European Journal of Pharmaceutical Sciences 14 (2001) 101–114

www.elsevier.nl / locate / ejps

Review

Novel mechanisms and devices to enable successful transdermal drug

delivery
B.W. Barry*
Drug Delivery Group, School of Pharmacy, University of Bradford, Bradford BD7 1 DP, UK
Received 28 March 2001; received in revised form 11 June 2001; accepted 14 June 2001

Abstract

Optimisation of drug delivery through human skin is important in modern therapy. This review considers drug–vehicle interactions
(drug or prodrug selection, chemical potential control, ion pairs, coacervates and eutectic systems) and the role of vesicles and particles
(liposomes, transfersomes, ethosomes, niosomes). We can modify the stratum corneum by hydration and chemical enhancers, or bypass or
remove this tissue via microneedles, ablation and follicular delivery. Electrically assisted methods (ultrasound, iontophoresis,
electroporation, magnetophoresis, photomechanical waves) show considerable promise. Of particular interest is the synergy between
chemical enhancers, ultrasound, iontophoresis and electroporation.  2001 Elsevier Science B.V. All rights reserved.

Keywords: Review; Skin enhancement; Iontophoresis; Ultrasound; Liposomes

1. Introduction cifically, the stratum corneum) provides the major control

element — most small water-soluble non-electrolytes
Recently, the transdermal route has vied with oral diffuse into the systemic circulation a thousand times more
treatment as the most successful innovative research area rapidly when the horny layer is absent. Thus, to maximise
in drug delivery. In the USA (the most important clinical drug flux we usually try to reduce this barrier’s hindrance,
market), out of 129 drug delivery candidate products under although sometimes the follicular route may also be
clinical evaluation, 51 are transdermal or dermal systems; important. This review considers how molecules cross
30% of 77 candidate products in preclinical development intact, healthy skin and considers attempts to circumvent
represent such drug delivery. The worldwide transdermal the problems of an almost impermeable barricade ex-
patch market approaches £2 billion, yet is based on only hibiting considerable patient variability.
ten drugs — scopolamine (hyoscine), nitroglycerine,
clonidine, estradiol (with and without norethisterone or
levonorgestrel), testosterone, fentanyl and nicotine, with a
lidocaine patch soon to be marketed. The fundamental 3. Routes of penetration
reason for such few transdermal drugs is that highly
impermeable human skin limits daily drug dosage, de- At the skin surface, molecules contact cellular debris,
livered from an acceptable sized patch, to about 10 mg. microorganisms, sebum and other materials, which neg-
This review deals with ways to raise significantly this low ligibly affect permeation. The penetrant has three potential
limit for topical systems in general. pathways to the viable tissue — through hair follicles with
associated sebaceous glands, via sweat ducts, or across
continuous stratum corneum between these appendages
2. Drug transport through human skin (Fig. 1).
Fractional appendageal area available for transport is
Human skin is an effective, selective barrier to chemical only about 0.1%; this route usually contributes negligibly
permeation (Barry, 1983). In general, the epidermis (spe- to steady state drug flux. The pathway may be important
for ions and large polar molecules that struggle to cross
*Corresponding author. intact stratum corneum. Appendages may also provide
E-mail address: [email protected] (B.W. Barry). shunts, important at short times prior to steady state

0928-0987 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved.
PII: S0928-0987( 01 )00167-1
102 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114

although they may bind e.g. testosterone, inhibiting its

systemic removal.

4. Optimising transdermal drug delivery

Fig. 3 summarises some ways for circumventing the

stratum corneum barrier.

4.1. Drug and vehicle interactions

4.1.1. Selection of correct drug or prodrug

The simplest approach chooses a drug from a congeneric
series or pharmacological class with the correct physico-
Fig. 1. Simplified diagram of skin structure and macroroutes of drug chemical properties to translocate across the barrier at an
penetration: (1) via the sweat ducts; (2) across the continuous stratum acceptable rate. A useful way to consider factors affecting
corneum or (3) through the hair follicles with their associated sebaceous drug permeation rate through stratum corneum is via the
glands.
simple equation for steady state flux (Eq. (1); Barry,
1983). In general, features controlling such permeation
also similarly modify short time or finite dose (depleting)
diffusion. Additionally, polymers and colloidal particles
situations. If we plot the cumulative mass of diffusant, m,
can target the follicle.
passing per unit area through the membrane, at long times
The intact stratum corneum thus provides the main
the graph approaches linearity and its slope yields the
barrier; its ‘brick and mortar’ structure is analogous to a
steady flux, dm / dt, (Eq. (1))
wall (Fig. 2; reviewed in Barry and Williams, 1995). The
corneocytes of hydrated keratin comprise the ‘bricks’, dm DC0 K
embedded in a ‘mortar’, composed of multiple lipid ] 5 ]] (1)
dt h
bilayers of ceramides, fatty acids, cholesterol and choles-
terol esters. These bilayers form regions of semicrystalline, where C0 is the constant concentration of drug in donor
gel and liquid crystals domains. Most molecules penetrate solution, K is the partition coefficient of solute between
through skin via this intercellular microroute and therefore membrane and bathing solution, D is the diffusion coeffi-
many enhancing techniques aim to disrupt or bypass its cient and h is thickness of membrane.
elegant molecular architecture. From Eq. (1), we deduce the ideal properties of a
Viable layers may metabolise a drug, or activate a molecule penetrating stratum corneum well. These are
prodrug. The dermal papillary layer is so rich in capillaries
that most penetrants clear within minutes. Usually, deeper • Low molecular mass, preferably less than 600 Da, when
dermal regions do not significantly influence absorption, D tends to be high
• Adequate solubility in oil and water — so the mem-
brane concentration gradient (the driving force for
diffusion) may be high (C0 is large). Saturated solutions
(or suspensions having the same maximum thermo-
dynamic activity) promote maximum flux in equilib-
rium systems.
• High but balanced (optimal) K (too large may inhibit
clearance by viable tissues)
• Low melting point, correlating with good solubility as
predicted by ideal solubility theory

These features explain why transdermal patches deliver

adequate amounts of nicotine for effective smoking cessa-
tion therapy — this drug illustrates all these requirements.
The partition coefficient is crucially important in estab-
lishing a high initial penetrant concentration in the first
stratum corneum layer. If our agent does not possess the
Fig. 2. Simplified diagram of stratum corneum and two microroutes of correct physicochemical properties (usually K is too low),
drug penetration. a suitable prodrug may have an optimal partition coeffi-
 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114 103

Fig. 3. Some methods for optimising transdermal drug therapy.

cient for skin entry. After permeation to viable tissues, adhesive (Kondon and Sugimoto, 1987; Kondon et al.,
enzymes activate the prodrug. 1987a,b; Chiang et al., 1989; Davis and Hadgraft, 1991;
Kemken et al., 1992; Henmi et al., 1994; Pellett et al.,
1994, 1997a,b; Fang et al., 1999; Iervolino et al., 2000;
4.1.2. Chemical potential adjustment
Raghavan et al., 2000; Lipp, 1998; Lipp and Muller-
An alternative form of Eq. (1) uses thermodynamic
Fahrnow, 1999; Hadgraft, 1999). To illustrate the mag-
activities (Higuchi, 1960), when
nitude of the phenomenon, for estradiol at 18-times
dm aD saturation, Megrab et al. (1995) achieved an 18-fold
]5] (2) increase in stratum corneum uptake and a 13-times in-
dt gh
crease in flux.
where a is the thermodynamic activity of drug in its However, Schwarb et al. (1999) were unable to show an
vehicle and g is the effective activity coefficient in the effect of supersaturation in increasing the delivery of
skin barrier. For maximum penetration rate, the drug fluocinonide to the skin, as assessed by the vasoconstrictor
should be at its highest thermodynamic activity. Now assay.
dissolved molecules in saturated solution are in equilib-
rium with pure solid (which by definition is at maximum 4.1.3. Ion pairs and complex coacervates
activity for an equilibrated system). The solute molecules Charged molecules do not readily penetrate stratum
are also thus at maximum activity. Thus all vehicles corneum. One technique forms a lipophilic ion pair, by
containing drug as a finely ground suspension should adding an oppositely charged species. The complex parti-
produce the same penetration rate, provided that the tions into the stratum corneum lipids, as charges tempo-
systems behaves ideally i.e. D, g and h remain constant. rarily neutralise. The ion pair diffuses to the aqueous
Ideality is difficult to maintain, as most topical vehicles viable epidermis, there to dissociate into its charged
interact to some extent with the horny layer. species, which partition into the epidermis and diffuse
Supersaturated solutions (i.e. nonequilibrated systems) onward (e.g. Megwa et al., 2000a,b; Valenta et al., 2000).
may arise, either by design or via a cosolvent evaporating Stott et al. (2001) considered the relationship between
on the skin (Coldman et al., 1969). The theoretical ion-pair permeation of addition compounds and eutectic
maximum flux may then increase manyfold. Polymers may systems. Generally, enhancement is modest (twofold).
be incorporated to inhibit crystallisation in unstable super- Sometimes with penetration enhancers, it is unnecessary to
saturated preparations. The metastability period is usually consider ion-pair phenomena (Smith and Irwin, 2000).
short, but may be prolonged in transdermal patches Complex coacervation is the separation of oppositely
because of their mode of preparation — drug dissolution in charged ions into a coacervate oil phase, rich in ionic
hot solvents, evaporation to supersaturation and crystal complex. The coacervate partitions into stratum corneum,
inhibition by the polymers of the high viscosity matrix or where it behaves as ion pairs, diffusing, dissociating and
104 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114

passing into viable tissues; flux enhancement is again

modest (Stott et al., 1996).

4.1.4. Eutectic systems

The formulation advantages of a eutectic mixture of
prilocaine and lidocaine in EMLA cream (Nyqvist-Mayer
et al., 1986) prompted study of such systems for other
drugs. For example, Stott et al. (1998, 2001) investigated
eutectic systems of ibuprofen formed with seven terpenes
and propranolol with fatty acids, correlating their interac-
tions with increased transdermal permeation. Kang et al.
(2000) showed that the lidocaine — menthol system Fig. 4. Ultradeformable transfersome squeezing through minute pores in
promoted permeation through snake skin. the stratum corneum, driven by the water concentration gradient. The
liposome with edge-activators thus penetrates from the horny layer
surface (relatively dry) to the wet viable tissues (modified from Cevc et
4.2. Vesicles and particles
al., 1996).

4.2.1. Liposomes and other vesicles

Liposomes are colloidal particles, typically consisting of Remarkable results are claimed for transfersomes. Data
phospholipids and cholesterol, with other possible ingredi- indicate that as much as 50% of a topical dose of a protein
ents. These lipid molecules form concentric bimolecular or peptide (such as insulin) penetrates skin in vivo in 30
layers that may entrap and deliver drugs to the skin. Most min.
reports cite a localising effect whereby vesicles accumulate Other workers measured drug delivery from ul-
drugs in stratum corneum or other upper skin layers (e.g. tradeformable liposomes and traditional vesicles using
Mezei and Gulasekharam, 1980; Mezei and Gulasekharam, open and occluded conditions in vitro. Both liposome
1982; Touitou et al., 1994; Fresta and Puglisi, 1996; types improved maximum flux and skin deposition com-
Meidan et al., 1998a; Cheng and Chien, 1999). Generally, pared to saturated aqueous drug solution (maximum
liposomes are not expected to penetrate into viable skin, thermodynamic control) under non-occluded conditions
although occasional transport processes were reported (El Maghraby et al., 1999, 2000a,b, 2001a,b). However,
(Mezei, 1992). How well vesicles transport drugs through positive results did not reach the values obtained by Cevc
the skin is debatable. and co-workers, as only 1–3% of drug was delivered. Five
This controversy grew with the introduction of transfer- potential mechanisms of action of these liposomes were
somes, which incorporate ‘edge activators’ — surfactant assessed
molecules such as sodium cholate (Planas et al., 1992;
Cevc and Blume, 1992; Cevc et al., 1993, 1995, 1997; 1. A free drug process — drug releases from vesicle and
Cevc, 1996; Paul et al., 1995). The inventors claim that independently permeates skin.
such vesicles, being ultradeformable (up to 10 5 times that 2. Enhancement due to release of lipids from vesicles and
of an unmodified liposome), squeeze through pores in interaction with skin lipids.
stratum corneum less than one-tenth the liposome’s diam- 3. Improved drug uptake by skin.
eter. Thus, sizes up to 200–300 nm can penetrate intact 4. That different entrapment efficiencies of the liposomes
skin. Two features are claimed to be important. Transfer- controlled drug input.
somes require a hydration gradient to encourage skin 5. Penetration of stratum corneum by intact liposomes.
penetration, that is, nonoccluded conditions. Then the
gradient operating from the (relatively) dry skin surface Data indicated no evidence for (i), but revealed a
towards waterlogged viable tissues drives transfersomes possible penetration enhancing effect for pure phos-
through the horny layer (Fig. 4). Thus, phospholipids tend phaditylcholine vesicles, although this was not the only
to avoid dry surroundings; a suspension of such vesicles mechanism operating. There was evidence of an uptake
deposited on the skin surface non-occlusively will evapo- effect but no correlation of entrapment efficiency and drug
rate and partially dehydrate. For vesicles to remain maxi- delivery. The data did not confirm that liposomes penetrate
mally swollen, they must follow the local hydration through, as distinct from into, the horny layer, in vitro (El
gradient and penetrate into more strongly hydrated and Maghraby et al., 1999).
deeper skin layers of viable epidermis and dermis. Tradi- Fluid liposomes delivered more fluorescein into stratum
tional liposomes in this situation are expected to confine corneum than did rigid liposomes (Perez-Cullell et al.,
themselves to surface or upper layers of stratum corneum, 2000).
where they dehydrate and fuse with skin lipids (Cevc, Ethosomes are liposomes high in ethanol content (up to
1992; Cevc and Blume, 1992; Cevc et al., 1995, 1996; Guo 45%). They penetrate skin and enhance compound delivery
et al., 2000). Secondly, transfersomes work best under in to deep skin strata or systemically (Touitou, 1996, 1998;
vivo conditions. Touitou et al., 2000a,b; Dayan and Touitou, 2000).
 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114 105

Touitou et al. (2000c) suggest that ethanol fluidises both However, there have been problems with bruising and
ethosomal lipids and bilayers of the mortar (Fig. 2). The particles bouncing off skin surfaces. Regulatory authorities
soft, malleable vesicles then penetrate through the dis- will need convincing that high velocity particles smashing
organised lipid bilayers. through the stratum corneum (Fig. 2) really do no damage
Niosomes use nonionic surfactants to form vesicles to this elegant structure which is not readily repaired, nor
(Schreier and Bouwstra, 1994). Transport of entrapped do they carry surface contaminants such as bacteria into
spin labelled compounds into skin was examined by viable skin layers.
electron paramagnetic resonance imaging methods (Sen- The leading products in development include lignocaine
tjurc et al., 1999) and mechanistic aspects of cyclosporin- and levobupivacaine for local anaesthesia, proteins (follicle
A skin delivery were assessed by Waranuch et al. (1998). stimulating hormone and b-interferon) and hepatitis B
Niosomes (e.g. urea formulations Mazda et al., 1997) have DNA and other vaccines (Sarphie et al., 1997; Degano et
been much promoted by the cosmetic industry, sometimes al., 1998; Vanderzanden et al., 1998; Tacket et al., 1999;
as almost magical ingredients. Roy et al., 2000).
The Intraject is a development of the vaccine gun
4.2.2. High velocity particles designed to deliver liquids through skin without using
The PowderJect system fires solid particles (20–100 needles. It is surprising that, after the widespread use of
mm) through stratum corneum into lower skin layers, using similar devices for vaccination — such as by the US
a supersonic shock wave of helium gas (Burkoth et al., military in Vietnam — it was not developed for drug
1999). The claimed advantages of the system include delivery earlier.

• Pain-free delivery — particles are too small to trigger 4.3. Stratum corneum modified
pain receptors in skin
• Improved efficacy and bioavailability 4.3.1. Hydration
• Targeting to a specific tissue, such as a vaccine Hydration of stratum corneum increases the penetration
delivered to epidermal cells rate of most (but not all) substances; water opens up the
• Sustained release, or fast release compact structure of horny layer (Menon et al., 1994).
• Accurate dosing Moisturising factors, occlusive films, hydrophobic oint-
• Overcomes needle phobia ments and transdermal patches all enhance drug bioavail-
• Safety — the device avoids skin damage or infection ability into skin (Barry and Williams, 1995; Wester and
from needles or splashback of body fluids — par- Maibach, 1995; Haigh and Smith, 1995; Hollingsbee et al.,
ticularly important for HIV and hepatitis B virus 1965). Table 1 illustrates general effects on drug permea-

Table 1
Expected effects of skin delivery systems on horny layer hydration and skin permeability — in approximate order of decreasing hydration
Delivery system Examples / constituents Effect on skin hydration Effect on skin
permeability
Occlusive dressing Plastic film, unperforated Prevents water loss; Marked increase
waterproof plaster full hydration
Occlusive patch Most transdermal patches Prevents water loss; Marked increase
full hydration
Lipophilic material Paraffins, oils, fats, waxes, Prevents water loss; may Marked increase
fatty acids and alcohols, produce full hydration
esters, silicones
Absorption base Anhydrous lipid material Prevents water loss; Marked increase
plus water–oil emulsifiers marked hydration
Emulsifying base Anhydrous lipid material Prevents water loss; Marked increase
plus oil–water emulsifiers marked hydration
Water–oil emulsion Oily creams Retards water loss; Increase
raised hydration
Oil–water emulsion Aqueous creams May donate water; slight Slight increase?
hydration increase
Humectant Water-soluble bases, May withdraw water; Can decrease or act as
glycerol, glycols decreased hydration penetration enhancer
Powder Clays, organics, inorganics, Aid water evaporation, Little effect on
‘shake’ lotions decreased excess hydration stratum corneum
106 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114

tion when pharmaceutical systems influence stratum cor- bilayer interface. Even a slight increase in free volume
neum water content. Raised hydration may not always fraction as enhancers molecules congregate there dramati-
increase drug permeation (Bucks et al., 1989). cally increases D. The bilayer centre is always somewhat
disordered, with a high free volume, so that enhancer
4.3.2. Chemical penetration enhancers effects on diffusivity here are marginal.
Substances temporarily diminishing the barrier of the Many enhancers operate mainly in this way (e.g. azone,
skin, known also as accelerants or sorption promoters, can terpenes, fatty acids, DMSO and alcohols). It was assumed
enhance drug flux. Skin enhancer literature is now so that such enhancers would penetrate into, and mix
extensive that we consider only representative references, homogeneously with, the lipids. However, oleic acid and
concentrating mainly on reviews. terpenes, at high loadings, pool within lipid domains i.e.
A sample summary of enhancers includes: water, hydro- they phase-separate. Permeable ‘pores’ form which, for
carbons, sulphoxides (especially dimethylsulphoxide) and polar molecules, allow easier access to viable epidermis
their analogues, pyrrolidones, fatty acids, esters and al- (Ongpipattanakul et al., 1991; Cornwell et al., 1994, 1996).
cohols, azone and its derivatives, surfactants (anionic, Some solvents (e.g. DMSO, ethanol) and micellar
cationic and nonionic), amides (including urea and its solutions may also extract lipids, making the horny layer
derivatives), polyols, essential oils, terpenes and deriva- more permeable through forming aqueous channels (Men-
tives, oxazolidines, epidermal enzymes, polymers, lipid czel, 1995). Menon et al. (1998) discuss well solvent
synthesis inhibitors, biodegradable enhancers and synergis- effects on the lipid domain of the horny layer.
tic mixtures (Williams and Barry, 1995; Smith and
Maibach, 1995 — chapters therein; Asbill and Michniak, 4.3.2.2. Protein modification
2000; Asbill et al., 2000; Sinha and Kaur, 2000). Reddy et Ionic surfactants, decylmethylsulphoxide and DMSO
al. (2000) concisely review enantioselective permeation, interact well with keratin in corneocytes, opening up the
with and without chiral enhancers, including terpenes. The dense protein structure, making it more permeable, and
effect of ionisation and enhancers on permeation through thus increasing D (Eq. (1)). However, the intracellular
skin and silastic has been considered (Smith and Irwin, route is not usually important in drug permeation, although
2000). drastic reductions to this route’s resistance could open up
For safety and effectiveness, the best penetration en- an alternative pathway. Such molecules may also modify
hancer is water (see above). Most substances penetrate peptide / protein material in the bilayer domain, a feature
better through hydrated stratum corneum than through dry usually neglected in the literature (Barry, 1991).
tissue, hence the value of occlusive patches. Thus, any
chemical which is pharmacologically inactive, non-damag- 4.3.2.3. Partitioning promotion
ing and which promotes horny layer hydration, is a Many solvents enter stratum corneum, change its solu-
penetration enhancer. Examples include the natural mois- tion properties by altering the chemical environment, and
turising factor and urea. thus increase partitioning of a second molecule into the
An important theme in enhancer research is how to horny layer (i.e. raise K in Eq. (1)). This molecule may be
classify accelerant action and explain (and rationalise) the a drug, a coenhancer or a cosolvent (including water). For
various mechanisms responsible for increased drug per- example, ethanol increases the penetration of nitro-
meation. The hope is that by understanding fundamental glycerine and estradiol. Propylene glycol is also widely
principles, we move away from empirical testing of employed, particularly to provide synergistic mixtures with
promoter activity to prediction. The structural diversity of molecules such as azone, oleic acid and the terpenes i.e. to
enhancer molecules makes this a challenge. raise the horny layer concentration of these enhancers.
One simple classification is via the lipid–protein–parti- In theory, nonsolvent enhancers that mainly act to raise
tioning concept (Barry, 1988, 1991; Goodman and Barry, drug diffusivity by mechanisms discussed above (lipid
1989; Williams and Barry, 1991a). This hypothesis sug- action) should also increase the partition coefficient for
gests that accelerants act by one or more ways selected lipid drugs. That is, by disordering the lipid interfacial
from three main possibilities (see Fig. 2). Studies by domain they increase free volume and make a larger
Aungst et al. (1990) broadly support this concept. fraction of the bilayer available for solute partitioning. The
nonsolvent enhancer, of course, also affects the chemical
4.3.2.1. Lipid action environment throughout the lipid domain and thus, theoret-
The enhancer disrupts stratum corneum lipid organisa- ically, modifies the solute partition coefficient. When only
tion, making it permeable. The essential action increases low concentrations of bilayer-disrupting agents enter the
the drug’s diffusion coefficient (Eq. (1)). The accelerant stratum corneum, we can ignore this minor effect.
molecules jump into the bilayer, rotating, vibrating and Many chemical enhancers combine these three LPP
translocating, forming microcavities and increasing the mechanisms. Thus, high concentrations of DMSO (above
free volume available for drug diffusion. Without enhancer, 60%) disturb intercellular organisation, extract lipids,
the free volume fraction is lowest (and D lowest) near the interact with keratin and facilitate lipid drug partitioning.
 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114 107

Because of the availability of extensive data on enhancer repellent N,N-diethyl-m-toluamide is also an enhancer and
effects, investigation of structure–activity relationships is is now formulated into an estradiol patch.
an obvious approach. Terpenes and sesquiterpenes have Mitragotri (2000) discussed synergy between chemical
received this treatment (Williams and Barry, 1991; Cor- enhancers and electrically assisted methods of (ultrasound,
nwell and Barry, 1994). Other attempts (based on factors iontophoresis and electroporation; see Section 4.5 and Fig.
such as chain length, polarity, unsaturation and presence of 5).
special groups) were summarised by Kanikkannan et al.
(2000). 4.4. Stratum corneum bypassed or removed
An alternative scheme for classifying enhancer action
uses a conceptual diagram of three areas based on the 4.4.1. Microneedle array
organic and inorganic characters of enhancers (Hori et al., Stratum corneum can be bypassed by injection and one
1989, 1990). Area I encloses enhancers which are solvents, development of this approach is a device of 400 micronee-
Area II designates accelerants for hydrophilic drugs and dles which insert drug just below the barrier (Henry et al.,
Area III contains promoters for lipophylic compounds. 1998; McAllister et al., 2000; Asbill et al., 2000). The
Barry and Williams (1995) applied their data on terpenes solid silicon needles (coated with drug) or hollow metal
to this conceptual diagram, showing that it predicted the needles (filled with drug solution) penetrate the horny layer
activity of some terpenes but not others. A shortcoming of without breaking it or stimulating nerves in deeper tissues;
the scheme is that it implies that an enhancer may be the feel to the skin is rather like a cat’s tongue, or
effective for either hydrophilic or hydrophobic compounds. sharkskin. Flux increases up to 100 000-fold are claimed.
However, a terpene such as 1,8-cineole promotes the The technique may also be combined with iontophoresis. It
penetration of polar 5-fluorouracil and lipophylic estradiol. would be interesting to see if the microneedle approach
(The scope for enhancement of hydrophilic drugs is greater could be combined with a microchip to control the release
than that for hydrophobic penetrants. We can allow for this of the drug through the needles (Santini et al., 1999;
in comparing the activities of enhancers by using an Langer, 2000).
enhancement index; see Williams and Barry, 1991b).
An unfortunate feature of many potent enhancers (which 4.4.2. Stratum corneum ablated
can be deduced from their abilities to disrupt organised As the horny layer usually provides the permeation
lipid structures) is that they irritate, as they also interfere barrier, we could consider simply removing it. Chemical
with viable cell membranes. Industrial scientists therefore peels may provide superficial or light (epidermal), medium
often limit their investigations for a suitable enhancer to (epidermal–dermal junction) or deep (deep papillary or
materials known to be benign on skin e.g. GRAS (general- papillary reticular dermis) treatments. Microdermabrasion
ly regarded as safe) substances. For example, the insect uses a stream of aluminium oxide crystals and dermabra-

Fig. 5. Suggested mechanisms for the actions of transdermal penetration enhancers (in main rectangular boxes) and possible synergistic actions between
methods as illustrated in connecting boxes (rounded rectangles). Modified from Mitragotri (2000).
108 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114

sion employs a motor-driven abrasive fraise or cylinder was extended to transdermal drug delivery studies (Kost,
(Friedland and Buchel, 2000). Laser ablation applies high- 1995; Camel, 1995; Byl, 1995; Mitragotri and Kost, 2000).
powered pulses to vapourise a section of the horny layer so The ultrasonic energy (at low frequency) disturbs the lipid
as to produce permeable skin regions (Dover et al., 2000). packing in stratum corneum (see Fig. 2) by cavitation.
The apparatus is costly and requires expert operation to Shock waves of collapsing vacuum cavities increase free
avoid damage such as burns — it is inappropriate for home volume space in bimolecular leaflets and thus enhance
use. drug penetration into the tissue (Menon et al., 1994;
Adhesive tape can remove stratum corneum prior to Mitragotri et al., 1995a,c; Simonin, 1995; Ueda et al.,
drug application; tape-stripping is used to measure drug 1995; Liu et al., 1998).
uptake into skin (Touitou et al., 1998; Bashir et al., 2001). Initial investigations suffered from using standard high
A microinfusor device has been proposed to delivery frequency devices that focused the energy into deeper,
peptides, proteins and other macromolecules (Meehan et muscular tissues, rather then the correct delivery target, the
al., 1997). One other method forms a blister by suction, an stratum corneum. Now, however, low frequency (| 20
epidermatome removes the raised tissue, after which a kHz) rather than therapeutic ultrasound (| 1 MHz up-
morphine solution delivered directly to the exposed dermis wards) increases enhancement a thousand-fold (Mitragotri
produces fast pain relief (Svedman et al., 1996). et al., 1995c, 1996, 2000d). Below a threshhold value for
cavitation (which depends on conditions, Langer, 2000),
4.4.3. Follicular delivery promotion is inversely proportional to frequency. As usual,
The pilosebaceous unit (hair follicle, hair shaft and a clear goal is the transdermal delivery of large polar
sebaceous gland) provides a route that bypasses intact molecules, and work on the phonophoresis of insulin,
stratum corneum; it also represents a drug delivery target. erythropoietin and interferon is especially significant (Mit-
The sebaceous gland cells are more permeable than ragotri et al., 1995b; Tachibana, 1992).
corneocytes and thus drugs can reach the dermis by Other investigations have shown: a possible deactivation
entering the follicle (bypassing the invaginated stratum of skin enzymes by ultrasound (Hikima et al., 1998); effect
corneum), passing through the sebaceous gland or penetrat- of pulsed delivery (Asano et al., 1997); synergistic co-
ing the epithelium of the follicular sheath. The rich blood operation of ultrasound with iontophoresis (Le et al.,
supply aids absorption, even though the shunt route cross- 2000), penetration enhancers (Johnson et al., 1996; Mit-
sectional area is small. ragotri et al., 2000a) and electroporation (Kost et al.,
Even such a large molecule as ‘naked’ DNA can 1996); phonophoresis used to probe the relative contribu-
immunise by topical application and the use of the hair tion of the follicular route to the penetration of hydrophilic
follicle as a gene therapy target is exciting (e.g. Fan et al., permeants (Meidan et al., 1998b); and its potential for the
1999; Hoffman, 2000). It was speculated that normal transdermal extraction of analytes (Mitragotri et al.,
follicles have efficient mechanisms for inducing immune 2000b,c; Cantrel et al., 2000).
responses to proteins in the follicle. A preparation made A problem is the need to validate the technique for
from antibodies from transgenic plants, when rubbed into effectiveness and safety in patients. As yet, it is not readily
the scalp, neutralised hair-loss effects of toxic chemicals suitable for home use.
used in chemotherapy. Colloidal particles, such as lipo-
somes and analogues (e.g., Tschan et al., 1997 Weiner, 4.5.2. Iontophoresis
1998; Agarwal et al., 2000; Touitou et al., 2000) and small Iontophoresis, the electrical driving of charged mole-
crystals (Allec et al., 1997) target the hair follicle. In cules into tissue, passes a small direct current (approxi-
general, particles .10 mm remain on the skin surface, mately 0.5 mA / cm 2 ) through a drug-containing electrode
those ¯3–10 mm concentrate in the follicle and when ,3 in contact with the skin. A grounding electrode elsewhere
mm, they penetrate follicles and stratum corneum alike on the body completes the circuit (Sage, 1995; Banga,
(Schaefer and Redelmeier, 1996). 1998; Guy, 1998). Three main mechanisms enhance
The importance of shunt route penetration of liposomes molecular transport: (a) charged species are driven primari-
was researched using a novel technique whereby the shunts ly by electrical repulsion from the driving electrode; (b)
were blocked by a second layer of stratum corneum (El the flow of electric current may increase the permeability
Maghraby et al., 2000b). Shunts played only a very minor of skin; and (c) electroosmosis may affect uncharged
role in liposomal delivery to lower skin layers. molecules and large polar peptides. Efficiency of transport
depends mainly on polarity, valency and mobility of the
4.5. Electrically assisted methods charged species, as well as electrical duty cycles and
formulation components (Naik et al., 2000).
4.5.1. Ultrasound ( phonophoresis, sonophoresis) Considerable interest is now shown in possible transder-
This technique, used originally in physiotherapy and mal delivery of therapeutic peptides (Miller et al., 1990;
sports medicine, applies a preparation topically and mas- Bhatia and Singh, 1998a,b; Chiang et al., 1998), proteins
sages the site with an ultrasound source. The procedure (Mitragotri et al., 1995c) and oligonucleotides (Oldenburg
 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114 109

et al., 1995; Brand et al., 1998), as well as many other that travel straight through the horny layer (Pliquett et al.,
drugs. Clinical trials have proceeded with lidocaine and 1996; Prausnitz et al., 1996; Higuchi et al., 1999; Teissie et
fentanyl (Banga, 1998; Gupta et al., 1998). al., 1999; Jadoul et al., 1999; Weaver, 2000). During the
Polar neutral molecules can be delivered by a current- pulse, drugs transport via iontophoresis and / or electroos-
induced convective flow of water — electroosmosis mosis. Significant movement can also occur between
(Banga, 1998; Sims and Higuchi, 1990; Pikal, 1992; pulses by simple diffusion due to relatively persistent
Delgado-Charro and Guy, 1994; Peck et al., 1996; Lin et changes in the stratum corneum lowering its resistance
al., 1997; Burnette and Ongpipattanakul, 1987; Singh et (Prausnitz, 1999).
al., 1998; Merino et al., 1999; Bath et al., 2000). Thus, at Fluxes increased 10–10 4 -fold for neutral and highly
above pH|4, stratum corneum is negatively charged and charged molecules of up to 40 kDa (Vanbever and Preat,
therefore the preferential transport of small cations such as 1995, 1998; Prausnitz et al., 1995; Zewert et al., 1995;
buffer components (e.g. Na 1 ) imposes a net solvent flow Zhang et al., 1996, 1997; Vanbever et al., 1996; Jadoul and
from anode to cathode, carrying with it unionised species Preat, 1997; Wang et al., 1997; Regnier et al., 1997, 1999,
(or even cations). Elecroosmosis may even be the main 2000; Lombry et al., 2000; Chang et al., 2000). The
force driving peptides and proteins through skin. process may also transport into the integument, vaccines
A lidocaine–epinephrine (adrenaline) device for local (Misra et al., 1999), liposomes (Badkar et al., 1999), as
anaesthesia is now available, and work proceeds on the well as nanoparticles and microspheres (Prausnitz et al.,
development of iontophoretic patch systems (Naik et al., 1996; Hofmann et al., 1995), although failures have been
2000). reported (Cheng et al., 1999). An interesting development
As for other enhancing techniques, workers investigate is electroporation used to deliver physostigmine as a
the synergy of iontophoresis with e.g. penetration en- pretreatment for anticipated organophosphate poisoning
hancers (Bhatia and Singh, 1998a,b; Choi et al., 1999; (Rowland and Chilcott, 2000).
Wang et al., 2000) and ultrasound (Le et al., 2000; Macromolecules and small molecules may enhance
Mitragotri et al., 2000). electroporation by stabilising sterically pores created in
An interesting development is reverse iontophoresis by skin (Vanbever et al., 1997; Weaver et al., 1997; Zewert et
which molecules in the systemic circulation (such as al., 1999; Ilic et al., 1999). Ilic et al. (2001) propose
glucose) can be extracted at the skin surface using the microengineering aqueous pathways for transdermal deliv-
electroosmotic effect (Tamada et al., 1995; Santi and Guy, ery and for sampling skin fluids.
1996). The GlucoWatch Biographer aims to monitor blood Electroporation may combine with iontophoresis to
glucose concentrations in diabetics using this procedure enhance the penetration of peptides such as vasopressin,
(Naik et al., 2000). neurotensin, calcitonin and LHRH (Bommannan et al.,
A problem with iontophoresis is that, although the 1994; Riviere et al., 1995; Banga et al., 1999). Electropo-
apparent current density per unit area is low, most of the ration has also been combined with ultrasound (Kost et al.,
current penetrates via the low resistance route i.e. the 1996).
appendages, particularly hair follicles (Abramson and Again, instrumentation for home use for this potent
Engle, 1941; Grimmes, 1984; Burnette and Ongpipat- technique is problematical, and concern relating to possible
tanakul, 1988; Cullander and Guy, 1991; Scott et al., skin damage requires further study (Prausnitz, 1999;
1993;). Thus the actual current density in the follicle may Vanbever and Preat, 1999).
be high enough to damage growing hair. (Pores, whose Mitragotri (2000) has published an excellent thought-
identity has not been elucidated, may also contribute to provoking review of synergistic interactions between
iontophoretic flux — Burnette and Ongpipattanakul, 1988; chemical enhancers (Section 4.3 and Fig. 5) and ultra-
Wearley et al., 1989). There is also concern about other sound, iontophoresis or electroporation.
possible irreversible changes to the skin. The biophysical
effects of iontophoresis (and electroporation) have been
4.5.4. Magnetophoresis
reviewed by Jadoul et al. (1999) and Curdy et al. (2001).
Limited work probed the ability of magnetic fields to
As for ultrasound, there is the problem of home use,
move diamagnetic materials through skin (Murthy, 1999).
although considerable work has been done on miniaturis-
Langer (2000) discussed the interesting idea of employing
ing systems e.g. paper batteries and wristwatch-like de-
intelligent systems based on magnetism or microchip
vices are being investigated.
technology to deliver drugs in controlled, pulsatile mode
(Santini et al., 1999).
4.5.3. Electroporation
Skin electroporation (electropermeabilization) (Prausnitz
et al., 1993) creates transient aqueous pores in the lipid 4.5.5. Photomechanical wave
bilayers (Fig. 2) by application of short (micro- to milli- A drug solution, placed on the skin and covered by a
second) electrical pulses of approximately 100–1000 V/ black polystyrene target, is irradiated with a laser pulse.
cm. These pores provide pathways for drug penetration The resultant photomechanical wave stresses the horny
110 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114

layer and enhances drug delivery (Lee et al., 1999). The Drug Delivery, 2nd Edition. Marcel Dekker, New York and Basel, pp.
technique is likely to remain experimental. 77–93.
Burkoth, T.L., Bellhouse, B.J., Hewson, G., Longridge, D.J., Muddle,
A.G., Sarphie, D.F., 1999. Transdermal and transmucosal powdered
drug delivery. Crit. Rev. Ther. Drug Carrier Sys. 16, 331–384.
Burnette, R.R., Ongpipattanakul, B., 1987. Characterisation of the
References permselective properties of excised human skin during iontophoresis.
J. Pharm. Sci. 76, 765–773.
Abramson, H.A., Engle, M.G., 1941. Skin reactions. XII. Patterns Burnette, R.R., Ongpipattanakul, B., 1988. Characterisation of the pore
produced in the skin by electrophoresis of dyes. Arch. Dermatol. transport properties and tissue alteration of excised human skin during
Syphilol. 44, 190–200. iontophoresis. J. Pharm. Sci. 77, 132–137.
Agarwal, R., Katare, O.P., Vyas, S.P., 2000. The pilosebaceous unit: a Byl, N.N., 1995. The use of ultrasound as an enhancer for transcutaneous
pivotal route for topical drug delivery. Methods Find Exp. Clin. drug delivery: phonophoresis. Physica Ther. 75, 539–553.
Pharmacol. 22, 129–133. Camel, E., 1995. Ultrasound. In: Smith, E.W., Maibach, H.I. (Eds.),
Allec, J., Chatelus, A., Wagner, N., 1997. Skin distribution and pharma- Percutaneous Penetration Enhancers. CRC Press, Boca Raton, FL, pp.
ceutical aspects of adapalene gel. J. Am. Acad. Dermatol. 36, S119– 369–382.
S125. Cantrel, J.T., McArthur, M.J., Pishko, M.V., 2000. Transdermal extraction
Asano, J., Suisha, F., Takada, M., Kawasaki, M., Miyazaki, S., 1997. of interstitial fluid by low-frequency ultrasound quantified with
Effect of pulsed output ultrasound on the transdermal absorption of (H 2 O)–H 3 as a tracer molecule. J. Pharm. Sci. 89, 1170–1179.
indomethacin from an ointment in rats. Biol. Pharm. Bull. 20, 288– Cevc, G., 1996. Transfersomes, liposomes and other lipid suspensions on
291. the skin: permeation enhancement, vesicle penetration, and transder-
Asbill, C.S., El-Kattan, A.F., Michniak, B., 2000. Enhancement of mal drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 13, 257–388.
transdermal drug delivery: chemical and physical approaches. Crit. Cevc, G., Blume, G., 1992. Lipid vesicles penetrate into intact skin owing
Rev. Ther. Drug Carrier Sys. 17, 621–658. to the transdermal osmotic gradient and hydration force. Biochim.
Asbill, C.S., Michniak, B.B., 2000. Percutaneous penetration enhancers: Biophys. Acta 1104, 226–232.
local versus transdermal activity. PSTT 3, 36–41. Cevc, G., Blume, G., Schatzlein, A., 1997. Transfersomes-mediated
Aungst, B.J., Blake, J.A., Hussain, M.A., 1990. Contributions of drug transepidermal delivery improves the regio-specificity and biological
solubilisation, partitioning, barrier disruption and solvent permeation activity of corticosteroids in vivo. J. Control. Rel. 45, 211–226.
to the enhancement of skin permeation of various compounds with Cevc, G., Blume, G., Schatzlein, A., Gebauer, D., Paul, A., 1996. The
fatty acids and amines. Pharm. Res. 7, 712–718. skin: a pathway for systemic treatment with patches and lipid-based
Badkar, A.V., Betageri, G.V., Hofmann, G.A., Banga, A.K., 1999. En- carriers. Adv. Drug Del. Rev. 18, 349–378.
hancement of transdermal iontophoretic delivery of a liposomal Cevc, G., Schatzlein, A., Blume, G., 1995. Transdermal drug carriers:
formulation of colchicine by electroporation. Drug Del. 6, 111–115. basic properties, optimisation and transfer efficiency in the case of
Banga, A.K., 1998. Electrically Assisted Transdermal and Topical Drug epicutaneously applied peptides. J. Control. Res. 36, 3–16.
Delivery. Taylor and Francis, London. Cevc, G., Schatzlein, A., Gebauer, D., Blume, G., 1993. Ultra-high
Banga, A.K., Bose, S., Ghosh, T.K., 1999. Iontophoresis and electropora- efficiency of drug and peptide transfer through the intact skin by
tion: comparisons and contrasts. Int. J. Pharm. 179, 1–19. means of novel drug carriers, transfersome. In: Brain, K.R., James,
Barry, B.W., 1983. Dermatological Formulations: Percutaneous Absorp- V.A., Walters, K.A. (Eds.) Prediction of Percutaneous Penetration. 3rd
tion. Dekker, New York. International Conference. Vol. 3b. STS Publishing, Cardiff, 226–236.
Barry, B.W., 1988. Action of skin penetration enhancers — the lipid Chang, S.L., Hofmann, G.A., Zhang, L., Deftos, L.J., Banga, A.K., 2000.
protein partitioning theory. Int. J. Cosmet. Sci. 10, 281–293. The effect of electroporation on iontophoretic transdermal delivery of
Barry, B.W., 1991. Lipid–protein partitioning theory of skin penetration calcium regulating hormones. J. Control. Res. 66, 127–133.
enhancement. J. Control. Rel. 15, 237–248. Cheng, L.L.H., Chien, Y.W., 1999. Enhancement of skin permeation. In:
Barry, B.W., Williams, A.C., 1995. Permeation enhancement through skin. Magdassi, S., Touitou, E. (Eds.), Novel Cosmetic Delivery Systems.
In: Swarbrick, J., Boylan, J.C. (Eds.). Encyclopedia of Pharmaceutical Marcel Dekker, New York, pp. 5–70.
Technology, Vol. 11. Marcel Dekker, New York, pp. 449–493. Cheng, T., Langer, R., Weaver, J.C., 1999. Charged microbeads are not
Bashir, S.J., Chew, A.L., Anigbogu, A., Dreher, F., Maibach, H.I., 2001. transported across the human stratum corneum in vitro by short
Physical and physiological effects of stratum corneum tape stripping. high-voltage pulses. Bioelectrochem. Bioenerg. 48, 181–192.
Skin Res. Technol. 7, 40–48. Chiang, C.M., Flynn, G.L., Weiner, G.J., 1989. Bioavailability assessment
Bath, B.D., White, H.S., Scott, E.R., 2000. Visualisation and analysis of of topical delivery systems: effect of vehicle evaporation upon in vitro
electroosmotic flow in hairless mouse skin. Pharm. Res. 17, 471–475. delivery of minoxidil from solution formulations. Int. J. Pharm. 55,
Bhatia, K.S., Singh, J., 1998a. Mechanism of transport enhancement of 229–236.
LHRH through porcine epidermis by terpenes and iontophoresis: Chiang, C-H., Shao, C-H., Chen, J-L., 1998. Effects of pH, electric
permeability and lipid extraction studies. Pharm. Res. 15, 1857–1862. current, and enzyme inhibitors on iontophoresis of delta sleep-inducing
Bhatia, K.S., Singh, J., 1998b. Synergistic effect of iontophoresis of a peptide. Drug Devel. Ind. Pharm. 24, 431–438.
series of fatty acid on LHRH permeability through human skin. J. Choi, E.H., Lee, S.H., Ahn, S.K., Hwang, S.M., 1999. The pretreatment
Pharm. Sci. 87, 462–469. effect of chemical skin penetration enhancers in transdermal drug
Bommannan, D., Tamada, J., Leung, L., Potts, R.O., 1994. Effect of delivery using iontophoresis. Skin Pharmacol. Appl. Skin Physiol. 12,
electroporation on transdermal iontophoretic delivery of luteinizing 326–335.
hormone releasing hormone (LHRH) in vitro. Pharm. Res. 11, 1809– Coldman, M.F., Poulsen, B.J., Higuchi, T., 1969. Enhancement of
1814. percutaneous absorption by the use of volatile: nonvolatile systems as
Brand, R.H., Wahl, A., Iversen, P.L., 1998. Effects of size and sequence vehicles. J. Pharm. Sci. 58, 1098–1102.
on the iontophoretic delivery of oligonucleotides. J. Pharm. Sci. 87, Cornwell, P.A., Barry, B.W., 1994. Sesquiterpene components of volatile
49–52. oils as skin penetration enhancers for the hydrophilic permeant 5-
Bucks, D.A.W., Maibach, H.I., Guy, R.H., 1989. Occlusion does not fluorouracil. J. Pharm. Pharmacol. 46, 261–269.
uniformly enhance penetration in vivo. In: Bronaugh, R.L., Maibach, Cornwell, P.A., Barry, B.W., Bouwstra, J.A., Gooris, G.S., 1996. Modes
H.I. (Eds.), Percutaneous Absorption; Mechanisms, Methodology, of action of terpene penetration enhancers in human skin: differential
 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114 111

scanning calorimetry, small-angle X-ray diffraction and enhancer absorption. In: Smith, E.W., Maibach, H.I. (Eds.), Percutaneous
uptake studies. Int. J. Pharm. 127, 9–26. Penetration Enhancers. CRC Press, Boca Raton, FL, pp. 29–34.
Cornwell, P.A., Barry, B.W., Stoddart, C.P., Bouwstra, J.A., 1994. Wide- Henmi, T., Fujii, M., Kikuchi, K., Yamanobe, N., Matsumoto, M., 1994.
angle X-ray diffraction of human stratum corneum: effects of hydra- Application of an oily gel formed by hydrogenated soybean phos-
tion and terpene enhancer treatment. J. Pharm. Pharmacol. 46, 938– pholipids as a percutaneous absorption-type ointment base. Chem.
950. Pharm. Bull. 42, 651–655.
Cullander, C., Guy, R.H., 1991. Sites of iontophoretic current flow into Henry, S., McAllister, D., Allen, M.G., Prauznitz, M.R., 1998. Mi-
the skin: identification and characterisation with the vibrating probe crofabricated microneedles: a novel method to increase transdermal
drug delivery, J. Pharm. Sci., 922–925.
electrode. J. Invest. Dermatol. 97, 55–64.
Higuchi, T., 1960. Physical chemical analysis of percutaneous absorption
Curdy, C., Kalia, Y.N., Guy, R.H., 2001. Non-invasive assessment of the
process. J. Soc. Cosmetic Chemists 11, 85–97.
effects of iontophoresis on human skin in vivo. J. Pharm. Pharmacol.
Higuchi, W.I., Li, S.K., Ghanem, A.H., Zhu, H.G., Song, Y., 1999.
53, 769–777.
Mechanistic aspects of iontophoresis in human epidermal membrane.
Davis, A.F., Hadgraft, J., 1991. Effect of supersaturation on membrane
J. Control. Res. 62, 13–23.
transport: 1. Hydrocortisone acetate. Int. J. Pharm. 76, 1–8.
Hoffman, R.M., 2000. The hair follicle as a gene therapy target. Nature
Dayan, N., Touitou, E., 2000. Carriers for skin delivery of trihex-
Biotechnol. 18, 20–21.
yphenidyl HCI: ethosomes vs. liposomes. Biomaterials 21, 1879– Hofmann, G.A., Rustrum, W.V., Suder, K.S., 1995. Electro-incorporation
1885. of microcarriers as a method for the transdermal delivery of large
Degano, P., Sarphie, D.F., Bangham, C.R.M., 1998. Intradermal DNA molecules. Bioelectrochem. Bioenerg. 38, 209–222.
immunization of mice against influenza A virus using the novel Hollingsbee, D.A., White, R.J., Edwardson, D.A., 1965. Use of occluded
PowderJect (R) system. Vaccine 16, 394–398. hydrocolloid patches. In: Smith, E.W., Maibach, H.I. (Eds.), Percuta-
Delgado-Charro, M.B., Guy, R.H., 1994. Characterisation of convective neous Penetration Enhancers. CRC Press, Boca Raton, FL, pp. 35–43.
solvent flow during iontophoresis. Pharm. Res. 11, 929–935. Hori, M., Satoh, S., Maibach, H.I., 1989. Classification of percutaneous
Dover, J.S., Hruza, G.J., Arndt, K.A., 2000. Lasers in skin resurfacing. penetration enhancers: a conceptual diagram. In: Bronaugh, R.L.,
Semin. Cutan. Med. Surg. 19, 207–220. Maibach, H.I. (Eds.), Percutaneous Absorption; Mechanisms, Meth-
El Maghraby, G.M.M., Williams, A.C., Barry, B.W., 1999. Skin delivery odology, Drug Delivery, 2nd Edition. Marcel Dekker, New York and
of estradiol from deformable and traditional liposomes: mechanistic Basel, pp. 197–211.
studies. J. Pharm. Pharmacol. 51, 1123–1134. Hori, M., Satoh, S., Maibach, H.I., 1990. Classification of penetration
El Maghraby, G.M.M., Williams, A.C., Barry, B.W., 2000a. Skin delivery enhancers: a conceptual diagram. J. Pharm. Pharmacol. 42, 71–72.
of estradiol from ultradeformable liposomes: refinement of surfactant Hikima, T., Hirai, Y., Tojo, K., 1998. The effect of ultrasound application
concentration. Int. J. Pharm. 196, 63–74. on skin metabolism of prednisolone 21-acetate. Pharm. Res. 15,
El Maghraby, G.M.M., Williams, A.C., Barry, B.W., 2000b. Skin delivery 1680–1683.
of estradiol from lipid vesicles: importance of liposome structure. Int. Iervolino, M., Raghavan, S.L., Hadgraft, J., 2000. Membrane penetration
J. Pharm. 204, 159–169. enhancement of ibuprofen using supersaturation. Int. J. Pharm. 198,
El Maghraby, G.M.M., Williams, A.C., Barry, B.W., 2001a. Skin delivery 229–238.
of 5-fluorouracil from ultradeformable and standard liposomes in vitro. Ilic, L., Gowrishankar, T.R., Vaughan, T.E., Herndon, T.O., Weaver, J.C.,
J. Pharm. Pharmacol., in press. 1999. Spatially constrained skin electroporation with sodium thiosul-
El Maghraby, G.M.M., Williams, A.C., Barry, B.W., 2001b. Skin hydra- fate and urea creates transdermal microconduits. J. Control. Res. 61,
tion and possible shunt route penetration in controlled estradiol 185–202.
delivery from ultradeformable and standard liposomes. J. Pharm. Ilic, L., Gowrishankar, T.R., Vaughan, T.E., Herndon, T.O., Weaver, J.C.,
Pharmacol., in press. 2001. Microfabrication of individual 200 mm diameter transdermal
Fan, H.R., Lin, Q., Morrissey, G.R., Khavari, P.A., 1999. Immunization microconduits using high voltage pulsing in salicylic acid and benzoic
via hair follicles by topical application of naked DNA to normal skin. acid. J. Invest. Dermatol. 116, 40–49.
Nature Biotechnol. 17, 870–872. Jadoul, A., Boustra, J., Prear, V., 1999. Effects of iontophoresis and
Fang, J-Y., Kuo, C-T., Huang, Y-B., Wu, P-C., Tsai, Y-H., 1999. electroporation on the stratum corneum — review of the biophysical
Transdermal delivery of sodium nonivamide acetate from volatile studies. Adv. Drug Del. Rev. 35, 89–105.
vehicles: effects of polymers. Int. J. Pharm. 176, 157–167. Jadoul, A., Preat, V., 1997. Electrically-enhanced transdermal delivery of
Fresta, M., Puglisi, G., 1996. Application of liposomes as potential domperidone. Int. J. Pharm. 154, 229–234.
cutaneous drug delivery systems: in vitro and in vivo investigation Johnson, M.E., Mitragotri, S., Patel, A., Blankschtein, D., Langer, R.,
with radioactivity labelled vesicles. J. Drug Target 4, 95–101. 1996. Synergistic effects of chemical enhancers and therapeutic
Friedland, J.A., Buchel, E.W., 2000. Skin care and the topical treatment of ultrasound on transdermal drug delivery. J. Pharm. Sci. 85, 670–679.
aging skin. Clin. Plastic Surg. 27, 501–506. Kang, L.S., Jun, H.W., McCall, J.W., 2000. Physicochemical studies of
Goodman, M., Barry, B.W., 1989. Lipid–protein partitioning (LPP) theory lidocaine–menthol binary systems for enhanced membrane transport.
of skin enhancer activity: finite dose technique. Int. J. Pharm. 57, Int. J. Pharm. 206, 35–42.
29–40. Kanikkannan, N., Kandimalla, K., Lamba, S.S., Singh, M., 2000. Struc-
Grimmes, S., 1984. Pathways of ionic flow through human skin in vivo. ture–activity relationship of chemical penetration enhancers in trans-
Acta Derm. Venereol. 64, 93–98. dermal drug delivery. Curr. Med. Chem. 7, 593–608.
Guo, J., Ping, Q., Sun, G., Jiao, C., 2000. Lecithin vesicular carriers for Kemken, J., Ziegler, A., Muller, B.W., 1992. Influence of supersaturation
transdermal delivery of cyclosporin A. Int. J. Pharm. 194, 201–207. on the thermodynamic effect of bupranolol after dermal administration
Gupta, S.K., Southam, M., Sathyan, G., Klausner, M., 1998. Effect of using microemulsions as vehicle. Pharm. Res. 9, 554–558.
current density on pharmacokinetics following continuous or intermit- Kondon, S., Sugimoto, I., 1987. Enhancement of transdermal delivery by
tent input from a fentanyl electrotransport system. J. Pharm. Sci. 87, superfluous thermodynamic potential. I. Thermodynamic analysis of
976–981. nifedipine transport across the lipoidal barrier. J. Pharmacobio-Dyn.
Guy, R.H., 1998. Iontophoresis — recent developments. J. Pharm. 10, 587–594.
Pharmacol. 50, 371–374. Kondon, S., Yamasaki-Konishi, H., Sugimoto, I., 1987a. Enhancement of
Hadgraft, J., 1999. Passive enhancement strategies in topical and transder- transdermal delivery by superfluous thermodynamic potential. II. In
mal drug delivery. Int. J. Pharm. 184, 1–6. vitro–in vivo correlation of percutaneous nifedipine transport. J.
Haigh, J.M., Smith, E.W., 1995. Hydration and topical corticosteroid Pharmacobio-Dyn. 10, 662–668.
112 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114

Kondon, S., Yamanaka, D., Sugimoto, I., 1987b. Enhancement of Merino, V., Lopez, A., Kalia, Y.N., Guy, R.H., 1999. Electrorepulsion
transdermal delivery by superfluous thermodynamic potential. III. versus electroosmosis: effect of pH on the iontophoretic flux of
Percutaneous absorption of nifedipine in rats. J. Pharmacobio-Dyn. 10, 5-fluorouracil. Pharm. Res. 16, 758–761.
743–749. Mezei, M., 1992. Biodisposition of liposome-encapsulated active ingredi-
Kost, J., 1995. Phonophoresis. In: Berner, B., Dinh, S. (Eds.), Electroni- ents applied on the skin. In: Falco, O.B., Korting, H.C., Maibach, H.I.
cally Controlled Drug Delivery. CRC Press, Boca Raton, FL, pp. (Eds.), Liposome Dermatics. Springer-Verlag, Berlin, pp. 206–214.
2115–2128. Mezei, M., Gulasekharam, V., 1980. Liposomes: a selective drug delivery
Kost, J., Pliquett, U., Mitragotri, S., Yamamoto, A., Langer, R., Weaver, system for the topical route of administration. I. Lotion dosage form.
J., 1996. Synergistic effect of electric field and ultrasound on transder- Life Sci. 26, 1473–1477.
mal transport. Pharm. Res. 13, 633–638.
Mezei, M., Gulasekharam, V., 1982. Liposomes: a selective drug delivery
Langer, R., 2000. Biomaterials in drug delivery and tissue engineering:
system for the topical route of administration: gel dosage form. J.
one laboratory’s experience. Acc. Chem. Res. 33, 94–101.
Pharm. Pharmacol. 34, 473–474.
Le, L., Kost, J., Mitragotri, S., 2000. Combined effect of low frequency
Miller, L.L., Kolaskie, C.J., Smith, G.A., Rivier, J., 1990. Transdermal
ultrasound and iontophoresis: application for transdermal heparin
iontophoresis of gonadotropin releasing hormone and two analogues.
delivery. Pharm. Res. 17, 1151–1154.
J. Pharm. Sci. 79, 490–493.
Lee, S., Kollias, N., McAuliffe, D.J., Flotte, T.J., Doukas, A.G., 1999.
Misra, A., Ganga, S., Upadhyay, P., 1999. Needle-free non-adjuvanted
Topical drug delivery in humans with a single photomechanical wave.
Pharm. Res. 16, 1717–1721. skin immunization by electroporation-enhanced transdermal delivery
Lin, R.Y., Chien, Y.C., Chen, W.Y., 1997. The role of electroosmotic flow of diphtheria toxoid and a candidate peptide vaccine against hepatitis
on in vitro transdermal iontophoresis. J. Control. Rel 43, 23–33. B virus. Vaccine 18, 517–523.
Lipp, R., 1998. Selection and use of crystallisation inhibitors for matrix- Mitragotri, S., 2000. Synergistic effect of enhancers for transdermal drug
type transdermal drug-delivery systems containing sex steroids. J. delivery. Pharm. Res. 17, 1354–1359.
Pharm. Pharmacol. 50, 1343–1349. Mitragotri, S., Blankschtein, D., Langer, R., 1995a. In: Swarbrick, J.,
Lipp, R., Muller-Fahrnow, A., 1999. Use of X-ray crystallography for the Boylan, J. (Eds.), Enc. of Pharm. Tech.. Marcel Dekker, New York,
characterisation of single crystals grown in steroid containing transder- pp. 103–122.
mal drug delivery systems. Eur. J. Pharm. Biopharm. 47, 133–138. Mitragotri, S., Blankschtein, D., Langer, R., 1995b. Ultrasound-mediated
Liu, J., Lewis, T.N., Prausnitz, M.R., 1998. Non-invasive assessment and transdermal protein delivery. Science 269, 850–853.
control of ultrasound-mediated membrane permeabilisation. Pharm. Mitragotri, S., Blankschtein, D., Langer, R., 1996. Transdermal drug
Res. 15, 918–924. delivery using low-frequency sonophoresis. Pharm. Res. 13, 411–420.
Lombry, C., Dujardin, N., Preat, V., 2000. Transdermal delivery of Mitragotri, S., Coleman, M., Kost, J., Langer, R., 2000b. Transdermal
macromolecules using skin electroporation. Pharm. Res. 17, 32–37. extraction of analytes using low-frequency ultrasound. Pharm. Res. 17,
McAllister, D.V., Allen, M.G., Prausnitz, M.R., 2000. Microfabricated 466–470.
microneedles for gene and drug delivery. Annu. Rev. Biomed. Eng. 2, Mitragotri, S., Coleman, M., Kost, J., Langer, R., 2000c. Analysis of
289–313. ultrasonically extracted interstitial fluid as a predictor of blood glucose
Mazda, F., Ozer, A.Y., Ercan, M.T., Hincal, A.A., 1997. Preparation and levels. J. Appl. Phys. 89, 961–966.
characterisation of urea niosomes — in vitro and in vivo studies. STP Mitragotri, S., Edwards, D., Blankschtein, D., Langer, R., 1995c. A
Pharm. Sci. 7, 205–214. mechanistic study of ultrasonically enhanced transdermal drug deliv-
Meehan, E., Gross, Y., Davidson, D., Martin, M., Tsals, I., 1997. A ery. J. Pharm. Sci. 84, 697–706.
microinfusor device for the delivery of therapeutic levels of peptides Mitragotri, S., Farrell, J., Tang, H., Terahara, T., Kost, J., Langer, R.,
and macromolecules. J. Control. Rel. 46, 107–116. 2000d. Determination of threshold energy dose for ultrasound-induced
Megrab, N.A., Williams, A.C., Barry, B.W., 1995. Estradiol permeation transdermal drug transport. J. Control. Rel. 63, 41–52.
through human skin and silastic membrane: effects of propylene glycol Mitragotri, S., Kost, J., 2000. Low frequency sonophoresis: a noninvasive
and supersaturation. J. Control. Rel. 36, 277–294. method of drug delivery and diagnostics. Biotech. Prog. 16, 488–492.
Megwa, S.A., Cross, S.E., Benson, H.A.E., Roberts, M.S., 2000a. Ion-pair Mitragotri, S., Ray, D., Farrell, J., Tang, H., Yu, B., Kost, J., Blanksch-
formation as a strategy to enhance topical delivery of salicylic acid. J. tein, D., Langer, R., 2000a. Synergistic effect of low-frequency
Pharm. Pharmacol. 52, 919–928. ultrasound and sodium lauryl sulphate on transdermal transport. J.
Megwa, S.A., Cross, S.E., Whitehouse, M.W., Benson, H.A.E., Roberts, Pharm. Sci. 89, 892–900.
M.S., 2000b. Effect of ion pairing with alkylamines on the in vitro Murthy, S.N., 1999. Magnetophoresis: an approach to enhance transder-
dermal penetration and local tissue disposition of salicylates. J. Pharm. mal drug diffusion. Pharmazie 54, 377–379.
Pharmacol. 52, 929–940. Naik, A., Kalia, Y.N., Guy, R.H., 2000. Transdermal drug delivery:
Meidan, V., Alhaique, F., Touitou, E., 1998a. Vesicular carriers for topical overcoming the skin’s barrier function. PSTT 3, 318–326.
delivery. Acta Technol. Legis. Medic. 9, 1–6. Nyqvist-Mayer, A.A., Brodin, A.F., Frank, S.G., 1986. Drug release
Meidan, V.M., Docker, M., Walmsey, A.D., Irwin, W.J., 1998b. Low studies on an oil–water emulsion based on a eutectic mixture of
intensity ultrasound as a probe to elucidate the relative follicular lidocaine and prilocaine as the dispersed phase. J. Pharm. Sci. 75,
contribution to total transdermal absorption. Pharm. Res. 15, 85–92. 365–373.
Menczel, E.M., 1995. Delipidization of the cutaneous permeability barrier Oldenburg, K., Vo, K.T., Smith, G.A., Selick, H.E., 1995. Iontophoretic
and percutaneous penetration. In: Smith, E.W., Maibach, H.I. (Eds.), delivery of oligonucleotides across full thickness hairless mouse skin.
Percutaneous Penetration Enhancers. CRC Press, Boca Raton, FL, pp. J. Pharm. Sci. 84, 915–921.
383–392. Ongpipattanakul, B., Burnette, R.R., Potts, R.O., Francoeur, M.L., 1991.
Menon, G.K., Bommannan, D.B., Elias, P.M., 1994. High-frequency Evidence that oleic acid exists in a separate phase within stratum
sonophoresis: permeation pathways and structural basis for enhanced corneum lipids. Pharm. Res. 8, 350–354.
permeation. Skin Pharmacol. 7, 130–139. Paul, A., Cevc, G., Bachhawat, B.K., 1995. Transdermal immunization
Menon, G.K., Lee, S.H., Roberts, M.S., 1998. Ultrastructural effects of with large proteins by means of ultradeformable drug carriers. Eur. J.
some solvents and vehicles on the stratum corneum and other skin Immunol. 25, 3521–3524.
components: evidence for an ‘extended mosaic-partitioning model of Peck, K.D., Srinivasan, V., Li, S.K., Higuchi, W.I., Ghanem, A.H., 1996.
the skin barrier’. In: Roberts, M.S., Walters, K.A. (Eds.), Dermal Quantitative description of the effect of molecular size upon electro-
Absorption and Toxicity Assessment. Marcel Dekker, New York, pp. osmotic flux enhancement during iontophoresis for a synthetic mem-
727–751. brane and human epidermal membrane. J. Pharm. Sci. 85, 781–788.
 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114 113

Pellett, M.A., Castellano, S., Hadgraft, J., Davis, A.F., 1997a. The of radiolabeled inulin to hairless guinea pigs. J Control. Rel. 47,
penetration of supersaturated solutions of piroxicam across silicone 61–69.
membranes and human skin in vitro. J. Control. Rel 46, 205–214. Schaefer, H., Redelmeier, T.E., 1996. In: Skin Barrier. Principles of
Pellett, M.A., Davis, A.F., Hadgraft, J., 1994. Effect of supersaturation on Percutaneous Absorption. Karger, Basel, pp. 235–237.
membrane transport: 2. Piroxicam. Int. J. Pharm. 111, 1–6. Schreier, H., Bouwstra, J., 1994. Liposomes and niosomes as topical drug
Pellett, M.A., Roberts, M.S., Hadgraft, J., 1997b. Supersaturated solutions carriers: dermal and transdermal drug delivery. J. Control. Rel. 30,
evaluated with an in vitro stratum corneum tape stripping technique. 1–15.
Int. J. Pharm. 151, 91–98. Schwarb, F.P., Imanidis, G., Smith, E.W., Haigh, J.M., Surber, C., 1999.
Perez-Cullell, N., Coderch, L., de la Maza, A., Parra, J.L., Estelrich, J., Effect of concentration and degree of saturation of topical fluocinonide
2000. Influence of the fluidity of liposome compositions on percuta- formulations on in vitro membrane transport and in vivo availability
neous absorption. Drug Del. 7, 7–13. on human skin. Pharm. Res. 16, 909–915.
Pikal, M.J., 1992. The role of electroosmosis in transdermal ion- Scott, E.R., Laplaza, A.I., White, H.S., Phipps, J.B., 1993. Transport of
tophoresis. Adv. Drug Del. Rev. 9, 201–237. ionic species in skin: contribution of pores to the overall skin
Planas, M.E., Gonzalez, P., Rodriquez, L., Sanchez, S., Cevc, G., 1992. conductance. Pharm. Res. 10, 1699–1709.
Noninvasive percutaneous induction of topical analgesia by a new type Sentjurc, M., Vrhovnik, K., Kristl, J., 1999. Liposomes as a topical
of drug carrier and prolongation of local pain insensitivity by delivery system: the role of size on transport studied by the EPR
anesthetic liposomes. Anesth. Analg. 75, 615–621. imaging. J. Control. Rel. 59, 87–97.
Prausnitz, M.R., 1999. A practical assessment of transdermal drug Simonin, J.-P., 1995. On the mechanisms of in vitro and in vivo
delivery by skin electroporation. Adv. Drug Del. Rev. 35, 61–76. phonophoresis. J. Control. Rel. 33, 125–141.
Prausnitz, M.R., Bose, V.G., Langer, R., Weaver, J.C., 1993. Electropora- Sims, S.M., Higuchi, W.I., 1990. Baseline studies on iontophoretic
tion of mammalian skin: a mechanism to enhance transdermal drug transport in hairless mouse skin: the effect of applied voltage drop and
delivery. Proc. Natl. Acad. Sci. USA 90, 10504–10508. pH on the iontophoresis of a model weak electrolyte. J. Membr. Sci.
Prausnitz, M.R., Edelman, E.R., Gimm, J.A., Langer, R., Weaver, J.C., 49, 305–320.
1995. Transdermal delivery of heparin by skin electroporation. Bio- Singh, S., Bi, M., Jayaswal, S.B., Singh, J., 1998. Effect of current
technology 13, 1205–1209. density on the iontophoretic permeability of benzyl alcohol and surface
Prausnitz, M.R., Gimm, J.A., Guy, R.H., Langer, R., Weaver, J.C., characteristics of human epidermis. Int. J. Pharm. 166, 157–166.
Cullander, C., 1996. Imaging of transport pathways across human Sinha, V.R., Kaur, M.P., 2000. Permeation enhancers for drug delivery.
stratum corneum during high-voltage and low-voltage electrical expo- Drug. Devel. Ind. Pharm. 26, 1131–1140.
sures. J. Pharm. Sci. 85, 1363–1370. Smith, E.W., Maibach, H.I. (Eds.), 1995. Percutaneous Penetration
Raghavan, S.L., Trividic, A., Davis, A.F., Hadgraft, J., 2000. Effect of Enhancers. CRC Press, Boca Raton, FL.
cellulose polymers on supersaturation and in vitro membrane transport Smith, J.C., Irwin, W.J., 2000. Ionisation and the effect of absorption
of hydrocortisone acetate. Int. J. Pharm. 193, 231–237. enhancers on transport of salicylic acid through silastic rubber and
Reddy, I.K., Kommuru, T.R., Zaghloul, A.A.A., Khan, M.A., 2000. human skin. Int. J. Pharm. 210, 69–82.
Chirality and its implications in transdermal drug development. Crit. Stott, P.W., Williams, A.C., Barry, B.W., 1996. Characterisation of
Rev. Ther. Drug Carrier Syst. 17, 285–325. complex coacervates of some tricyclic antidepressants and evaluation
Regnier, V., De Morre, N., Jadoul, A., Preat, V., 1999. Mechanisms of a of their potential for enhancing transdermal flux. J. Control. Rel. 41,
phosphorothioate oligonucleotide delivery by skin electroporation. Int. 215–227.
J. Pharm. 184, 147–156. Stott, P.W., Williams, A.C., Barry, B.W., 1998. Transdermal delivery from
Regnier, V., Le Doan, T., Preat, V., 1997. Parameters controlling topical eutectic systems: enhanced permeation of a model drug, ibuprofen. J.
delivery of oligonucleotides by electroporation. Drug Target. 5, 1–16. Control. Rel. 50, 297–308.
Regnier, V., Tahiri, A., Andre, N., Lemaitre, M., Le Doan, T., Preat, V., Stott, P.W., Williams, A.C., Barry, B.W., 2001. Mechanistic study into the
2000. Electroporation-mediated delivery of 39-protected phosphodies- enhanced transdermal permeation of a model b-blocker, propranolol,
ter oligodeoxynucleotides to the skin. J. Control. Rel. 67, 337–346. by fatty acids: a melting point depression effect. Int. J. Pharm. 219,
Riviere, J.E., Monteiro-Riviere, N.A., Rogers, R.A., Bommannan, D., 161–176.
Tamada, J.A., Potts, R.O., 1995. Pulsatile transdermal delivery of Svedman, P., Lundin, S., Hoglund, P., Hammarlund, C., Malmros, C.,
LHRH using electroporation: drug delivery and skin toxicology. J. Pantzar, N., 1996. Passive drug diffusion via standardized skin mini-
Control. Rel. 36, 229–233. erosion; Methodological aspects and clinical findings with new device.
Rowland, C.A., Chilcott, R.P., 2000. The electrostability and electrically Pharm. Res. 13, 1354–1359.
assisted delivery of an organophosphate pretreatment (physostigmine) Tachibana, K., 1992. Transdermal delivery of insulin to aloxan-diabetic
across human skin in vitro. J. Control. Rel. 68, 157–166. rabbits by ultrasound exposure. Pharm. Res. 9, 952–954.
Roy, M.J., Wu, M.S., Barr, L.J., Fuller, J.T., Tussey, L.G., Speller, S., Tacket, C.O., Roy, M.J., Widera, G., Swain, W.F., Broome, S., Edelman,
Culp, J., Burkholder, J.K., Swain, W.F., Dixon, R.M., Widera, G., R., 1999. Phase 1 safety and immune response studies of a DNA
Vessey, R., King, A., Ogg, G., Gallimore, A., Haynes, J.R., Fuller, vaccine encoding hepatitis B surface antigen delivered by a gene
D.H., 2000. Induction of antigen-specific CD81T cells, T helper cells, delivery device. Vaccine 17, 2826–2829.
and protective levels of antibody in humans by particle-mediated Tamada, J.A., Bohannon, N.J.V., Potts, R.O., 1995. Measurement of
administration of a hepatitis B virus DNA vaccine. Vaccine 19, glucose in diabetic subjects using non-invasive transdermal extraction.
764–778. Nature Med. 1, 1198–1201.
Sage, B.H., 1995. Iontophoresis. In: Smith, E.W., Maibach, H.I. (Eds.), Teissie, J., Eynard, N., Gabriel, B., Rols, M.P., 1999. Electropermeabili-
Percutaneous Penetration Enhancers. CRC Press, Boca Raton, FL, pp. zation of cell membranes. Adv. Drug Deliv. Rev. 35, 3–19.
351–368. Touitou, E., 1996. Compositions for applying active substances to or
Santi, P., Guy, R.H., 1996. Reverse iontophoresis – parameters determin- through the skin. US patent, 5,540,934.
ing electroosmotic flow: 1. pH and ionic strength. J. Control. Rel. 38, Touitou, E., 1998. Composition for applying active substances to or
159–165. through the skin. US patent, 5,716,683.
Santini, J.T., Cima, M.J., Langer, R., 1999. A controlled-release microch- Touitou, E., Dayan, N., Bergelson, L., Godin, B., Eliaz, M., 2000a.
ip. Nature 397, 335–338. Ethosomes – novel vesicular carriers for enhanced delivery: charac-
Sarphie, D.F., Johnson, B., Cormier, M., Burkoth, T.L., Bellhouse, B.J., terisation and skin penetration properties. J. Control. Rel. 65, 403–
1997. Bioavailability following transdermal powdered delivery (TPD) 418.
114 B.W. Barry / European Journal of Pharmaceutical Sciences 14 (2001) 101 – 114

Touitou, E., Godin, B., Weiss, C., 2000b. Enhanced delivery of drugs into cyclosporin-A coevaporate using electroporation technique. Drug Dev.
and across the skin by ethosomal carriers. Drug Dev. Res. 50, Ind. Pharm. 23, 657–663.
406–415. Waranuch, N., Ramachandran, C., Weiner, N.D., 1998. Controlled topical
Touitou, E., Godin, B., Weiss, C., 2000c. Enhanced delivery of drugs into delivery of cyclosporin-A from nonionic liposomal formulations:
and across the skin by ethosomal carriers. Drug Devel. Res. 50, mechanistic aspects. J. Liposome Res. 8, 225–238.
406–415. Wearley, L., Liu, J., Chien, Y.W., 1989. Iontophoresis facilitated transder-
Touitou, E., Meidan, V.M., Horwitz, E., 1998. Methods of quantitative mal delivery of verapamil. II. Factors affecting reversibility of skin
determination of drug localized in the skin. J. Control. Rel. 56, 7–21. permeability. J. Control. Rel. 9, 231–242.
Touitou, E., Schaffer, F.L., Dayan, N., Alhaique, F., Riccieri, F., 1994. Weaver, J.C., 2000. Electroporation of cells and tissues. IEEE Trans.
Modulation of caffeine delivery by carrier design: liposomes versus Plasma Sci. 28, 24–33.
permeation enhancers. Int. J. Pharm. 103, 131–136. Weaver, J.C., Vanbever, R., Vaughan, T.E., Prausnitz, M.R., 1997. Heparin
Tschan, T., Steffen, H., Supersaxo, A., 1997. Sebaceous-gland deposition alters transdermal transport associated with electroporation. Biochem.
of isotretinoin after topical application: An in vitro study using human Biophys. Res. Commun. 234, 637–640.
facial skin. Skin Pharmacol. 10, 126–134. Weiner, N., 1998. Targeted follicular delivery of macromolecules via
Ueda, H., Sugibayashi, K., Morimoto, Y., 1995. Skin penetration-enhanc- liposomes. Int. J. Pharm. 162, 29–38.
ing effects of drugs by phonophoresis. J. Control. Rel. 37, 291–297. Wester, R.C., Maibach, H.I., 1995. Penetration enhancement by skin
Valenta, C., Siman, U., Kratzel, M., Hadgraft, J., 2000. The dermal hydration. In: Smith, E.W., Maibach, H.I. (Eds.), Percutaneous Pene-
delivery of lignocaine: influence of ion pairing. Int. J. Pharm. 197, tration Enhancers. CRC Press, Boca Raton, FL, pp. 21–28.
77–85. Williams, A.C., Barry, B.W., 1991a. Terpenes and the lipid–protein
Vanbever, R., De Morre, N., Preat, V., 1996. Transdermal delivery of partitioning theory of skin penetration enhancement. Pharm. Res. 8,
fentanyl by electroporation II. Mechanisms involved in drug transport. 17–24.
Pharm. Res. 9, 1360–1366. Williams, A.C., Barry, B.W., 1991b. The enhancement index concept
Vanbever, R., Prausnitz, M.R., Preat, V., 1997. Macromolecules as novel applied to terpene penetration enhancers for human skin and model
transdermal transport enhancers for skin electroporation. Pharm. Res. lipophilic (estradiol) and hydrophilic (5-fluorouracil) drugs. Int. J.
14, 638–644. Pharm. 74, 157–168.
Vanbever, R., Preat, V., 1995. Factors affecting transdermal delivery of Zewert, T.E., Pliquett, U.F., Langer, R., Weaver, J.C., 1995. Transdermal
metoprolol by electroporation. Bioelectrochem. Bioenerg. 38, 223– transport of DNA antisense oligonucleotides by electroporation.
228. Biochem. Biophys. Res. Commun. 212, 286–292.
Vanbever, R., Preat, V., 1998. Transdermal delivery of fentanyl: rapid Zewert, T.E., Pliquett, U.F., Vanbever, R., Langer, R., Weaver, J.C., 1999.
onset of analgesia using skin electroporation. J. Control. Rel. 50, Creation of transdermal pathways for macromolecule transport by skin
225–235. electroporation and a low toxicity, pathway-enlarging molecule.
Vanbever, R., Preat, V., 1999. In vivo efficacy and safety of skin Bioelectrochem. Bioenerg. 49, 11–20.
electroporation. Adv. Drug Del. Rev. 35, 77–88. Zhang, L., Li, L., Hofmann, G.A., Hoffman, R.M., 1996. Depth-targeted
Vanderzanden, L., Bray, M., Fuller, D., Roberts, T., Custer, D., Spik, K., efficient gene delivery and expression in the skin by pulsed electric
Jahrling, P., Huggins, J., Schmaljohn, A., Schmaljohn, C., 1998. DNA fields: an approach to gene therapy of skin ageing and other diseases.
vaccines expressing either the GP or NP genes of Ebola virus protect Biochem. Biophys. Res. Commun. 220, 633–636.
mice from lethal challenge. Virology 246, 134–144. Zhang, L., Li, L., An, Z., Hoffman, R.M., Hofmann, G.A., 1997. In vivo
Wang, Y.M., Allen, L.V., Li, L.C., 2000. Effect of sodium dodecyl transdermal delivery of large molecules by pressure-mediated elec-
sulphate on iontophoresis of hydrocortisone across hairless mouse troincorporation and electroporation: a novel method for drug and gene
skin. Pharm. Dev. T. 5, 533–542. delivery. Bioelectrochem. Bioenerg. 42, 283–292.
Wang, S., Kara, M., Krishnan, T.R., 1997. Transdermal delivery of