Gel was carried out by Arevaloet al.60 Firstly, analgesic activity was tested inrats made hyperalgesic or allodynic by carragee-nan-induced inflammation. The microemulsionproduced the fastest antihyperalgesic effect andwas the only topical formulation with an anti-allodynic effect. Drug release from the micro-

DOI 10.1002/jps


emulsion was supposed to be more easily thanfrom gel or cream. The second experiment wasconducted on healthy, selected heat- or touch-hypersensitive rats. Paw withdrawal time from aheat and a mechanical stimulus was used as painindex. Here, all formulations were effective inreducing heat-induced pain in both the treatedand the non-treated paw. However, touch inducedwithdrawal time of both paws increased onlyfollowing application of the microemulsion andamethocaine infiltration. All in all a rapid painrelief due to improved drug penetration using themicro-emulsion was concluded.

Kantarci et al. were interested in the enhance-ment of topical penetration of diclofenac sodiumand its modulation by DMSO and propyleneglycol.61 Two microemulsions were prepared fromsoybean oil, water, and Brij158/Span180 assurfactant blend. Either propanol or isopropylalcohol were added as co-surfactant. The permea-tion behavior was determined by Franz diffusioncells equipped with rabbit skin and analyzed by afactorial randomized design. Different effects ofthe enhancers depending on the formulation wereobvious. Propylene glycol had a stronger influencein the microemulsion prepared with isopropylalcohol, whereas DMSO was superior whenincorporated into the propanol-containing vehicle.Nonetheless, both additives led to an improvedpermeation. Histopathological changes of thetreated skin, mainly swelling, as observed bylight microscopy could not be related to thedifferent microemulsions since they also occurredin the saline treated control samples. Accordingto the literature, they were supposed to be a resultof the exposure of the skin to humidity andtemperature of the Franz cell experiment.

El laithy and El-Shaboury compared Cutinalipogels and microemulsion gels as possiblevehicles for the topical use of the antifungal drugfluconazole.62 Although they focused the differentCutina based lipogels, it turned out that themicroemulsion showed the highest in vitro drugrelease and the best in vitro percutaneousabsorption on mice skin.

In Table 3 Brij1-containing colloidal carriersare listed.

Microemulsions With (PEGylated) SorbitanFatty Acid Esters

The following chapter includes colloidal drugcarrier systems prepared with polysorbates


(Tween1) and Span1, respectively, having eitherno co-surfactant or a short or medium chainalcohol (Tab. 4).

A w/o microemulsion composed of polysorbate,silicon fluid as oil phase, and water was developedby Linn et al. in order to investigate dermaldelivery of the model drugs octyl dimethyl PABAand cetyl alcohol in vitro.63 The authors quantifiedrate and depth of penetration. The results werecompared with two macroemulsions—a creamand a lotion. The microemulsion delivered cetylalcohol into the skin faster and at least twice asmuch as cream and lotion. Interestingly, theabsorption of cetyl alcohol from the macroemul-sions was enhanced if the skin had been pre-treated with the microemulsion prior to productapplication.

Gasco et al. examined the transport of azelaicacid through mice skin from a viscosized micro-emulsion and a gel.64 A lag time was observedwith both systems. It was rather longer for thecolloidal vehicle than for the gel. However, theamount permeated from the microemulsion wassevenfold higher than from the gel. Lag timedisappeared when the enhancer DMSO was addedto the ME and a further increase in drug diffusionwas reached.

Since drugs are able to enter the skin only in adissolved state and microemulsions offer highsolubilization capacity and maximum thermody-namic activity, drug load usually has its limit atsaturation level. In spite of this fact, Pattarinoet al. increased the amount of azelaic acid in themicroemulsion (6.4%, 10%, 15%) to achieve ahigher drug permeation.65 In the system with thelowest content of azelaic acid the drug was totallydissolved. It showed the lowest permeation rate.Enhanced drug diffusion was obtained by thesaturated vehicle including a small amount ofsuspended drug. This trend did not continue byfurther addition of azelaic acid. The presence of alarger amount of suspended drug probablyobstructed the skin.

Ktistis et al. examined the effect of polysorbate80 concentration on the permeation of propranololin different vehicles (emulsion, microemulsionand micellar system) through an artificial doublelayer membrane.66 Basically, emulsion and micro-emulsion were made of propranolol, water, IPM,and polysorbate 80. For each system the apparentpermeation coefficient decreased with increasingsurfactant content. For a specific polysorbate80 concentration, the parameter increased whenthe disperse system changed from emulsion to



microemulsion and further to a dissolved system.The authors argued that a larger interfacial areaof the dispersed phase enables a faster drugtransfer, which is reflected in the increasedtransdermal permeation in the above-mentionedorder. A similar approach was applied by Sintovand Shapiro.18 But in their study, conducted withrat skin, drug fluxes decreased in the order ofME — micellar system — macroemulsion. Sincethey used higher surfactant amounts for themicellar solution, drug flux might have beenhampered due to interfacial interactions.

Mei et al. developed several solid lipid nano-particles (SLNs) and microemulsions as vehiclesfor the anti-inflammatory drug triptolide.67 Drugrelease from both systems was examined using ratskin. The microemulsions demonstrated a higherand constant flux having no burst release likeSLNs. Furthermore, the authors tested thepharmacodynamic effect of triptolide in vivo.Carrageenan-induced rat paw edema could beinhibited by all the formulations. In this case,SLNs were superior to the microemulsions.However, treating edema as a result of a chronicinflammation, the strongest chronic anti-inflam-matory activity was observed applying the w/omicroemulsion.

Based on this work, Chen et al. modifiedmicroemulsion systems for triptolide.68 Physico-chemical properties, transdermal ability of thedrug, and skin irritation were evaluated. Com-pared to a propylene glycol containing aqueoussolution, the microemulsions showed a controlled,sustained and prolonged delivery in the in vitrotest. Moreover, microemulsions with loweramounts of surfactant exhibited increased per-meation and, therefore, were supposed to besuitable for long-term use in contrast to themicroemulsions of Mei et al.67 having a surfactantcontent of 50%. The optimized vehicle containingtriptolide did not show any visible irritation onrabbit skin. Thus, the incorporation of triptolideseemed to protect the skin from the toxic potentialof the drug.

The same group developed microemulsions fortopical delivery of ibuprofen.20 Screening severaloils to find an optimum, ethyl oleate was chosenbecause of the best ibuprofen solubility and itsproperties as effective permeation enhancer.Permeation profiles of several microemulsions,determined by Franz diffusion cells equipped withporcine ear skin, showed zero order kinetics andhigher fluxes than a saturated aqueous ibuprofensolution. According to Peltola et al.,69 it was


explained by the higher concentration gradientof the drug due to the solubilizing capacity ofMEs and the droplet like microstructure of theformulations. Further aim of the work was toobtain microemulsion-based hydrogels that aremore suitable for topical application. Therefore,Chen et al. added xanthan gum and created stableformulations. Unfortunately, no permeation stu-dies were carried out in order to evaluate the in-fluence of the viscosity on the permeation profile.

For cosmetic purpose, Viyoch et al. incorporatedThai basil oils into o/w microemulsions.70 Thein vitro activity against Propionibacterium acneswas tested by means of an agar dilution assay.Application of the pure basil oils resulted in ahigher inhibition compared to the loaded micro-emulsions, which was due to the higher oilcontents when they were used in pure form. Inspite of this, the microemulsions resulted goodinhibition effects and would be an effective carrierin acne skin care. Thickening of the vehiclesby hydroxyethyl cellulose led to slightly lowerantibacterial activities.

Different oils and non-ionic surfactants werescreened by Yuan et al. in order to develop anoptimized microemulsion for meloxicam.22 Sim-ilar to Rhee et al.19 the authors observed anincreased skin permeation rate with decreasedsurfactant content, but also with decreased oilconcentration.

Transdermal administration of estradiol is afrequently used way for increasing systemicbioavailability by avoiding the first pass metabo-lism that occurs after oral treatment. Peltola et al.used various o/w microemulsions to deliver thedrug across human skin in vitro.69 The flux fromthe microemulsions was 200–700-fold higher thanfrom control, whereas the permeation coefficientdecreased 5–18-fold. This result was assumed tobe due to the improved solubility of the lipophilicdrug in the microemulsions and the correspond-ingly increased concentration gradient towardsthe skin. Finally, it was concluded that micro-emulsions might be appropriate vehicles for theabove-mentioned purpose.

For a drug entering the stratum corneum, theintercellular route is known to be the mostimportant. However, the follicular route maybe involved to a greater extent and could bepotentially more useful than previously assumed.Therefore, Biju et al. determined the follicularconcentration of tea tree oil after topical applica-tion of several formulations (e.g., microemulsion,liposomal dispersion, and multiple emulsion)

DOI 10.1002/jps


in vitro using a perfused bovine udder model.71

Interestingly, microemulsion and liposomal for-mulation exhibited about a twofold increasedtransfollicular penetration compared to the multi-ple emulsion. Hence, a kind of follicular targetingis conceivable which can be useful in the treat-ment of acne vulgaris.

Microemulsions With Polysorbates Combined WithOther Non-ionic Surfactants

Polysorbates are also often found in combinationwith other types of non-ionic surfactants. Inves-tigations with those systems are summarizedbelow (Tab. 5).

Schmalfuss et al. described the possibility ofcontrolling the penetration behavior of a hydro-philic model drug (diphenhydramine HCl) bymeans of additives. Ex vivo penetration studieson human skin were performed, analyzing thedrug concentration in different skin layers.72

Administration of a standard w/o microemulsionresulted in an accumulation of diphenhydramineHCl (DPH) in the dermis layer. Addition ofcholesterol as penetration enhancer caused agenerally higher penetration rate and a shift ofthe drug towards the epidermis. Cholesterol wasassumed to loosen the stratum corneum lipidbilayers enabling an increased hydration of thepolar headgroups and, therefore, facilitatingpenetration of DPH along the polar route. Thismechanism is proposed for hydrophilic sub-stances. Unlike this, incorporation of oleic acidas enhancer changed neither penetration rate norconcentration profile, probably because it influ-ences only the lipophilic pathway by altering theceramide chains mobility. In a further study, aglycolipid was found to slightly facilitate DPHpermeation from the microemulsion.73

Kemken et al. tested water-free microemulsionpre-formulations nearly saturated with differentbeta-blockers.74 Pharmacodynamic effects afterdermal administration of the model drugs wereevaluated in vivo using rabbits. The pre-formula-tions were applied on an occlusive patch. Thisshould lead to water uptake from the skin and,hence, to a change of the formulations into watercontaining supersaturated microemulsions. Theobserved high pharmacodynamic responses wereassumed to be due to rising thermodynamicactivity as driving force for enhanced dermaldrug uptake. However, not all effects could bedescribed by dose dependency, influence of drug


concentration, and drug lipophilicity because ofmany interactions occurring between drug, micro-emulsion and skin. The authors also found arelationship between pharmacodynamic effectand solubility as studied with bupranolol indifferent water-free microemulsion bases.75

Increasing amounts of water were added to theformulations and the corresponding solubility wasdetermined. The rise of the pharmacodynamiceffects in vivo correlated with the decline of thesolubility-versus-water content curves in vitro.

The oil phase composition as a further para-meter influencing the skin permeation of o/wmicroemulsions was presented by Trotta et al.76

As lipophilic ingredients, benzyl alcohol or differ-ent ratios of benzyl alcohol and IPM were incor-porated into the systems, keeping the amount ofthe other phases nearly constant. The in vitropermeation of felodipine increased with the ratioof benzyl alcohol/IPM and, therefore, with thesolubility of the drug in the internal phase. Incontrast, permeation rate of the comparator, afelodipine suspension in the apparent externalphase, decreased over time.

Baroli et al. incorporated 8-methoxsalen in o/wand w/o microemulsions made of the samecompounds but combined in different ratios.77

Cutaneous accumulation and percutaneous deliv-ery of the photoactive drug in saturated micro-emulsions were studied using vertical diffusioncells. All microemulsions exhibited an increase inboth parameters compared to a saturated IPMsolution, which was the oil phase of the formula-tions, and a clinical used aqueous solution onnewborn pig skin. Since 8-methoxsalen is effectivein psoriasis therapy, retaining of the drug in theskin is required. The quotient of accumulated todelivered drug could be modified by changing theratio of the ingredients.

In vitro investigations on pig skin regardingtransdermal delivery of methotrexate (MTX) werecarried out by Alvarez-Figueroa and Blanco-Mendez.78 Topical application of this drug isproblematic because of its hydrophilic character,the high molecular weight, and the high dissocia-tion degree at physiological pH. The authors foundincorporation of MTX in microemulsions, mainlyof the o/w type, to be more effective compared tosimple solutions. Iontophoretic delivery fromsolutions exceeded the ME results, probably dueto the lower solubility of MTX in microemulsionsthan in aqueous solutions.

Transdermal transport of hydrophilic andlipophilic drugs such as lidocaine base, lidocaine



HCl, estradiol, and diltiazem HCl from w/o ando/w microemulsions composed of IPM, polysorbate80, water, ethanol as well as n-methyl pyrrolidone(NMP) and oleyl alcohol as enhancer was studiedby Lee et al.47 For all the drugs a considerableimproved transport by microemulsions com-pared to the solution in either water or IPMwas observed, with a significantly better fluxfrom the o/w system than from the w/o. Theenhancement from the o/w formulation was 17-fold for lidocaine base, 30-fold for lidocaine HCl,58-fold for estradiol, and 520-fold for diltiazemHCl. Moreover, the simultaneous delivery of botha hydrophilic and a hydrophobic drug from themicroemulsion was indistinguishable from eitherdrug alone. The results suggest that transportfrom the aqueous phase is the most importantfactor for both kinds of drugs whereas the oilphase serves as a drug depot. This could be con-firmed by removing surfactant and oil from thesystem. The flux from the remaining water phasecomponents was comparable to that from the o/wME. It was concluded that presence of NMPincreases the partition of the lipophilic drugs intothe water phase, hence making them available forthe transport across the skin.

Subramanian et al. developed a stable micro-emulsion system for celecoxib and found out thatthe droplet size of the vehicles increased with drugaddition.79 Caused by a higher amount of mono-and di-glycerides as co-surfactant, droplet sizeand viscosity increased. These changes wereaccompanied by lower drug permeation ratesthrough rat skin. Comparing the permeationobtained with microemulsions, a viscosized MEand a cream, the microemulsions were superior tothe other formulations.

Podlogar et al. identified different types andstructures of microemulsions along a dilution linewithin the phase diagram by a combination ofexperimental methods.27 Addition of water to asurfactant/oil mixture led to changes in theinternal structure from w/o to bicontinuous andfurther to o/w microemulsions. Gel-like structureswere formed at a water content of more than 45%.Ketoprofen was incorporated into selected for-mulations. Its release was tested by Franz diffu-sion cells with an artificial hydrophilic membrane.Although release rates for all systems followed azero order kinetic, different microstructurescaused different profiles. The slowest releasewas observed from the w/o microemulsion. In thisregion, strong interactions between ketoprofen,oil and the surfactants were assumed. O/w


systems showed higher fluxes and were thesuperior structure in this work.

Phospholipid-based Microemulsions

Natural lecithin is one of the most promising anduseful pharmaceutical agents in topical formula-tions. It is non-toxic even in high concentrationsand does not lead to skin irritation. Furthermore,it is able to increase skin permeation.80 Due totheir amphiphilic lipid structure, phospholipidsare able to form liposomes, but also microemul-sions—either on their own in narrow compositionranges or with co-surfactants like short chainalcohols. During the past several years, phospho-lipids have been used in different approaches asamphiphile for dermal drug delivery by micro-emulsions (Tab. 6).

A meaningful study was conducted by Kriwetand Mueller-Goymann.32 They investigated therelationship between the colloidal structure ofternary phospholipid-containing formulationsand kinetics of drug release as well as stratumcorneum permeability. The amphiphilic moleculediclofenac diethylamine was chosen as model drugand represented also the oil phase of the systems.Depending on the ratio of the components, variouscolloidal structures from liposomal dispersions viamicroemulsions to lamellar liquid crystals couldbe generated. Drug release through a silicon-impregnated membrane strongly depended onthe vehicle’s microstructure—Just as stratumcorneum permeation. Whereas in liposomesand lamellar phases strongly bound drug andphospholipids hamper the interaction with thehorny layer, incorporation into microemulsionsenhances permeability.

Different colloidal structures were also com-pared by Bonina et al., who examined the percu-taneous absorption of methyl nicotinate.80 Thedrug elicits a distinctive erythema and generatesa vasodilatory effect in vivo. The correspondingmeasurements showed that liposomes could infact lead to a good skin partitioning of bioactivecompounds, improving their topical activity,compared to conventional formulations likecreams and gels. The lecithin microemulsion gelshowed an activity profile characterized by astrong initial vasodilatory response followed by arapid decline. The fast passage of the drug seemedto be caused by a disruption of the stratumcorneum, but the microemulsion could not furtherpenetrate in the skin.

DOI 10.1002/jps


Dreher et al.81 investigated different micro-emulsion gels containing indomethacin and diclo-fenac, respectively, dissolved in lecithin, IPP andwater with saturated solutions of the drugs, eachdissolved in the pure oil. In permeation studies,higher drug fluxes were obtained by the MEgels compared to the solution in IPP. However,permeability coefficients acted vice versa. Thiswas assumed to be due to the higher solubilizationcapacity of the microemulsion on the one hand,and an unfavorable partitioning of the drugsbetween ME and stratum corneum compared toIPP solution/stratum corneum on the other hand.The role of lecithin as enhancer could not finallybe clarified by interaction studies on humanstratum corneum by means of Fourier TransformInfrared spectroscopy and DSC. Low-temperaturescanning electron microscopy showed in some firstresults a change in the ultrastructure of theintercellular lipid regions after incubation withlecithin microemulsion gel.

Good human skin tolerability of a lecithin-basedo/w microemulsion compared to conventionalvehicles (o/w and w/o cream, and gel) was observedby Paolino et al.82 It could be demonstrated thatincorporation of 1% of the enhancer oleic acidinto the microemulsion was significantly lessirritant than an oleic acid dispersion of the sameconcentration. This effect was supposed to be dueto the incorporation of oleic acid into the colloidalmicrostructure and the impossibility to stronglyperturb the stratum corneum lipids. For the samereason, the oleic acid containing microemulsionsexhibited poor additional enhancing activity onskin permeation of the model drug ketoprofen, butboth vehicles clearly improved transdermal deliv-ery with respect to the conventional vehicles.

Changez et al. did not only compare transder-mal delivery potential of microemulsions and anaqueous solution.83 They also studied the effect ofthe composition of microemulsions on barrierproperties of the skin. W/o and o/w microemul-sions were made of tetracaine HCl (THCl),lecithin, n-propanol, IPM, and water. Both typesof colloidal formulations showed an increasedTHCl flux by elevating the water concentration.Additionally, amount and ratio of S/CoS influ-enced steady state flux, probably by swelling andextraction of stratum corneum lipids. From DSC,TEM and confocal laser scanning microscopy(CLSM) studies, the authors suggested that thecolloidal formulations generate a hydration gra-dient across the skin accompanied by an increasedintercellular space in epidermis and dermis


facilitating drug uptake. CLSM results showedthat sweat glands and hair follicles also providethe path for transdermal permeation of micro-emulsions. Further conducted in vivo studies onrats demonstrated increased local analgesicresponses of THCl by elevating drug concentra-tion and water content.84 The advantage of o/wmicroemulsions was explained by the hydrophilicnature of THCl which provides a better avail-ability in the system. Histopathological investiga-tions and biochemical findings indicated that thedeveloped vehicles are safe for transdermal drugdelivery.

Peira et al. evaluated the capability of theinternal phase of w/o microemulsions to act asdrug reservoir.86 Among other ingredients, thecolloidal systems contained apomorphine HCl,Epicuron 200 (soybean lecithin) and bile salts.Antioxidants were added to avoid the oxidation ofthe drug. The lipophilicity of apomorphine wasincreased by forming ion pairs with octanoic acid,which was found to be the main reason for theobtained facilitated drug transport through hair-less mouse skin in vitro. It was concluded, thatapomorphine concentration in plasma followingtransdermal administration might reach a ther-apeutic effect. Later on, one of Peira’s microemul-sions was employed within a clinical trial on thetreatment of Parkinson’s disease.87 The pharma-cokinetic analysis of human blood samples showedthat apomorphine HCl was indeed absorbed by thetransdermal route. The formulation was able toprovide a sustained drug release and therapeuticplasma levels for a prolonged period of time.However, it needed 1 h to reach therapeuticconcentrations.

The concept of ion pairing in order to increasedrug lipophilicity was also successfully used byTrotta et al.88 They studied the permeation ofmethotrexate in vitro from w/o microemulsions inabsence and presence of counter ions at differentpH values.

Topical delivery of retinoic acid ion paired withamino esters was also investigated.89 Permeationbehavior through a siloxan membrane dependedon the type of microemulsion. Systems having thedrug pure or formed as ion pair in the continuousphase, exhibited higher permeability coefficientsthan those showing a favored drug partitioningtowards the internal phase. In diffusion experi-ments on pig skin, very low flux rates resultedfollowing administration of microemulsions com-pared to aqueous solutions. However, since thedrug is used in the treatment of acne vulgaris, the



observed retinoic acid accumulation in pig skinusing o/w microemulsions indicated optimizeddrug targeting without increased systemic sideeffects.

Microemulsions with Sugar-Based Surfactants

In the 1990s a promising class of non-ionicsurfactants came up in the development ofcolloidal carriers. Based on the renewable rawmaterials starch and natural oils, alkyl polyglyco-sides (APGs) show excellent environmental andskin compatibility.90,91 In contrast to the use ofethoxylated fatty alcohols, APG-based microemul-sions are temperature-stable. Their phase beha-vior can only be varied by the combination with asuitable co-surfactant and the oil to waterratio.92,93 Qualitative composition as well ascorresponding in vitro and in vivo studies arepresented in Table 7.

Glycolipids are able to penetrate the stratumcorneum and have a slightly enhancing effect onthe permeation of hydrophilic drugs as studiedwith diphenhydramine HCl which was incor-porated into a w/o microemulsion.73 It wasassumed that the glycolipid increases the spacebetween the polar headgroups of the stratumcorneum lipids, thus, enabling an increasedhydration.

Besides APGs, sucrose esters are in use, e.g.,in studies of Lehmann et al.94 They tested ano/w and a w/o microemulsion for their suitabilityin dermatological use. In hen’s egg test onchorioallantoic membrane (HET-CAM) bothvehicles were classified as non-irritant. Butfrom an in vivo skin blanching test on humansarose, that despite the enhanced hydrocortisonepenetration from the colloidal systems, neithermicroemulsion conferred benefit in this therapybecause irritant effects of the formulationsoutbalanced the improved penetration of theanti-irritant drug. The authors concluded thatuse of microemulsions as drug delivery systemsis more valuable when irritant effects arenegligible. A study of Gloor et al. gave anexample for such a case.95 They demonstratedthat the above mentioned drug-free microemul-sions exhibit a keratolytic activity and are,therefore, suitable for elimination or preventionof plantar desquamative and hyperkeratoticskin changes.

Sucrose fatty acid ester-stabilized bicontinu-ous microemulsions were applied as carriersystem for niflumic acid by Bolzinger et al.96


The authors also employed a pharmacodynamicassessment and found that the effect of thenovel formulation, saturated with the drug (1%),was as efficient as a commercially available 3%o/w emulsion. The accumulation of niflumic acidin the interfacial film of the microemulsionwas considered to be responsible for the occur-ring lag time, which could control the drugrelease.

Microemulsions With Ionic Surfactants

AOT (sodium bis(2-ethyl hexyl)sulfosuccinate) is afrequently used anionic surfactant that formsstable w/o microemulsions without the addition ofcosurfactants. In the literature, it can be foundcombined with IPM or octanol and water as acarrier for hydrophilic drugs. Several formula-tions were classified to be safe for dermalapplication.97,98

Investigating the transdermal permeation ofglucose as hydrophilic model drug from micro-emulsions through human cadaver skin, Osborneet al. found a relationship between drug flux andwater content in the formulation.33 Presence offree water was shown to be essential for glucosetransport. At lower water contents, all moleculesare used for hydrating the surfactant headgroups,thus being not available for partitioning into theskin.

Already in a previous study, the authorshypothesized that a hydrophilic drug would notbe available for percutaneous transport unlesswater from the microemulsion is freely trans-ported into the skin.99

Changez and Varshney used AOT microemul-sions for topical application of the local anaes-thetic drug tetracaine HCl.97 Local analgesicresponse as a measure for the therapeuticpotential was evaluated on rats. The optimumformulation exhibited an eightfold enhancementof this parameter compared to an aqueous solutionof the drug. It was assumed that AOT is able tosoften the stratum corneum, but it did not alterthe structure as observed microscopically. More-over, application of the microemulsions did notinduce oxidative stress in mice skin.

In further experiments, the water-soluble drug5-fluorouracil was used.98 Permeation studies ondepilated mouse skin resulted in water and AOTconcentration as enhancing factors. Deeperinsides into the effect of the ME on the stratumcorneum structure were given by Fourier Trans-

DOI 10.1002/jps


form Infrared-Attenuated Total Reflectance Spec-troscopy (FTIR-ATR) examinations of untreatedand treated skin. The frequency shifts of specificIR-bands provided useful information. Main find-ings were the increased disordering of thehydrocarbon chains of the stratum corneum lipidsas well as the increased hydration of the skin byboth, water and AOT, which explained theenhancing properties of the tested formulations.

Liu et al. formulated a bicontinuous microemul-sion system for transdermal delivery of theoligopeptide cyclosporine A.97,100 Subsequentlyto the physicochemical characterization, in vitropermeation studies through rat skin were con-ducted and showed an up to 10 times increasedtransdermal delivery of the drug by the micro-emulsion compared to a suspension. The extent ofthe enhancing effect depended on water contentand microstructure of the formulations.

Another anionic, sodium dodecyl sulfate con-taining microemulsion system was investigatedby Park et al.101 Their objective was to introducebutyl lactate as a new skin compatible co-surfactant. However, up to now there have notbeen conducted any dermal drug delivery studies.

Cationic microemulsions containing piroxicamand a piroxicam-ß-cyclodextrin inclusion complex,respectively, were developed by Dalmoraet al.102,103 These systems, exhibiting a remark-ably increased solubility of the drug compared tosimple solutions, demonstrated in in vitro drugrelease studies a reservoir effect for piroxicam.The following in vivo assessment of anti-inflam-matory activity on rats resulted in significantlyinhibited inflammatory reactions after topicalapplication relative to control and an improvedeffect of the microemulsions after subcutaneousadministration compared to a buffered solution ofthe drug. Moreover, a prolonged pharmacologicalactivity after subcutaneous application confirmedthe potential of modifying dermal drug delivery byME systems.

An overview of the microemulsions underinvestigation is given in Table 8.

Fluorosurfactant-based Microemulsions

Cui et al. are working in the highly challengingfield of topical immunization. As carrier systemsfor plasmid DNA they used w/o microemul-sions.104 A non-ionic fluorosurfactant was chosenand combined with perflubron, which is safe forpharmaceutical use as well as chemically and


biologically inert. A stable ethanol-in-fluorocar-bon formulation was selected for in vivo studies inmice (Tab. 9). Compared to ‘‘naked’’ plasmid DNAin saline or ethanol, the novel system led tosignificant enhancements in immune responseagainst the encoded model antigen. For example,a 45-fold and over 1000-fold increase in thespecific serum IgG and IgA titers, respectively,was detected.

The same vehicle was used to incorporate ananthrax protective antigen (PA) protein-encodingplasmid (pGPA).85 The anti-PA immuneresponses following topical application on micewere measured. In contrast to pGPA alone, pGPAapplied in the microemulsion induced a significantlevel of anti-PA IgG in the serum of the mice. Thistiter was still lower than the one reached bysubcutaneous injection of the current anthraxvaccine in the United States. However, themicroemulsion was successfully used for topicalboosting of mice primed with PA protein, whichoffers a simplified dosing schedule.

FACTORS INFLUENCING THE PENETRATIONBEHAVIOR OF MICROEMULSIONS

Although the drug delivery potential of micro-emulsions is widely accepted, up to now itsmechanism is not yet well understood. Most likelyit is attributable to a variety of factors dependingon the composition and the resulting microstruc-ture of the formulation.

Influence of surfactant content on drug fluxhas been studied several times. It turned outthat the more surfactant is not the bet-ter.16,18,19,22,31,46,66,68 Indeed within formulationspecific limits, an inverse correlation arises. Someauthors suggested that the thermodynamic activ-ity of the drugs got lower due to increasingsurfactant amounts.22,68 Therefore, a generalenhancement by alteration of the stratum cor-neum barrier properties due to this class ofexcipients 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 ofnon-ionic surfactants combined with glycols orTranscutol as co-surfactant, higher S/CoS ratiosare beneficial.18,20,46 However, higher drug fluxeswere obtained at lower S/CoS values.17,18

Another important factor concerning drugdelivery potential is the amount of water in amicroemulsion. Osborne et al. found a correlation



to the glucose flux in their permeation studies.Presence of free water was shown to be essentialfor glucose transport into skin. At lower watercontents, all molecules are used for hydrating thesurfactant headgroups, thus being not availablefor partitioning into the skin.33 Sintov andShapiro reported on similar effects for lidocaineflux18 as well as Changez et al. which were usinglecithin-containing microemulsions for dermaldelivery of tetracaine HCl.83 Also drug releaseis a function of water content. Djordjevic et al.found drug fluxes proportionally increasing to theamount of water in their microemulsions.41

In general, continuously and spontaneouslyfluctuating interfaces of microemulsions enablehigh drug mobility and might enhance the drugdiffusion process.31 Yet, NMR-studies of Kreil-gaard et al.16 and Hua et al.17 on dynamics withinthe colloidal formulations could give an explana-tion that comprises all the above mentioned facts.Both groups found a correlation between drugmobility resulting from a certain microstructureand drug flux. An optimum extent of hydration ofthe surfactant headgroups seems to be essentialwhere enough free water is additionally present toenable fast drug diffusion. The necessary amountof water is specific for each quaternary system andprobably depends on the kind of surfactant and co-surfactant, mainly size and water binding capa-city of the polar moiety. This principle seems toconcern not only hydrophilic drugs as describedby Osborne et al.33 Permeability of lipophilicdrugs is also correlated to water diffusivity.36

In this context it was suggested that thehydration of the stratum corneum by the vehicleplays a role.

Consequently, full drug diffusivity potential ofmicroemulsions can also be hampered by theircomposition and microstructure, e.g., due toadsorption of drug molecules to the surfactant,encapsulation or unfavorable partitioning of thedrug between formulation and skin.17,32,33 Theprobability is obviously higher in the case ofamphiphilic drugs and when high amounts ofsurfactants are employed. O/w type microemul-sions were convincing in most studies, even ifhydrophilic drugs were applied.

Incidentally, Hua et al. used two types of skinfor their permeation studies and obtained a linearrelationship between the mentioned parametersacross human skin as well as across rat skin. Thisis an important information considering that a lotof permeation studies throughout the literatureare conducted with other than human skin.


However, flux through rat skin was about fivetimes higher than through human one.

Besides the mobility parameters, the highsolubilization capacity of microemulsions forhydrophilic and lipophilic substances is an impor-tant feature. If maximum thermodynamic activityis used by incorporating the drug at saturationlevel or even supersaturated, it leads to a largeconcentration gradient towards the skin which isa driving force for drug transport.69,74–76

Concerning the pathway of a drug entering thestratum corneum, the intercellular route isaccepted as the preferred one. However, aparticipation of follicles and sweat glands has tobe taken into consideration as indicated by severalauthors.53,71,83 This finding might be attributableto the low surface tension that ensures an excel-lent contact to the skin, where the good spreadingis additionally supported by the low viscosity.Hence, the formulation is capable to enter the skineasily.

Interestingly, even pretreatment with a micro-emulsion can increase the percutaneous absorp-tion of a subsequently applied drug (cetyl alcohol)included in a cream and a lotion as presented byLinn et al.63

More or less successful in further increasingpermeation rate was the incorporation of pene-tration enhancer like oleic acid, DMSO, choles-terol, and terpenes. Remarkably, using ahydrophilic drug, it has been shown that theenhancer effect of the constituents depends alsoon the drug’s preferred route through the stratumcorneum.72

In summary, a number of influencing factors onthe penetration behavior of microemulsions couldbe found. A strong relationship between micro-structure and drug delivery potential exists.Nevertheless, more systematic research work isrequired for a detailed clarification of the pene-tration mechanism.

CURRENT FIELDS OF TOPICALADMINISTRATION AND FUTURE PROSPECTS

Since skin is the body’s largest organ, it does notonly fulfill physiological functions but is also animportant target site for the administration ofdrugs. Cutaneous drug delivery is gaining groundbecause it possesses advantages in relation toother administration routes in several aspects. Asit is well known, the main challenge is to overcomethe barrier function of the stratum corneum,

DOI 10.1002/jps


which hampers the achievement of therapeuticdrug levels in either skin or systemic circulation.Due to their penetration enhancing properties,microemulsions can find application in a numberof clinical areas as summarized below.

Site-specific treatment of dermatological dis-eases is a classical field of topical administration.For example, several anti-acne drugs were incor-porated into colloidal carriers, e.g., antimicrobialagents like basil oil,70 tea tree oil,71 retinoic acid,89

and azelaic acid64,65 as well as antibiotics (tetra-cycline HCl56). Since acne concerns sebaceousglands, the proposed follicular uptake by micro-emulsions might be advantageous.

Dermal delivery of antioxidants plays a role inprophylaxis and treatment of ultraviolet-induceddamage of the skin like photoaging and photo-carcinogenesis. They are related to increasedlevels of free radicals. An effective skin protectionby ascorbyl palmitate, incorporated into a micro-emulsion, has been demonstrated,40 but also a-tocopherol is in use.105

Application of microemulsions for local anaes-thetics like lidocaine and prilocaine appears tobe useful as well since a fast penetration and,hence, a fast occurring anaesthetic effect can bereached. Besides their use in minimal invasiveoperations, performing of other painful treat-ments might be more comfortable, especially inpaediatrics. Several investigations dealt with thistopic.18,35,36,60,83,84

One of the most significant skin diseases ispsoriasis vulgaris. Immunosuppressives likemethotrexate (MTX) and the oligopeptide cyclos-porine A (Cs A) belong to the standard treatmentand are usually applied orally or parenterally. Butsystemic administration is accompanied by severeside effects such as hepatotoxicity and nephro-toxicity, respectively. Physicochemical propertiesof both high molecular weight drugs do notprivilege them for transdermal delivery. MTX ishighly dissociated at physiological pH whereas inthe case of Cs A its lipophilicity leads to an accu-mulation in the stratum corneum with slow trans-port into deeper skin layers. However, a number ofencouraging in vitro and in vivo studies on theenhanced dermal drug uptake by microemulsionsystems have been published.51,52,78,88,100,106

Investigations were carried out aiming thedevelopment of optimized formulations for non-steroidal anti-inflammatory drugs. Percutaneouspenetration by microemulsions is appropriatesince these drugs are mostly sparingly soluble,induce gastrointestinal side effects and are liable


to first pass metabolism. Hence, for patientssuffering from tendinopathy, rheumatoid arthri-tis or osteoarthritis transdermal delivery might bean option.20,79,82

Topical administration of drugs can providetherapeutic plasma levels, i.e., transdermalabsorption. Significant advantages are theincrease in bioavailability by avoiding first passmetabolism and minimization of adverse effectssuch as gastrointestinal ones. Microemulsionsoffer a high solubilization capacity even for poorlysoluble drugs and combined with their permeationenhancing effect high flux rates can be obtained.For example for steroids like estradiol69 andtestosterone,21,57 but also for beta-blockers54,74,75

they are conceivable vehicles. In vitro experi-ments as well as a clinical trial concerning the useof topically applied apomorphine in the treatmentof Parkinson’s disease were successfully per-formed.86,87

A growing field in therapeutics is the applica-tion of peptides or peptide-like drugs. Because oftheir low oral bioavailability caused by extensiveproteolytic degradation in the gastrointestinaltract as well as weak permeability due to highmolecular weight and hydrophilic character theyare mostly applied parenterally. Therefore, alter-native administration routes have to be found.First attempts to incorporate peptides into micro-emulsion were made by Getie et al. who useddesmopressin as model drug.55

Topical genetic immunization using fluorosur-factant-based microemulsions is a highly innova-tive approach. In contrast to intramuscularinjection, the standard method, immunizationthrough intact skin seems to be ideal because theskin represents the body’s front line for immuno-survelliance.102 There is a need for optimizedvehicles, which can improve the potency of DNAvaccines since it was very limited and variable byintramuscular injection as studied on primatesand humans.107

However, topical application of microemulsionsmight not be convenient for all patients because ofthe low viscosity. Therefore, in several studiesthickening agents like carrageenan,58 carbo-pols54,69,79 or Aerosil40 were added. Anotherpossibility was given by Sintov and Shapiro.18

They created patches from pure microemulsionsby adding a polymer. Compared to a commercialproduct, this adapted formulation showedincreased drug fluxes similar to the fluid micro-emulsion and improved the drug disposition intothe dermis layer.



In summary, the utilization of microemulsionsystems offers a number of advantages. How-ever, they did not find broad use in practice up tonow. Main point of criticism is the necessity oflarge amounts of surfactants to form micro-emulsions. Throughout the literature this pro-blem occurs as most microemulsions contain<40% of surfactants. Therefore, a successfulextended use of these colloidal carrier systemsin the future depends on the choice of well-tolerated surfactants and the restriction of theiramounts.

Considering the potential in enhanced druguptake and facing the limitations their uniqueproperties make microemulsions a promisingvehicle for dermal and transdermal drug delivery.

REFERENCES

1. Moulik SP, Paul BK. 1998. Structure, dynamicsand transport properties of microemulsions. AdvColloid Interface Sci 78:99–195.

2. Danielsson I, Lindman B. 1981. The definition ofmicroemulsion. Colloids Surf 3:391–392.

3. Eccleston GM. 1994. Microemulsions. In: Swar-brick J, Boylan JC, editors. Encyclopedia of phar-maceutical technology. Vol. 9. New York: MarcelDekker.

4. Lawrence MJ, Rees GD. 2000. Microemulsion-based media as novel drug delivery systems. AdvDrug Del Rev 45:89–121.

5. Attwood D. 1994. Microemulsions. In: Kreuter J,editor. Colloidal drug delivery systems, Vol. 66.Drugs and the pharmaceutical sciences. NewYork: Marcel Dekker.

6. De Gennes PG, Taupin C. 1982. Microemulsionsand the flexibility of oil/water interfaces. J PhysChem 86:2294–2304.

7. Lam AC, Schechter RS. 1987. The theory of diffu-sion in microemulsion. J Colloid Interface Sci 120:56–63.

8. Ktistis G. 1990. A viscosity study on oil-in-watermicroemulsions. Int J Pharm 61:213–218.

9. Hoar TP, Schulman JH. 1943. Transparent water-in-oil dispersions: The oleopathic hydro-micelle.Nature 152:102–103.

10. Schulman JH, Stoeckenius W, Price LM. 1959.Mechanism of formation and structure of microemulsions by electron microscopy. J Phys Chem63:1677–1680.

11. Alany RG, Tucker IG, Davies NM, Rades T. 2001.Characterizing colloidal structures of pseudotern-ary phase diagrams formed by oil/water/amphi-phile systems. Drug Dev Ind Pharm 27:31–38.


12. Jahn W, Strey R. 1988. Microstructure of micro-emulsions by freeze fracture electron microscopy.J Phys Chem 92:2294–2301.

13. Kumar P, Mittal KL, editors. 1999. Handbook ofmicroemulsion science and technology. New York:Marcel Dekker.

14. Mrestani Y, Neubert RH, Krause A. 1998. Parti-tion behaviour of drugs in microemulsions mea-sured by electrokinetic chromatography. PharmRes 15:799–801.

15. Subramanian N, Ghosal SK, Acharya A, MoulikSP. 2005. Formulation and physicochemical char-acterization of microemulsion system using iso-propyl myristate, medium-chain glyceride,polysorbate 80 and water. Chem Pharm Bull 53:1530–1535.

16. Kreilgaard M, Pedersen EJ, Jaroszewski JW.2000. NMR characterisation and transdermaldrug delivery potential of microemulsion systems.J Control Rel 69:421–433.

17. Hua L, Weisan P, Jiayu L, Ying Z. 2004. Prepara-tion, evaluation, and NMR characterization ofvinpocetine microemulsion for transdermal deliv-ery. Drug Dev Ind Pharm 30:657–666.

18. Sintov AC, Shapiro L. 2004. New microemulsionvehicle facilitates percutaneous penetrationin vitro and cutaneous drug bioavailabilityin vivo. J Control Rel 95:173–183.

19. Rhee YS, Choi JG, Park ES, Chi SC. 2001. Trans-dermal delivery of ketoprofen using microemul-sions. Int J Pharm 228:161–170.

20. Chen H, Chang X, Du D, Li J, Xu H, Yang X. 2006.Microemulsion-based hydrogel formulation ofibuprofen for topical delivery. Int J Pharm 315:52–58.

21. Malcolmson C, Satra C, Kantaria S, Sidhu A,Lawrence MJ. 1998. Effect of oil on the level ofsolubilization of testosterone propionate into non-ionic oil-in-water microemulsions. J Pharm Sci87:109–116.

22. Yuan Y, Li S-M, Mo F-K, Zhong D-F. 2006. Inves-tigation of microemulsion system for transdermaldelivery of meloxicam. Int J Pharm 321:117–123.

23. Shukla A, Janich M, Jahn K, Krause A, KiselevMA, Neubert RHH. 2002. Investigation of phar-maceutical oil/water microemulsions by small-angle scattering. Pharm Res 19:881–886.

24. Attwood D, Ktistis G. 1989. A light scatteringstudy on oil-in-water microemulsions. Int J Pharm52:165–171.

25. Saint Ruth H, Attwood D, Ktistis G, Taylor CJ.1995. Phase studies and particle size analysis ofoil-in-water phospholipid microemulsions. Int JPharm 116:253–261.

26. Shukla A, Krause A, Neubert RHH. 2003. Micro-emulsions as colloidal vehicle systems for dermaldrug delivery. Part IV: Investigation of microemul-

DOI 10.1002/jps


sion systems based on a eutectic mixture of lido-caine and prilocaine as the colloidal phase bydynamic light scattering. J Pharm Pharmacol55:741–748.

27. Podlogar F, Bester Rogac M, Gasperlin M.2005. The effect of internal structure of selectedwater-Tween 40-Imwitor 308-IPM microemul-sions on ketoprofene release. Int J Pharm 302:68–77.

28. Podlogar F, Gasperlin M, Tomsic M, Jamnik A,Rogac MB. 2004. Structural characterisation ofwater-Tween 40/Imwitor 308-isopropyl myristatemicroemulsions using different experimentalmethods. Int J Pharm 276:115–128.

29. Djordjevic L, Primorac M, Stupar M, Krajisnik D.2004. Characterization of caprylocaproyl macro-golglycerides based microemulsion drug deliveryvehicles for an amphiphilic drug. Int J Pharm271:11–19.

30. Subramanian N, Ghosal SK, Acharya A, MoulikSP. 2005. Formulation and physicochemicalcharacterization of microemulsion system usingisopropyl myristate, medium-chain glyceride,polysorbate 80 and water. Chem Pharm Bull 53:1530–1535.

31. Delgado-Charro MB, Iglesias-Vilas G, Blanco-Mendez J, Lopez-Quintela MA, Marty JP, GuyRH. 1997. Delivery of a hydrophilic solute throughthe skin from novel microemulsion systems. Eur JPharm Biopharm 43:37–42.

32. Kriwet K, Mueller-Goymann CC. 1995. Diclofenacrelease from phospholipid drug systems and per-meation through excised human stratum cor-neum. Int J Pharm 125:231–242.

33. Osborne DW, Ward AJ, O’Neill KJ. 1991. Micro-emulsions as topical drug delivery vehicles: In-vitro transdermal studies of a model hydrophilicdrug. J Pharm Pharmacol 43:450–454.

34. Kreilgaard M. 2002. Influence of microemulsionson cutaneous drug delivery. Adv Drug Del Rev 54:(Suppl 1) S77–98.

35. Kreilgaard M. 2001. Dermal pharmacokinetics ofmicroemulsion formulations determined by in vivomicrodialysis. Pharm Res 18:367–373.

36. Kreilgaard M, Kemme MJ, Burggraaf J, Schoe-maker RC, Cohen AF. 2001. Influence of a micro-emulsion vehicle on cutaneous bioequivalence of alipophilic model drug assessed by microdialysisand pharmacodynamics. Pharm Res 18:593–599.

37. Spiclin P, Gasperlin M, Kmetec V. 2001. Stabilityof ascorbyl palmitate in topical microemulsions.Int J Pharm 222:271–279.

38. Kristl J, Volk B, Gasperlin M, Sentjurc M, Jurko-vic P. 2003. Effect of colloidal carriers on ascorbylpalmitate stability. Eur J Pharm Sci 19:181–189.

39. Gallarate M, Carlotti ME, Trotta M, Bovo S. 1999.On the stability of ascorbic acid in emulsified


systems for topical and cosmetic use. Int J Pharm188:233–241.

40. Jurkovic P, Sentjurc M, Gasperlin M, Kristl J,Pecar S. 2003. Skin protection against ultravioletinduced free radicals with ascorbyl palmitate inmicroemulsions. Eur J Pharm Biopharm 56:59–66.

41. Djordjevic L, Primorac M, Stupar M. 2005. In vitrorelease of diclofenac diethylamine from capryloca-proyl macrogolglycerides based microemulsions.Int J Pharm 296:73–79.

42. Escribano E, Calpena AC, Queralt J, Obach R,Domenech J. 2003. Assessment of diclofenac per-meation with different formulations: Anti-inflam-matory study of a selected formula. Eur J PharmSci 19:203–210.

43. Kweon J-H, Chi S-C, Park E-S. 2004. Transdermaldelivery of diclofenac using microemulsions. ArchPharm Res 27:351–356.

44. Park E-S, Cui Y, Yun B-J, Ko I-J, Chi S-C. 2005.Transdermal delivery of piroxicam using microe-mulsions. Arch Pharm Res 28:243–248.

45. Parikh DK, Ghosh TK. 2005. Feasibility oftransdermal delivery of fluoxetine. AAPSPharmSciTech 6.

46. Hua L, Weisan P, Jiayu L, Hongfei L. 2004. Pre-paration and evaluation of microemulsion ofvinpocetine for transdermal delivery. Pharmazie59:274–278.

47. Lee PJ, Langer R, Shastri VP. 2003. Novel micro-emulsion enhancer formulation for simultaneoustransdermal delivery of hydrophilic and hydropho-bic drugs. Pharm Res 20:264–269.

48. Sintov AC, Brandys-Sitton R. 2006. Facilitatedskin penetration of lidocaine: Combination of ashort-term iontophoresis and microemulsion for-mulation. Int J Pharm 316:58–67.

49. Sintov AC, Botner S. 2006. Transdermal drugdelivery using microemulsion and aqueous sys-tems: Influence of skin storage conditions on thein vitro permeability of diclofenac from aqueousvehicle systems. Int J Pharm 311:55–62.

50. Lee J, Lee Y, Kim J, Yoon M, Choi YW. 2005.Formulation of microemulsion systems for trans-dermal delivery of aceclofenac. Arch Pharm Res28:1097–1102.

51. Jahn K. 2002. Moderne galenische Zubereitungenzur dermalen Anwendung von Ciclosporin A undMycophenolatmofetil. PhD thesis, Martin LutherUniversity, Halle-Wittenberg, Germany.

52. Wohlrab J, Neubert R, Jahn K. 2002. Drug com-positions containing cyclosporin and their applica-tion as topical systems. PCT/EP 021053565.

53. Teichmann A, Heuschkel S, Jacobi U, Presse G,Neubert RHH, Sterry W, Lademann J. 2007. Com-parison of stratum corneum penetration and loca-lization of a lipophilic model drug applied in ano/w microemulsion and an amphiphilic cream.



Accepted for publication, Eur J Pharm Biopharm.in press.

54. Pattarino F, Carlotti ME, Trotta M, Gasco MR.1995. Release of b-blockers from o/w microemul-sions: Influence of vehicle composition on the per-meation across hairless mouse skin. Acta TechnolLegis Med 6:79–88.

55. Getie M, Wohlrab J, Neubert RHH. 2005. Dermaldelivery of desmopressin acetate using colloidalcarrier systems. J Pharm Pharmacol 57:423–427.

56. Ziegenmeyer J, Fuehrer C. 1980. Microemulsionsas a topical drug form. Acta Pharm Technol 26:273–275.

57. Malcolmson C, Lawrence MJ. 1993. A comparisonof the incorporation of model steroids intonon-ionic micellar and microemulsion systems.J Pharm Pharmacol 45:141–143.

58. Valenta C, Schultz K. 2004. Influence of carragee-nan on the rheology and skin permeation of micro-emulsion formulations. J Control Rel 95:257–265.

59. Escribano E, Obach M, Arevalo MI, Calpena AC,Domenech J, Queralt J. 2005. Rapid human skinpermeation and topical anaesthetic activity of anew amethocaine microemulsion. Skin PharmacolPhys 18:294–300.

60. Arevalo MI, Escribano E, Calpena A, Domenech J,Queralt J. 2004. Rapid skin anesthesia using anew topical amethocaine formulation: A preclini-cal study. Anesth Analg 98:1407–1412.

61. Kantarci G, Ozgungey I, Karasulu HY, Guneri T,Basdemir G. 2005. In vitro permeation of diclofe-nac sodium from novel microemulsion formula-tions through rabbit skin. Drug Dev Res 65:17–25.

62. El Laithy HM, El-Shaboury KMF. 2002. Thedevelopment of cutina lipogels and gel microemul-sion for topical administration of fluconazole.AAPS PharmSciTech 3.

63. Linn EE, Pohland RC, Byrd TK. 1990. Microemul-sion for intradermal delivery of cetyl alcohol andoctyl dimethyl PABA. Drug Dev Ind Pharm 16:899–920.

64. Gasco MR, Gallarate M, Pattarino F. 1991. In vitropermeation of azelaic acid from viscosized micro-emulsions. Int J Pharm 69:193–196.

65. Pattarino F, Carlotti ME, Gasco MR. 1994. Topicaldelivery systems for azelaic acid: Effect of thesuspended drug in microemulsion. Pharmazie49:72–73.

66. Ktistis G, Niopas I. 1998. A study on the in-vitropercutaneous absorption of propranolol from dis-perse systems. J Pharm Pharmacol 50:413–418.

67. Mei ZN, Chen HB, Weng T, Yang YJ, Yang XL.2003. Solid lipid nanoparticle and microemulsionfor topical delivery of triptolide. Eur J PharmBiopharm 56:189–196.

68. Chen H, Chang X, Weng T, Zhao X, Gao Z, Yang Y,Xu H, Yang X. 2004. A study of microemulsion


systems for transdermal delivery of triptolide.J Control Rel 98:427–436.

69. Peltola S, Saarinen-Savolainen P, Kiesvaara J,Suhonen TM, Urtti A. 2003. Microemulsions fortopical delivery of estradiol. Int J Pharm 254:99–107.

70. Viyoch J, Pisutthanan N, Faikreua A, NupangtaK, Wangtorpol K, Ngokkuen J. 2006. Evaluation ofin vitro antimicrobial activity of Thai basil oils andtheir micro-emulsion formulas against Propioni-bacterium acnes. Int J Cosmet Sci 28:125–133.

71. Biju SS, Ahuja A, Khar RK. 2005. Tea tree oilconcentration in follicular casts after topical deliv-ery: Determination by high-performance thinlayer chromatography using a perfused bovineudder model. J Pharm Sci 94:240–245.

72. Schmalfuss U, Neubert R, Wohlrab W. 1997. Mod-ification of drug penetration into human skinusing microemulsions. J Control Rel 46:279–285.

73. Neubert RHH, Schmalfuss U, Wolf R, WohlrabWA. 2005. Microemulsions as colloidal vehiclesystems for dermal drug delivery. Part V: Micro-emulsions without and with glycolipid as penetra-tion enhancer. J Pharm Sci 94:821–827.

74. Kemken J, Ziegler A, Muller BW. 1991. Investiga-tions into the pharmacodynamic effects of der-mally administered microemulsions containingbeta-blockers. J Pharm Pharmacol 43:679–684.

75. Kemken J, Ziegler A, Mueller BW. 1992. Influenceof supersaturation on the pharmacodynamic effectof bupranolol after dermal administration usingmicroemulsions as vehicle. Pharm Res 9:554–558.

76. Trotta M, Morel S, Gasco MR. 1997. Effect of oilphase composition on the skin permeation of felo-dipine from o/w microemulsions. Pharmazie 52:50–53.

77. Baroli B, Lopez-Quintela MA, Delgado-CharroMB, Fadda AM, Blanco-Mendez J. 2000. Microe-mulsions for topical delivery of 8-methoxsalen.J Control Rel 69:209–218.

78. Alvarez-Figueroa MJ, Blanco-Mendez J. 2001.Transdermal delivery of methotrexate: Ionto-phoretic delivery from hydrogels and passivedelivery from microemulsions. Int J Pharm 215:57–65.

79. Subramanian N, Ghosal SK, Moulik SP. 2005.Enhanced in vitro percutaneous absorption andin vivo anti-inflammatory effect of a selectivecyclooxygenase inhibitor using microemulsion.Drug Dev Ind Pharm 31:405–416.

80. Bonina FP, Montenegro L, Scrofani N, Esposito E,Cortesi R, Menegatti E, Nastruzzi C. 1995. Effectsof phospholipid-based formulations on in vitro andin vivo percutaneous absorption of methyl nicoti-nate. J Control Rel 34:53–63.

81. Dreher F, Walde P, Walther P, Wehrli E. 1997.Interaction of a lecithin microemulsion gel with

DOI 10.1002/jps


human stratum corneum and its effect on trans-dermal transport. J Control Rel 45:131–140.

82. Paolino D, Ventura CA, Nistico S, Puglisi G,Fresta M. 2002. Lecithin microemulsions for thetopical administration of ketoprofen: Percuta-neous adsorption through human skin andin vivo human skin tolerability. Int J Pharm244:21–31.

83. Changez M, Varshney M, Chander J, Dinda AK.2006. Effect of the composition of lecithin/n-pro-panol/isopropyl myristate/water microemulsionson barrier properties of mice skin for transdermalpermeation of tetracaine hydrochloride: In vitro.Colloid Surf B 50:18–25.

84. Changez M, Chander J, Dinda AK. 2006. Trans-dermal permeation of tetracaine hydrochloride bylecithin microemulsion: In vivo. Colloid Surf B48:58–66.

85. Cui Z, Sloat BR. 2006. Topical immunization ontomouse skin using a microemulsion incorporatedwith an anthrax protective antigen protein-encod-ing plasmid. Int J Pharm 317:187–191.

86. Peira E, Scolari P, Gasco MR. 2001. Transdermalpermeation of apomorphine through hairlessmouse skin from microemulsions. Int J Pharm226:47–51.

87. Priano L, Albani G, Brioschi A, Calderoni S,Lopiano L, Rizzone M, Cavalli R, Gasco MariaR, Scaglione F, Fraschini F, Bergamasco B, MauroA. 2004. Transdermal apomorphine permeationfrom microemulsions: A new treatment in Parkin-son’s disease. Movement Disord 19:937–942.

88. Trotta M, Pattarino F, Gasco MR. 1996. Influenceof counter ions on the skin permeation of metho-trexate from water–oil microemulsions. PharmActa Helv 71:135–140.

89. Trotta M, Ugazio E, Peira E, Pulitano C. 2003.Influence of ion pairing on topical delivery of reti-noic acid from microemulsions. J Control Rel 86:315–321.

90. Busch P, Hensen H, Tesmann H. 1993. Alkylpolyglycosides—A new generation of surfactantsfor cosmetics. Tenside Surfact Det 30:116–121.

91. Steber J, Guhl W, Stelter N, Schroeder FR. 1995.Alkyl polyglycosides—Ecological evaluation of anew generation of nonionic surfactants. TensideSurfact Det 32:515–521.

92. Foerster T, Guckenbiehl B, Hensen H, VonRybinski W. 1996. Physico-chemical basics ofmicroemulsions with alkyl polyglycosides. ProgColloid Polym Sci 101:105–112.

93. von Rybinski W, Guckenbiehl B, Tesmann H.1998. Influence of co-surfactants on microemul-sions with alkyl polyglycosides. Colloid Surf A142:333–342.

94. Lehmann L, Keipert S, Gloor M. 2001. Effects ofmicroemulsions on the stratum corneum and


hydrocortisone penetration. Eur J Pharm Bio-pharm 52:129–136.

95. Gloor M, Haus G, Keipert S. 2003. Keratolyticactivity of microemulsions. Skin Pharmacol ApplSkin Physiol 16:151–155.

96. Bolzinger MA, Carduner TC, Poelman MC. 1998.Bicontinuous sucrose ester microemulsion: A newvehicle for topical delivery of niflumic acid. Int JPharm 176:39–45.

97. Changez M, Varshney M. 2000. Aerosol-OT micro-emulsions as transdermal carriers of tetracainehydrochloride. Drug Dev Ind Pharm 26:507–512.

98. Gupta RR, Jain SK, Varshney M. 2005. AOTwater-in-oil microemulsions as a penetrationenhancer in transdermal drug delivery of 5-fluor-ouracil. Colloid Surf B 41:25–32.

99. Osborne DW, Ward AJI, O’Neill KJ. 1988. Micro-emulsions as topical drug delivery vehicles 1.Characterization of a model system. Drug DevInd Pharm 14:1203–1219.

100. Liu H, Li S, Wang Y, Han F, Dong Y. 2006.Bicontinuous water-AOT/Tween85-isopropyl myr-istate microemulsion: A new vehicle for transder-mal delivery of cyclosporin A. Drug Dev IndPharm 32:549–557.

101. Park SJ, Won JH, Lim J-C, Kim JH, Park S. 2005.Phase behavior and characterization of W/Omicroemulsion systems containing sodium dodecylsulfate/butyl lactate/isopropyl myristate/water.J Ind Eng Chem 11:20–26.

102. Dalmora MEA, Oliveira AG. 1999. Inclusioncomplex of piroxicam with b-cyclodextrin andincorporation in hexadecyltrimethylammoniumbromide based microemulsion. Int J Pharm 184:157–164.

103. Dalmora ME, Dalmora SL, Oliveira AG. 2001.Inclusion complex of piroxicam with beta-cyclo-dextrin and incorporation in cationic micro-emulsion. In vitro drug release and in vivotopical anti-inflammatory effect. Int J Pharm222:45–55.

104. Cui Z, Fountain W, Clark M, Jay M, Mumper RJ.2003. Novel ethanol-in-fluorocarbon microemul-sions for topical genetic immunization. PharmRes 20:16–23.

105. Rangarajan M, Zatz JL. 2003. Effect of formula-tion on the topical delivery of a-tocopherol.J Cosmet Sci 54:161–174.

106. Boinpally RR, Zhou SL, Devraj G, Anne PK, Poon-dru S, Jasti BR. 2004. Iontophoresis of lecithinvesicles of cyclosporin A. Int J Pharm 274:185–190.

107. Mumper RJ, Ledebur HC. 2001. Dendritic celldelivery of plasmid DNA—Applications for con-trolled genetic immunization. Mol Biotechnol19:79–95.


3b7e26cdd01

Documents