overcoming stratum corneum_modulation of skin penetration_trommer & neubert

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Skin Pharmacol Physiol 2006;19:106121

DOI: 10.1159/000091978

Overcoming the Stratum Corneum:

The Modulation of Skin PenetrationA Review

H. Trommer R.H.H. Neubert

School of Pharmacy, Institute of Pharmaceutics and Biopharmaceutics, Martin Luther University

Halle-Wittenberg, Halle, Germany

tion reducers can be used to prevent chemicals entering

the systemic circulation. This article concentrates on the

progress made mainly over the last decade by use of

chemical penetration enhancers. The different action

modes of these substances are explained, including the

basic principles of the physical skin penetration enhance-

ment techniques and examples for their application.

Copyright 2006 S. Karger AG, Basel

Structure of the Stratum Corneum and Drug

Options to Overcome the Barrier

The skin is the largest human organ. It ensures thatharmful substances and drugs released from topically ap-plied formulations cannot intrude into the organism off-hand [1]. The evolutionary development of the humanskin as a potential protective barrier keeping water in andnoxious substances out of the human body was a require-

ment for terrestrial life [2]. Figure 1 illustrates the com-plex structure of the human skin and the several layersschematically [3].

The outermost layer of the skin, the stratum corneum,is of particular interest as it determines this barrier func-tion [4]. The qualification for this is the unique physico-chemical composition of the stratum corneum [5]. Thebrick and mortar model is applied to describe the struc-ture of the horny layer. Corneocytes are the bricks em-

Key Words

Skin penetration Stratum corneum Transdermal

drug delivery Penetration enhancers Penetration

retarders Sonophoresis Iontophoresis

Abstract

It is preferred that topically administered drugs act either

dermally or transdermally. For that reason they have to

penetrate into the deeper skin layers or permeate the

skin. The outermost layer of the human skin, the stratum

corneum, is responsible for its barrier function. Most top-

ically administered drugs do not have the ability to pen-

etrate the stratum corneum. In these cases modulations

of the skin penetration profiles of these drugs and skin

barrier manipulations are necessary. A skin penetration

enhancement can be achieved either chemically, physi-

cally or by use of appropriate formulations. Numerous

chemical compounds have been evaluated for penetra-

tion-enhancing activity, and different modes of actionhave been identified for skin penetration enhancement.

In addition to chemical methods, skin penetration of

drugs can be improved by physical options such as ion-

tophoresis and phonophoresis, as well as by combina-

tions of both chemical and physical methods or by com-

binations of several physical methods. There are cases

where skin penetration of the drug used in the formula-

tion is not the aim of the topical administration. Penetra-

Received: November 1, 2005

Accepted: January 27, 2006

Published online: May 9, 2006

Dr. H. Trommer

Bernhard-Kellermann-Strasse 16DE04279 Leipzig (Germany)Tel./Fax +49 341 330 320 2E-Mail [email protected]

2006 S. Karger AG, Basel

16605527/06/01920106$23.50/0

Accessible online at:www.karger.com/spp


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The Modulation of Skin Penetration

Skin Pharmacol Physiol 2006;19:106121 107

bedded in an intercellular lipid matrix of mainly fattyacids, ceramides, cholesterol and cholesterol sulfate [6].In 1994 a more differentiated variation of this model, thedomain mosaic model, was introduced by Forslind [7].Recently, Norlen postulated two new models for stratumcorneum characterization. For skin barrier formation a

membrane-folding model was proposed [8] and skin bar-rier structure and function was simplified by a single gelphase model [9].

Three different functions may be achieved when ap-plying drugs to the human skin. Firstly, it may be desir-able to have the active remaining on the surface of theskin, e.g. for skin disinfection, dermal insect repellentsand cosmetics for skin decoration. These pharmaceuti-cals or cosmetics are called epidermal formulations.

The second function is when formulations for topicaladministration are designed to allow the dermal penetra-tion of their actives into the deeper regions of the skin

such as the viable epidermis and the dermis. These areendodermal or diadermal formulations. The absorptioninto the systemic circulation is not the aim of these for-mulations. If partial absorption was to occur it could leadto adverse side effects after extensive use of these formu-lations [10].

Thirdly, the systemic action of drugs by transdermalapplication can be the aim of the topical therapy. Localreactions are undesired in this case.

All three kinds of administration are controlled by theanatomical properties of the skin (e.g. skin type and ac-tual skin condition), drug features (e.g. lipophilicity, par-ticle size, protein binding capacity) and the formulationfeatures (e.g. vehicle composition, rheological proper-ties).

There are two general options for drug substances topermeate the stratum corneum: the transepidermal routeand the route via pores. Figure 2 illustrates these drugpermeation options [10]. The transepidermal route canbe divided into the transcellular and the intercellularroute. The more direct route is the transcellular. Here thedrug has to cross the skin by directly passing through boththe lipid structures of the stratum corneum and the cyto-

plasm of the dead keratinocytes. This is the shortest routefor the drug substance, but the substances encounter sig-nificant resistance to permeation because they have tocross both lipophilic and hydrophilic structures. Themore common route for drugs to permeate the skin is theintercellular route [11]. Here the permeant overcomes thestratum corneum by passing between the corneocytes.Since the skin appendages (glands and hair follicles) oc-cupy only 0.1% of the total human skin surface, the con-

tribution to the pore route was primarily considered to besmall [12]. A theoretical system validation approach hasbeen applied for shunt route analysis [13]. Recently, itwas shown that follicular penetration may also be an im-portant pathway for the penetration of topically admin-

istered substances [14]. The follicular apparatus of hairfollicles, the sweat glands and microlesions in the interfol-licular horny layer were introduced as theoretical verticalpathways for percutaneous penetration [15]. The penetra-tion of microparticles into the hair follicles and the result-ing opportunities, e.g. for the transport of UV protectiveagents in sunscreens, have been illustrated [16].

Stratum corneum

Stratum basale

Stratum granulosum

Stratum spinosum

Blood vessel

Sebaceous gland

Hair papilla

Perspiratory gland

Adipose tissue

Hydrolipid film

Epidermis

Subcutis

Dermis(Corium)

Fig. 1. The human skin schematically. Adapted from Skin CareForum [3].

Transepidermal Via pores

Gland

Hair papillaCorneocytes

intercellular transglandular transcellular transfollicular

Fig. 2. Options of drug penetration across the stratum corneumschematically. Adapted from Lippold [10].



Trommer/Neubert


Modulation of Skin Penetration

Penetration Enhancers

A penetration enhancement of drugs after topical ap-plication can be achieved by several compounds whichare able to promote the transport of actives across the skinbarrier. There are a variety of mechanisms for penetra-tion enhancement by these substances [17]. One possibil-ity is the interaction of the enhancers with the polar head-groups of the lipids. The lipid-lipid headgroup interac-tions and the packing order of the lipids are thus dis-turbed. The result is the facilitation of the diffusion ofhydrophilic drugs [18]. By the increased flow the contentof free water molecules between the bilayers is increased,which leads to an augmentation of the cross-section forpolar drug diffusion. Simple hydration can be used instructure modification which results in changes to drugpenetration [19]. Water is one of the most effective andsafest penetration enhancers. By hydration of the stratumcorneum, the penetration of most drugs can be increased.Normally in the stratum corneum the water content is510%. The water content can be increased up to 50%under occlusive conditions (e.g. by use of impermeablefoil or by application of occlusive vehicles) [10]. Further-

more, moisturizers such as urea can be used to increasethe hydration of the stratum corneum and in consequenceto improve the diffusion of hydrophilic drugs.

The headgroup disturbance of lipids by polar enhanc-er substances can also affect the hydrophobic parts of thelipids and leads to rearrangements in these bilayer areas[20]. This also explains the penetration improvement forlipophilic drugs by use of lipid headgroup-influencing hy-drophilic penetration enhancers [17].

Another possibility is the interaction of lipophilic pen-

etration enhancers with the hydrocarbon chains of thebilayer lipids. The penetration of lipophilic drugs is fa-cilitated this way by packing order disturbance due to anincreased fluidization of the hydrocarbon chains. Thesechanges also influence the order of the polar headgroups,which explains the penetration enhancement of hydro-philic drugs by use of a lipophilic enhancer substance[21]. Figure 3 illustrates the influence of penetration en-hancers on both the lipophilic pathway and the hydro-philic pathway of drug penetration.

Some of the chemical enhancer substances (structuresof the frequently used substances are shown in figure 4)need suitable vehicles or cosolvents (e.g. propylene glycol)to reach the polar lipid parts and exert their functions[22]. The increase in the drug solubility and the improve-ment of its partition coefficient (skin/vehicle) is anothermechanism explaining the action of penetration enhanc-ers [23].

Additionally, the stratum corneum can be made morepermeable for drug substances by the extraction of its lip-ids as the result of an interaction with chemical penetra-tion enhancers [17].

AlcoholsEthanol is the most intensely investigated penetrationenhancer in relation to penetration behavior and its in-teraction with human skin. It is most commonly used inmany transdermal formulations and also in patches.There are several mechanisms for the permeation-en-hancing action of ethanol and higher alcohols [17]. As asolvent, ethanol is able to increase the solubility of thedrug already in the formulation. Furthermore, the solu-

1. Hydrophilic

pathway

2. Lipophilic

pathway

Skin penetration

of drugs

Action of penetration

enhancers

Polar

enhancers

Long-chained,

less polar

enhancersHydrophobic region

Aqueous regionPolar headgroup interaction

Lipid chain interaction

Fig. 3.Hydrophilic and lipophilic pathwaysof drug penetration and action mode of pen-etration enhancers.






bility properties of the tissue can be optimized for thedrug after the penetration of ethanol into the stratum cor-neum. Alcohols are able to extract lipids and proteins andthereby increase the porosity of the stratum corneum[19]. Thus, the penetration of hydrophilic drug substanc-

es is facilitated. The penetration enhancement of lipo-philic drugs by alcohols is due to the higher solubility ofthe drug substances in the lipophilic areas of the stratumcorneum because of the presence of alcoholic enhancers.For water soluble drugs a minimum amount of water isnecessary for an optimal penetration enhancement by al-cohols [17].

The length of the alkyl chain is important for the skinpenetration-enhancing action of alcohols. Up to six car-

bon atoms the enhancement can be increased by use ofalcohols with more carbon atoms. The use of alcoholswith higher carbon atom numbers showed a decrease inthe penetration rate during experiments with indometha-cin as a model drug [24].

Recently, Krishnaiah et al. [25] tested the effects ofseveral solvent systems on the in vitro permeability ofnicardipine hydrochloride through excised rat epidermis.They found that the use of the binary solvent system,ethanol and water in the ratio of 70:30 v/v, is an effectivevehicle for the development of a transdermal therapeuticsystem for nicardipine hydrochloride. A linear relation-ship between ethanol concentration and a surrogatemarker of lipid removal and disorganization in the stra-

Fatty acids

Oleic acid

OH

H3C

O

Surfactants

Sodium dodecyl sulphate

SO O

O O Na+

Esters

H3C O

O

CH3

Ethylacetate

Cyclodextrins

Beta-Cyclodextrin

O

O

O

O

OO

O

O

O

O

O

O

O

O

HOH2C

CH2OH

CH2OH

CH2OH

HOH2C

HOH2C

HOH2C

OHHO

HO

OH

OH

OH

OH

HOOH

HO

OH

HO

HO

OH

Alcohols

Ethanol

OH

H3C

Glycols

Propylene glycol

OH

OHH3C

Alkyl-N,N-disubstitutedaminoacetates

Dodecyl-N,N-dimethyl-aminoacetate

O

O

NCH3

CH3

Urea and derivatives

1,3-Diphenyl-urea

N N

O

HH

d-Limonene

Terpenes and terpenoids

CH3

H2C

H3C

Sulphoxides

Dimethylsulphoxide

H3CS

CH3

O

Pyrrolidones

N-Methyl-2-pyrrolidone

N O

CH3

Azoneand derivatives

Azone

N

O

Fig. 4. Categories of frequently used chemical skin penetration enhancers and the chemical structure of one typ-ical example of each group.



Trommer/Neubert


tum corneum has been found by means of corneoxenom-etry, a bioassay where interactions between xenobioticsand corneocytes are assessed using reflectance colorime-try [26]. The more lipophilic monoethylether of the biva-lent alcohol diethylene glycol (Transcutol) has been afrequently used skin penetration enhancer in recent years.

Transcutol was shown to effectively enhance the trans-port of the broad-spectrum antiparasitic agent ivermectinthrough porcine skin [27]. Harrison et al. [28] investi-gated the synergism of Transcutol and Azone on perme-ant diffusivity and solubility in human stratum corneum.It was shown that Azone reduced diffusional resistanceof the stratum corneum and Transcutol increased the sol-ubility of a model penetrant in this barrier. Mura et al.[29] evaluated Transcutol as a clonazepam transdermalpenetration enhancer and showed in the experiments anincrease in drug permeation as a function of Transcutolcontent in the formulation. Furthermore, a synergistic

enhancement of the clonazepam flux was shown after theuse of a combination of Transcutol and propylene glycol.The percutaneous penetration of nimesulide formulatedin carbopole 934 gels was significantly increased com-pared with a control formulation after the application ofa combination of oleic acid (3%) and Transcutol (30%)[30]. The incorporation of diethylene glycol monoethylether into a microemulsion resulted in an optimized for-mulation for the topical administration of the poorly wa-ter soluble drug vinpocetine [31]. This ether was also usedto increase the skin accumulation of the UV absorbersoxybenzone and cinnamate [32].

SulphoxidesAmong the sulphoxides, dimethylsulphoxide (DMSO)

and decylmethylsulphoxide (DCMS) are frequently usedas skin penetration enhancers. There are several mecha-nisms accountable for the enhancing effects of sulphox-ides. DMSO is a powerful aprotic solvent with a highdielectricity constant because of the S-O-bond polarity.The dissolving power of DMSO for salts and polar com-pounds is very high and may lead in some cases to a com-plete ionization of salts at concentrations below 1 mM

[19]. Because of its outstanding dissolving propertiesDMSO is able to generate solvent-filled spaces in the stra-tum corneum where the solubility of the drug substancesis increased. Furthermore, the organization of the barrierlipids of the stratum corneum is disturbed by DMSOwhen administered in concentrations above 60%. A de-naturation of intercellular structural proteins of the stra-tum corneum by DMSO and DCMS has been postulatedas an additional reason for the promotion of skin penetra-

tion when using sulphoxides as enhancers. DMSO is ableto change the intercellular keratin confirmation from analpha helix to a beta sheet [19].

There are many studies described in the literature il-lustrating the penetration-enhancing effects of DMSO forboth hydrophilic and lipophilic substances. The flux of

azathioprine studied using a Franz diffusion cell and ratskin was increased by DMSO by 20.7% [33]. Significantenhancement of the permeation of prazosin hydrochlo-ride through full-thickness skin of Swiss albino mice wasmeasured by use of 5% DMSO [34]. DCMS showed thehighest enhancing effect on the flux of isosorbide dinitratefrom acrylic adhesives [35].

The problem with DMSO, as with many potent chem-ical skin penetration enhancers, is the skin irritating ef-fects the substance may cause when used in the concen-tration required for skin penetration enhancement. Ery-thema, scaling, contact urticaria, stinging, burning and

systemic symptoms are described after DMSO applica-tion [36]. Due to its potential toxicity and the possibleside effects, other enhancers with similar effects could bea better choice [37].

Azone and DerivativesAzone (laurocapram) and its derivatives are the first

molecules which were specifically designed as penetrationenhancers. Azone is a highly lipophilic liquid with an oc-tanol/water partition coefficient of 6.21 [17]. It is a chem-ically stable compound and an excellent solvent for manydrugs. The substance has a low irritating potential, a verylow toxicity and nearly no pharmacological activity.Azone and its derivatives were heavily investigated in the1980s. They can be used as penetration enhancers for hy-drophilic and lipophilic substances and for peptide mol-ecules as well, e.g. insulin and vasopressin. Interestingly,Azone and derivatives are effective penetration enhanc-ers when used in low concentrations (15%). Their activ-ity can be increased by the addition of co-solvents likepropylene glycol or ethanol. Azone derivatives are solublein these liquids and compatible with most organic sol-vents, and these are other advantages of this type of arti-

ficial enhancers [19].Although Azone and its derivatives have now been inuse as penetration enhancers for over 20 years, theirmechanism of action is under ongoing research. The pen-etration-enhancing effects of these compounds are prob-ably due to an intercalation into the structured lipids ofthe stratum corneum and the disturbance of the lipidpacking order. The carbon chain of the Azone moleculeconsists of 12 carbon atoms. The dimensions of this chain






are comparable with the dimensions of the cholesterolskeleton. A decrease in the cholesterol-cholesterol inter-ferences and the cholesterol-ceramide interactions can beassumed in the presence of Azone derivatives. The fluid-ity of the hydrophobic stratum corneum regions is in-creased and the permeation resistance of the horny layer

against drug substances is reduced by Azone [17].Among the large number of investigated Azone de-rivatives, the compounds with a chain length of 12 carbonatoms were the most effective ones independent of thering dimensions.

The penetration behavior of sodium naproxen was de-termined recently by formulating the active in PluronicF-127 gels containing Azone and the powerful solubiliz-ing agent Transcutol. It was found that the combinationof Azone and Transcutol enhanced sodium naproxenpenetration, with enhancement ratios of up to 2-fold com-pared with the formulation containing only Transcutol

[38].

PyrrolidonesPyrrolidones and related compounds have been inves-

tigated as penetration enhancers. As with many otherpenetration enhancers, pyrrolidones are able to promoteboth the penetration of hydrophilic drugs and the pene-tration of lipophilic drug substances. N-Methyl-2-pyrrol-idone (NMP) and 2-pyrrolidone (2P) as well as 2-pyrrol-idone-5-carboxylic acid are the most widely used enhanc-ers of this group. NMP was shown to increase the skinpermeation of estradiol in Yucatan micropig epidermisusing a modified Franz-type diffusion cell when added ata concentration of 10% to an oily gel formulation consist-ing of isocetyl stearate and hydrogenated phospholipids[39]. More recently, the role of NMP as an enhancer forpermeants delivered from an aqueous phase was investi-gated in the transdermal delivery of the local anestheticslidocaine free base, lidocaine hydrochloride and prilo-caine hydrochloride [40]. A flux increase of all compoundstested in the study was measured, demonstrating the ca-pability of NMP to enhance hydrophilic and lipophilicdrugs from an aqueous phase. An improvement in the

skin permeation of griseofulvin, a drug with poor solubil-ity in both water and oil, was shown by use of NMP as apenetration enhancer as well [41].

Hydrophilic pyrrolidones primarily enhance penetra-tion via the polar route, whereas more lipophilic pyrrol-idone derivatives like NMP are able to penetrate into thehydrophobic regions of the stratum corneum and reducethe barrier function in these areas. The more lipophilicderivative N-dodecyl-2-pyrrolidone has been evaluated

as a transdermal penetration enhancer using a novel skinalternative for the test and showed a statistically signifi-cant higher skin content of the model drug hydrocorti-sone in comparison with the control [42]. The effects ofNMP and 2P on the release and skin permeation of bu-pranolol from reservoir-type transdermal delivery sys-

tems have recently been investigated. A 3-fold higher pen-etration rate was shown for 2P and a 1.5-fold higher pen-etration rate was measured in the case of NMP whenusing the pyrrolidones at a concentration of 5% in bu-pranolol polymer gels [43]. 1-octyl-2-pyrrolidone wasused as a penetration enhancer for model analysis of cor-ticosterone flux enhancement across hairless mouse skinusing a one-layer and a two-layer model [44].

However, the clinical use of pyrrolidones as skin pen-etration enhancers is limited because of adverse reactionsto these compounds. Erythema and other irritant cutane-ous reactions were observed after pyrrolidone use on hu-

man skin [45].

Urea and DerivativesUrea is an odorless and colorless crystalline solid. It is

a slightly hygroscopic substance with good water solubil-ity and weak alkaline properties. It is prone to hydroly-sis.

Urea is used in dermatology as a hydrating agent forthe treatment of psoriasis, neurodermatitis and other hy-perkeratotic skin conditions. As a moderate keratolyticsubstance, it influences the stratum corneum keratino-cytes with species-specific percutaneous absorption rates[17].

The keratolytic properties of urea and its derivativesare one reason for the modest penetration enhancementachieved by use of these compounds. The other reasonfor the enhancing effects of urea derivatives is the in-crease in the stratum corneum water content by thesemoisturizing agents. This may lead to hydrophilic diffu-sion channels within the barrier [19].

In a trial involving over 200 patients suffering fromvarious skin disorders, urea was suggested as an effectivemoisturizer and an enhancer of hydrocortisone penetra-

tion into the skin [46]. A nonirritating chemical enhanc-er system containing ethanol, menthol, camphor, methylsalicylate and urea in a hydrogel was shown to stronglyenhance the skin penetration of the nonapeptide leupro-lide [47]. In a study on the percutaneous absorption ofprogesterone, the most efficient skin penetration enhanc-er besides Azone was urea in polyethylene glycol bases.The diffusion was enhanced 2.5-fold compared with thepure base [48].



Trommer/Neubert


However, the application of urea and its derivativesas penetration enhancers is limited by their inadequatechemical stability, the proteolytic properties and the skinirritating effects connected with these properties [17].

To reduce skin irritation and increase skin penetrationenhancement, cyclic urea analogues were synthesized.

These was then tested using snake skin and hairless mouseskin with indomethacin as a model drug. The idea was tohave more effective penetration enhancers which are de-composed by skin esterases after drug penetration promo-tion. Wong et al. [49] synthesized urea derivatives withenhancing effects comparable to Azone.

Alkyl-N,N-Disubstituted AminoacetatesAs long chained alcohols, fatty acids and esters were

used for skin penetration enhancement, disubstitutedaminoacetates were introduced as skin penetration en-hancer substances. Representatives of this group of pen-

etration enhancers are dodecyl-N,N-dimethylaminoace-tate and dodecyl-2-methyl-2-(N,N-dimethylaminoace-tate) (DDAIP). These substances are not soluble in water,but soluble in most of the organic solvents and in waterand alcohol mixtures. The skin penetration promotionpotential of these substances is in the same dimension asAzone or even higher. The penetration enhancing activ-ity is decreased by the increase in the N,N-dialkyl carbonchain. The skin-irritating potential of the aminoacetatesis very low [17]. This is due to the biological decomposi-tion of these enhancers by the skin enzymes to N,N-di-methylglycine and the corresponding alcohols. They en-hance skin penetration by the interaction with stratumcorneum keratin and the increase in the hydration effi-ciency resulting from these interactions.

In 1989 Wong et al. [50] introduced the newly synthe-sized alcohol derivatives of N,N-disubstituted amino ac-ids with low toxicity, and evaluated the derivatives fortheir transdermal penetration-enhancing effects on thetransport of indomethacin from petrolatum ointmentsacross the shed skin of black rat snake (Elaphe obsolete).The penetration fluxes of indomethacin increased linear-ly as the concentration of DDAIP increased from 2.5 to

15%. Snake skin pretreatment experiments indicated thatthe application of DDAIP significantly increased skinpermeability. Electron micrograph studies showed clear-ly that the enhancer was able to interact with both lipid-rich layers and keratin-rich layers. Later, the effectivenessof DDAIP was tested using the above-mentioned snakeskin, rabbit pinna skin and human skin for penetrationexperiments with the drugs indomethacin, 5-fluorouraciland propranolol-HCl [51]. With all skins and all model

drugs, DDAIP increased drug permeability at least as wellas Azone. In most cases it was the more effective penetra-tion enhancer. The electrochemical investigation of hu-man cadaver skin by impedance spectroscopy with andwithout penetration enhancers (DDAIP and Azone wereused) revealed new insights into the mechanism of action

of the enhancers [52]. The enhancers appeared to opennew penetration routes and increased the ohmic resis-tance, capacity properties and fractal dimension of theskin. By fluorescence spectroscopic studies dodecyl-N,N-dimethylaminoacetate was shown to alter molecularmovement on the surface of the bilayers, resulting in adecrease in anisotropy of 19% [53]. By use of DDAIP asan enhancer in penetration studies of miconazole throughshed snake skin, the permeation increased 11-fold com-pared with that of the suspension without DDAIP pre-treatment [54]. The concentration of the azole in the skinincreased 8-fold, indicating that the enhancement effect

is connected with high partition of miconazole into theskin. Recently, Wolka et al. [55] studied the interactionof DDAIP with a phospholipid model membrane by dif-ferential scanning calorimetry for further clarification ofthe mechanism of action of this skin penetration enhanc-er. The results suggested that drug transport is enhancedby DDAIP by interaction with the polar regions of thephospholipid bilayers and also by increasing the motion-al freedom of lipid hydrocarbon chains.

Propylene GlycolAmong the polyvalent alcohols, propylene glycol is the

most frequently used co-solvent in dermatology. The ac-tion as a real penetration enhancer is debated controver-sially in the literature. Penetration and permeation en-hancement was shown as well as the opposite effectswhen using propylene glycol in formulations for topicaladministration. Thus, the action as a co-solvent seems tobe in the foreground [17]. The activity of propylene gly-col as a co-solvent is restricted to the formulation. How-ever, it is able to penetrate and thereby can transportlipophilic substances or other enhancers via solvent drag.This may account for the synergistic action of propylene

glycol and Azone and propylene glycol and oleic acid.The action of propylene glycol as a penetration enhancerseems to be the mechanism of action only for the skinpenetration of drugs which are better soluble in alcoholthan in water. The solvation of keratin within the stra-tum corneum by competition with water for the hydro-gen bond binding sites and the intercalation in the polarheadgroups of the lipid bilayers by propylene glycol arepostulated as mechanisms of action for the penetration-






enhancing effects of propylene glycol in the literature aswell [19].

Recently the in vitro percutaneous penetration of acy-clovir from solvent systems and from carpopol 971-P hy-drogels was studied regarding the influence of propyleneglycol [56]. It was shown quantitatively that the enhancer

effect of propylene glycol in the permeation of acycloviracross human epidermis depends on the concentration ofthe alcohol. The concentrations of propylene glycol usedin this study varied between 0 and 70% w/w. In the sol-vent systems a maximum enhancement ratio was deter-mined for the system containing 70% propylene glycol.On the other hand, carbopol 971-P gels containing 50%of propylene glycol provided the highest enhancer effectfor acyclovir skin penetration.

Funke et al. [57] investigated the transdermal deliveryof highly lipophilic antiestrogens by in vitro permeationstudies through excised skin of hairless mice. Several pen-

etration enhancers were tested in this study. It was shownthat an outstanding permeation enhancement can beachieved for the highly lipophilic drugs by the combina-tion of propylene glycol and lauric acid. Furthermore, thegroup demonstrated that the mechanism of the observedeffects is the mutual permeation enhancement of thesetwo penetration enhancers and their synergistic lipid-flu-idizing action in the stratum corneum.

Increased drug skin penetration after the use of pro-pylene glycol and fatty acid combinations was also ob-served by Larrucea et al. [58]. The combination of oleicacid with propylene glycol led to a greater absorption oftenoxicam formulated in carbopol 940 gels. The flux val-ues studied using Franz-type diffusion cells gradually in-creased with increasing concentrations of both com-pounds, showing the synergistic effects again.

SurfactantsSurfactants are frequently used as emulsifiers in for-

mulations for dermal application. They are added in or-der to solubilize lipophilic actives within the formula-tions. The improvement of the drug solubility can beachieved, for example, by the formation of micelles by

the surfactant molecules in the formulation. Surfactantshave the potential for the solubilization of the stratumcorneum lipids and thus act as penetration enhancers.Keratin interactions are also thought to explain thepenetration-enhancing effects of surfactants. Normally,cationic surfactants are more effective as penetrationenhancers than anionic or nonionic compounds. The po-tential for skin irritation is connected with the penetra-tion-enhancing effects of the surfactants. Therefore, in

formulations for dermal application, mostly nonionicsurfactants are used, which tend to be widely regarded assafe. Surfactants with an analogue structure to the stra-tum corneum bilayer lipids have low skin-irritating po-tentials, but also low skin penetration-enhancing effects.This is due to surfactant monomer integration into the

bilayers instead of micelle formation of the lipids.Among the nonionic surfactants, sucrose fatty acid es-ters have been shown to temporarily alter membrane bar-rier properties. These substances show many advantagesas penetration enhancers, e.g. biodegradability and lackof toxicity. Sucrose oleate and sucrose laureate wereshown to promote the in vivo percutaneous penetrationof the model permeant 4-hydroxy-benzonitril. The effectswere monitored by attenuated total reflectance Fouriertransform infrared spectroscopy in conjunction with tapestripping [59]. In another study, the effects of sucrose es-ters on the permeation of lidocaine were investigated as

a function of vehicle pH. The results suggested that su-crose laureate enhanced the penetration of the ionizedform of the drug (12-fold greater flux than control), where-as sucrose oleate was more effective in promoting thenonionic species. Transcutol was used additionally as asolubilizer in both experiments [60].

Besides the sugar-based surfactants, the fatty alcoholethers of polyoxyethylene are frequently used as nonion-ic surfactants for the promotion of the skin penetrationof drug substances. Shin et al. [61] showed the best en-hancing effect of polyoxyethylene-2-oleyl ether for en-hanced transdermal delivery from bioadhesive carbopolgels containing tretinoin, among various enhancers testedin the study. The ether was also able to increase the trans-dermal delivery of the antihistaminic tripolidine from anethylene vinyl acetate matrix system in rabbits and rats[62]. In a former study of the same research group, poly-oxyethylene-2-oleyl ether also showed the best enhance-ment among several enhancers tested for the atenololtransdermal drug delivery from an ethylene vinyl acetatematrix [63]. Another group of nonionic surfactants whichcan be used for skin penetration enhancement are thepartial fatty acid esters of sorbitan. Sorbitan monolaurate

20 (Span 20) has been tested as a potential skin penetra-tion enhancer in transdermal matrix type patches usingdiclofenac diethylamine as the active agent [64]. WithSpan 20, an enhancement of skin permeation of the drugof up to 30% was measured with rat skin using a modifiedKeshary-Chien diffusion cell.



Trommer/Neubert


Terpenes and TerpenoidsTerpenes and related substances are highly lipophilic

compounds and have high octanol/water permeation co-efficients. Terpenes are nonaromatic ingredients of essen-tial oils and consist of carbon, hydrogen and oxygen at-oms only. As penetration enhancers, they interact with

intercellular lipids and influence the nonpolar penetra-tion route. Co-solvents like propylene glycol or ethanolhave synergistic effects when added to the terpenoids.

Godwin and Michniak [65] studied the influences ofdrug lipophilicity on terpenes as transdermal penetrationenhancers. The drugs caffeine, hydrocortisone and tri-amcinolone acetonide in propylene glycol were investi-gated. Their results showed that the percutaneous pene-tration of hydrocortisone and caffeine can be significant-ly enhanced using a combination of terpenes andpropylene glycol. Geraniol was the most effective com-pound for caffeine penetration enhancement, and alpha-

terpineol the most effective for hydrocortisone penetra-tion enhancement. For triamcinolone acetonide no sig-nificant enhancement effects by terpene derivatives wereobserved.

Terpenes extracted from plants are good candidatesfor permeation enhancers because of their relatively lowirritation potential. They are designated as generally rec-ognized as safe by the FDA. The alcohol-type terpenep-menthane-3,6-diol, originating in the leaf ofEucalyptuscitriodora, was tested for its enhancement effect on invivo permeation of the hydrophilic drug antipyrine andthe lipophilic drug indomethacin through Yucatan mi-cropig skin [66]. The permeation of antipyrine was in-creased 3-fold by the terpene. Skin concentration of in-domethacin was increased about 11-fold.

Unjacketed Franz diffusion cells were used by Ota etal. [67] to study the enhancing effects of terpenes on per-cutaneous absorption of the highly lipophilic drug mid-azolam. Among the terpenes tested (geraniol, limonene,menthol and citronellol) only limonene was able to en-hance midazolam penetration through rat skin, and pro-vided useful information to develop a new dosage formu-lation for midazolam. Limonene also showed the greatest

ability to enhance the flux of sumatriptan succinate in astudy where several chemical penetration enhancers weretested. A 22-fold higher flux than the control was mea-sured [68].

The combination of terpenes (5%) and ethanol wasable to increase significantly the flux of the luteinizinghormone-releasing hormone through porcine epidermis.Consecutive iontophoresis synergistically enhanced thepermeability of luteinizing hormone-releasing hormone

through terpenes/ethanol-treated epidermis [69]. Limo-nene oxide and pinene oxide were used to study the pen-etration of haloperidol from ethanol and propylene glycoland to carry out haloperidol-stratum corneum bindingstudies. It was shown that the mode of interactions of ter-penes with the stratum corneum is different in two dif-

ferent solvent systems [70]. Essential oils from Ocimumbasilicum containing terpenes with various carbon num-bers effectively accelerated indomethacin permeationacross the skin and caused no or negligible irritation [71].In search of more effective and safer compounds for skinpenetration enhancement, Takanashi et al. [72] synthe-sized thiomenthol derivatives and introduced them asnovel percutaneous absorption enhancers providing bothenhancement factors and skin irritation factors.

Fatty AcidsThe penetration-enhancing effects of fatty acids have

been described many times in the literature. The mea-sured effects are strongly influenced by the fatty acidstructure and the vehicles used for the formulations. Themost frequently used compound in this field and the mostinvestigated substance is oleic acid. Generally, saturatedfatty acids are less effective than their unsaturated de-rivatives. The more double bonds there are in the mole-cules, the more effective are unsaturated fatty acids . Fur-thermore, fatty acids with cisconfigurations are more ef-fective penetration enhancers than fatty acids with transconfigured double bonds. The cisunsaturated compoundshave more potential for disturbing the lipid packing orderwithin the bilayers. Spectroscopic investigations withdeuterated oleic acid have revealed that oleic acid mole-cules at higher concentrations are able to form separatephases within the bilayer lipids. This would lead to per-meability defects within the bilayers and facilitate thepermeation of hydrophilic compounds through the stra-tum corneum.

The transdermal delivery of the nonsteroidal anti-in-flammatory agent ketorolac tromethamine was investi-gated studying the effects of vehicles and penetration en-hancers [73]. For the study, five fatty acids (caprylic, cap-

ric, lauric, oleic and linoleic acid) were added to propyleneglycol at concentrations of 1, 3, 5 and 10%. The highestenhancing effect was attained with 10% caprylic acid inpropylene glycol.

The effects of oleic acid on the ultrastructure of thestratum corneum lipids of rat skin were examined by elec-tron microscopy using osmium or rhutenium tetroxidepostfixation and lanthanum tracer studies. The resultsshowed that oleic acid might increase the epidermal per-


http:///reader/full/overcoming-stratum-corneummodulation-of-skin-penetrationtrOvercoming the Stratum Corneum:



meability via a mechanism involving perturbation ofstratum corneum lipid bilayers and lacunae formation aspenetration enhancing effects [74]. Butyl paraben, meth-yl paraben and caffeine were used as model penetrants totest the effects of unsaturated fatty acids in benzyl alcoholon percutaneous drug permeation. The permeation of bu-

tyl paraben was enhanced to a similar extent by all threefatty acids tested (oleic acid, palmitoleic acid and linole-ic acid), whereas palmitoleic acid caused a significantgreater enhancement in the flux of both methyl parabenand caffeine compared with the oleic and linoleic acid ef-fects and with the control. It was proposed that the syn-ergetic mechanisms of fatty acids and benzyl alcohol wereaugmenting the polar penetration route by interactionswith both polar and nonpolar stratum corneum lipids[75].

Even the in vitro permeability of the peptide drug in-sulin was increased by the use of fatty acids as skin pen-

etration enhancers. The 3-fold unsaturated linolenic acidproduced greater permeability through porcine epidermisthan the other fatty acids tested using Franz diffusioncells. The flux of the derivative lispro insulin was alsosignificantly higher by use of linolenic acid comparedwith the control [76].

Again, the skin-irritating potential of fatty acids whenused at higher concentrations is the disadvantage of theirapplication.

EstersAlkyl esters and fatty acid esters are also frequently

used skin penetration enhancers. Ethylacetate, methylac-etate, butylacetate and methylpropionate are used as wellas isopropyl-n-butyrate, isopropyl-n-decanoate, isopro-pylmyristate and isopropylpalmitate for example. Ethylacetate was found to be the best penetration enhancer forthe transdermal delivery of the contraceptive levonorg-estrel [77]. The ester was able to speed up absorption 17-fold in rat skin. Using excised hairless rat skin, the skinpermeation enhancement of papaverine hydrochlorideby monoglycerides and caprylic acid esters was evaluatedand compared with the enhancement effects of free fatty

acids [78]. It was shown that free fatty acids mainly af-fected the diffusion of the drug, and the monoglyceridesaffected the partition. Enhancement was marked in thecase of glyceryl monocaprylate. A linear relationship be-tween the flux of papaverine hydrochloride and theamount of enhancer in skin was established.

Glycerol monooleate in the presence of propylene gly-col was able to enhance the 5-aminolevulinic acid in vitroskin penetration and the in vivo protophorphyrin IX ac-

cumulation in hairless mouse skin. These are importantfactors for the success of the photodynamic therapy inskin cancer [79]. Porcine ear skin mounted in a Franz-type diffusion cell was used to investigate the topical de-livery of cyclosporin A. The drug is of great interest forthe treatment of autoimmune skin disorders, but is fre-

quently ineffective due to poor drug penetration in theskin. Glycerol monooleate at concentrations of up to 10%in propylene glycol formulations enhanced both the top-ical and the transdermal delivery [80].

By synthesis of esters with more optimized penetra-tion-enhancing action, several research groups tried tofind novel ester penetration enhancers. The facilitatedtransport of the two model steroids hydrocortisone-21-acetate and betamethasone-17-valerate by several synthe-sized esters and amides of clofibric acid was shown byMichniak et al. [81]. The amide analogues were more ef-fective in this study than the equivalent ester compounds

of the same carbon chain length. Lactam-N-acetic acidesters were synthesized and showed significantly higherenhancement ratios for hydrocortisone-21-acetate inhairless mouse skin than the ratio found when usingAzone as an enhancer [82]. The addition of an N-acetyl-prolinate ester with an alkyl length of 16 carbon atomssignificantly increased the fluxes of benzepril and hydro-cortisone compared with the control [83]. Franz diffusioncells were used for the experiments, and hairless mouseskin was used as the penetration barrier. Differentialscanning calorimetric studies suggested that the synthe-sized enhancer may be acting on the stratum corneumlipids with a similar effect to that of Azone. The corre-sponding membrane/vehicle partition coefficient studiesindicated an increase in the benzepril partition coefficientwith enhancer treatment compared to the control.

CyclodextrinsCyclodextrins are cyclic nonreducing maltooligosac-

charides. They are able to form inclusion complexes withlipophilic drugs and increase their solubility, particularlyin aqueous solutions. Cyclodextrins are not comparablewith the other penetration enhancers concerning their en-

hancing effects because they are not able to penetrate theskin under normal conditions. In combination with lipo-philic enhancers (fatty acids, Azone) a synergistic effectcan be achieved.

Uekama et al. [84] observed an improved transdermaldelivery of prostaglandin E1 through hairless mouse skinfrom an ointment by use of carboxymethyl-ethyl-beta-cy-clodextrin and Azone as a penetration enhancer. Further-more the cyclodextrin was able to markedly improve the


http:///reader/full/overcoming-stratum-corneummodulation-of-skin-penetrationtrTrommer/Neubert


stability of the prostaglandin in the fatty acid/propyleneglycol ointment. An in vivo transdermal absorption ratmodel was used to study the percutaneous absorption en-hancing effects of 2-hydroxypropyl-beta-cyclodextrinand 2,6-dimethyl-beta-cyclodextrin [85]. The transder-mal absorption of the cytochrome P450 inhibitor liaro-

zole was increased significantly. The results from differ-ential scanning calorimetry and those from permeabilityexperiments revealed that 2,6-dimethyl-beta-cyclodex-trin acted by modifying the stratum corneum barrier,whereas 2-hydroxypropyl-beta-cyclodextrin influencedthe partition behavior of the drug in the skin. Williamsat al. [86] investigated the transdermal permeation mod-ulation by cyclodextrins in a mechanistic study. The testdrugs were 5-fluorouracil and estradiol. Permeation mod-ulation by beta- and 2-hydroxypropyl-beta-cyclodextrinsalone and in combination with terpenes was tested. Thecyclodextrins did not enhance the flux of the test drugs.

Complexation of the terpenes resulted in reduced enhanc-er efficacy. The incorporation into a barrier cream re-tarded toluene permeation through the skin, and it wasconcluded that cyclodextrins themselves are not penetra-tion enhancers for the test substances but can be usefulto reduce percutaneous absorption of toxic materials onoccupational exposure. Ventura et al. [87] studied thepercutaneous absorption of papaverine through rat skin.A 10% aqueous solution of hydroxypropyl-beta-cyclodex-trin was suggested to be the most suitable transdermalpenetration enhancer for papaverin. Recently Babu andPandit [88] showed the effects of cyclodextrins on thecomplexation and transdermal delivery of bupranololthrough rat skin. They used side-by-side diffusion cellsand pH 7.4 phosphate buffered saline. Both cyclodextrinsinvestigated, hydroxypropyl-beta-cyclodextrin and par-tially methylated cyclodextrin, were found to be suitablefor improving the solubility, and showed penetration en-hancement of the beta-blocking agent bupranolol whenused in certain concentrations.

Novel Penetration Enhancers and Novel DiscoveryTechniques

The research work to find novel skin penetration en-hancers with higher enhancement action and less irrita-tion potency is still going on. Iminosulfuranes are syn-thetically designed DMSO-related compounds which canbe synthesized by DMSO treatment with trifluoroaceticanhydride. An enhancement activity has been achievedfor some of the compounds without any toxicity [89].Ascorbic acid has been tested for its penetration enhance-ment properties using haloperidol as a model drug and

amber glass Franz-type diffusion cells for the permeationstudies. Ascorbic acid did not increase the permeation ofthe drug but increased the haloperidol solubility in thevehicle, which leads to a concentration-dependent in-crease in the haloperidol flux [90]. The primary capsa-icinoid capsaicin was tested to compare its skin penetra-

tion-enhancing effects with those of Azone. It was foundthat capsaicin caused stratum corneum alterations andthat the capsaicinoid was able to enhance the penetrationof the model drug naproxen studied by use of the isolatedperfused rabbit ear model and full-thickness human skin[91].

As the topical therapy with peptides would be usefulfor the treatment of cutaneous diseases, a comparativestudy was carried out to test the skin penetration of pro-tein transduction domains and a conjugated peptide. Thetwo protein transduction domains tested in this studywere able to penetrate the porcine ear skin and carried a

conjugated model peptide with them. The normally usedchemical penetration enhancer oleic acid had no addi-tional penetration enhancing effect in this study [92]. Itwas able to increase the topical delivery of a nontransduc-ing peptide investigated as a control substance in thisstudy.

To evaluate the effects of penetration enhancers ondrug delivery through skin and to be able to predict theenhancing power, the quantitative structure-activity re-lationship (QSAR) technique is used more frequently inthis field. For 5-fluorouracil and diclofenac sodium theresulting QSARs indicated that less hydrophobic enhanc-ers were the most active. In contrast, for skin permeationpromotion of hydrocortisone, benazepril and estradiol, alinear relationship between enhancement activities andoctanol/water partition coefficients of enhancers were ev-ident [93]. Santos-Filho et al. [94] used molecular similar-ity and QSAR analyses to develop compact, robust anddefinite models for skin penetration of organic com-pounds. It was found that a combination of nonmem-brane interaction QSAR descriptors and membrane-in-teraction QSAR descriptors yielded the optimum modelsregarding both the statistical measures of fit and model

predictivity.An experimental tool, in vitro impedance-guided high-throughput screening (INSIGHT), was used by Karandeet al. [95] for the discovery of transdermal penetrationenhancers. The group reported an over 100-fold greaterefficiency compared with current tools. In another studyby the same group, more than 300 potential skin penetra-tion enhancers were designed by reengineering the knowl-edge on these compounds back into the molecular struc-





ture. The molecules found in his study were screened insilico and subsequently tested in vitrofor molecular de-livery [96].

Penetration Reducers

Under specific conditions the penetration of the epi-

dermis by xenobiotics is undesired. In these cases it hasto be inhibited or retarded that compounds (e.g. pesti-cides or other harmful substances) will reach the system-ic circulation. For these applications, skin penetrationreducers or retarders are used. Another domain for thesesubstances used to restrict the dermal and the transder-mal penetration route are topically administered formu-lations where the actives should only act locally. The ex-periences on the mechanisms of skin penetration on amolecular level gathered by penetration enhancement ex-periments established the basis to design compoundswith the opposite effect. However, the knowledge of the

exact mechanisms of skin penetration retardation is quitelimited up to this point, and there are only a few studiesreporting experiments on this topic.

Freeman et al. [97] observed the failure of topicaldrugs for herpes simplex treatment formulated in oint-ments to penetrate human skin. They studied acyclovirand idoxuridine. The delivery of these drugs from poly-ethylene glycol ointments was very slow for both humanand guinea pig skin. A change of the formulation to amodified aqueous cream and to DMSO resulted in an 8-and 60-fold increase in the flux of acyclovir. The retar-dant effect of polyethylene glycol may be due to its in-ability to hydrate the stratum corneum or to a relativeosmotic effect which tends to dehydrate the stratum cor-neum.

Fatty acids have the ability to act as skin penetrationretarders as well. The capability is dependent on theirstructure and on the vehicles used for the formulation[98]. The skin permeation of the highly lipophilic modelpermeant pyrene butyric acid was decreased or not af-fected when using unsaturated branched fatty acids in95% propylene glycol compared with the pure vehicle.The use of the enhancer oleic acid instead of the branched

fatty acids used for the retardation study led to a signifi-cant increase in skin penetration [99].Skin barrier creams and protective gloves were devel-

oped for topical skin protection from exposure to chemi-cal agents [100] and for the reduction of percutaneousabsorption of industrial solvents [101].

Further Possibilities to Modulate the Skin Penetration

of Drugs

Besides chemical skin penetration enhancement andaltering the barrier properties by hydration of the hornylayer, there are several physical skin penetration enhance-ment techniques which can be used to overcome some of

the limitations of the chemical skin penetration enhanc-ers.Phonophoresis or sonophoresis uses ultrasound energy

for the skin penetration enhancement of drugs [102].Here, the ultrasound waves propagate in the skin andcause effects that increase skin penetration of variousdrugs, including macromolecules, via enhanced diffusionor enhanced convection [103]. For sonophoresis, ultra-sound at various frequencies in the range of 20 kHz16 MHz has been used to increase skin permeability.Low-frequency sonophoresis which is conducted at fre-quencies between 20 kHz and 100 kHz has been found

to be more effective in transdermal transport enhance-ment than the techniques operating at high-frequency ul-trasound [104]. As the mechanism of the enhancing effectof ultrasound, a phenomenon called acoustic cavitationis assumed. This is when gas bubbles are formed and sub-sequently collapse, which leads to the formation of holesin the corneocytes, an enlargement of intercellular spaceand the perturbation of the stratum corneum lipids (il-lustrated schematically in figure 5). Another effect is thetemperature increase by which the fluidity of the stratumcorneum lipids is increased [105]. The application of low-frequency sonophoresis in dermatocosmetology has beenreported by Santoianni et al. [106]. Ultrasound waves at25 kHz were used for the treatment of alopecia arata us-ing a methylprednisolone ointment and a cyclosporinesolution. Furthermore, melasma and solar lentigo weretreated by azealic acid and kojic acid and low-frequencyultrasound.

The iontophoresis technique applies a small electriccurrent to the skin, providing the driving force to enablethe penetration of substances into the skin. Transdermaldrug transport enhancement by iontophoresis is causedvia direct electrophoresis, electroosmosis or enhanced

diffusion [107]. When using direct electrophoresis, an ac-tive iontophoresis electrode is placed above a drug reser-voir on the skin having the same charge as the penetrant.Another indifferent counter electrode is placed elsewhereon the skin (illustrated schematically in figure 6). The ac-tive electrode transports the drug into the skin by themechanism of repulsion of equally charged carriers [108].Electroosmosis results when the electric field of the hu-man skin is superimposed by the artificial electric field of




the iontophoretic device. A solvent flow across the skinis caused which is able to transport uncharged and largermolecules [109].

Like iontophoresis, electroporation enhances the

transdermal drug transport through enhanced diffusion,electrophoresis and electroosmosis. In contrast to the ion-tophoretic techniques, electroporation uses a large volt-age treatment for a short period of 10 s to 100 ms. Theshort pulses of high voltage current produce temporaryhydrophilic pores as aqueous pathways where drug sub-stances, e.g. macromolecules, can pass through the skin[110].

Recently, the use of radiofrequency-driven skin micro-channeling as a new way for electrically assisted transder-mal delivery of hydrophilic drugs was introduced. Sintovet al. [111] showed penetration enhancement by radiofre-

quency microchanneling for the drugs granisetron hydro-chloride and diclofenac sodium.The microneedle technique uses small needles (10

200 m height and 1050 m width) which are connect-ed with the drug reservoir. The microneedle delivery de-vice is applied to the skin surface without reaching thenerve endings of the upper dermis. The actives are ableto overcome the stratum corneum without causing pain[103].

Power Supply

Gas BubbleDrug Formulation

Ultrasound

DeviceStratum Corneum

and Cavities

Fig. 5. The principle of sonophoresis sche-matically. Adapted from Daniels [103].

Drug Formulation

Active

Electrode

Counter

ElectrodePower Supply

= Drug substance = Indifferent lonFig. 6. The principle of iontophoresis sche-matically. Adapted from Daniels [103].





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Conclusions

There are permanent efforts to improve dermal andtransdermal drug delivery into and across the humanskin. One main focus in this field of research is the evalu-ation of chemical substances for their skin penetration-enhancing properties in topically administered formula-

tions. Potential substances used for this purpose need tohave both features, i.e. drug penetration-promoting ef-fects and a low or no skin irritating potential. To obtainsubstances which fully meet these requirements, one ap-proach is to synthesize penetration enhancers with thedesired properties. Modern discovery techniques, e.g.

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