expert opinion on investigational drugs volume 6 issue 12 1997 [doi 10.1517%2f13543784.6.12.1887]...

Review

Biologicals & Immunologicals

Drug delivery across the skin

Gregor Cevc

Since the introduction of the first through the skin (TTS) thera-peutic in 1980, a total of 34 TTS products have been marketedand numerous drugs have been tested by more than 50 com-mercial organisations for their suitability for TTS delivery. Mostof the agents which have been investigated have had low mo-lecular weights due to the limited permeability of the skin bar-rier. This barrier resides in the outermost skin layer, the stratumcorneum. It is mechanical, anatomical, as well as chemical in na-ture: laterally overlapping cell multi-layers are sealed by tightlypacked, intercellular, lipid multi-lamellae. Chemical skin per-meation enhancers increase the transport across the barrier bypartly solubilising or extracting the skin lipids and by creatinghydrophobic pores. This is often irritating and not always well-tolerated. The TTS approach allows drugs (< 400 Da in size) topermeate through the resulting pores in the skin, with a shortlag-time and subsequent steady-state period. Drug bioavailabil-ity for TTS delivery is typically below 50% without the first passeffect. Wider, hydrophilic channels can be generated by skinporation with the aid of a small electrical current (≤ 0.4 mA/cm2)across the skin (iontophoresis) or therapeutic ultrasound (fewW/cm2; sonoporation). High-voltage (> 150 V; electroporation)widens the pores even more, and often irreversibly. These stan-dard poration methods require experience and equipment andare not practical; at best, charged/small molecules (≤ 4 kDa insize) can thus be delivered efficiently across the skin. In spite ofthe potential harm of gadget-driven skin poration, this methodis used to transport molecules that conventional TTS patches areunable to deliver, especially polypeptides. Lipid-based drugcarriers (liposomes, niosomes, nanoparticle microemulsions,etc.) were proposed as alternative, low-risk delivery vehicles.Such suspensions provide an improved drug reservoir on theskin, but the aggregates remain confined to the surface. Con-ventional carrier suspensions can also increase skin hydrationand/or behave as skin permeation enhancers. In contrast, therecently developed, highly deformable carriers, Transferomes,comprise pharmaceutically-acceptable, established compoundsand are thought to penetrate the skin barrier along the naturallyoccurring transcutaneous moisture gradient. Transfersomes arebelieved to penetrate the hydrophilic (virtual) channels in theskin, which they track and widen after non-occlusive admini-stration. Both small and large hydrophobic and hydrophilic

18871997 © Ashley Publications Ltd. ISSN 1354-3784

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molecules are therefore deliverable across the stratum after as-sociation with Transfersomes. Drug distribution after transder-mal delivery by means of carriers probably proceeds via thelymph. This results in quasi-zero order kinetics with significantsystemic drug levels reached after a lag-time of up to a fewhours. The relative efficiency of TTS drug delivery with Trans-fersomes is typically above 50%, with the added possibility ofregional drug targeting.

Keywords:adverse effects, buccal, clinical applications, cutaneous ad-ministration, diffusion, drug carriers, drug delivery, drug targeting, elec-troporation, iontophoresis, l iposomes, lymphatic clearance,macromolecules, microencapsulation, mixed micelles, niosomes, non-invasive, penetration enhancers, peptide delivery, permeation, pharma-cokinetics, protein delivery, skin barrier, sonoporation, specificity, stratumcorneum, suspensions, therapeutic use, topical, transcutaneous, transder-mal, Transfersomes, transport, ultradeformable membranes

Exp. Opin. Invest. Drugs (1997)6(12):1887-1937

1. Introduction

Through the skin (TTS) drug delivery now has an es-tablished place in the pharmaceutical industry. Thismethod, often called transdermal, but which shouldmore accurately be described as (trans)cutaneous ad-ministration, was first introduced to the USA market in1980. It now has an annual worldwide turnover closeto $2 bn. The inclusion of analgesic patches containingvarious nonsteroidal anti-inflammatory agents, whichare used for regional, rather than systemic therapy, in-creases the total market to $3 bn.

Transcutaneous nitrates hold the largest TTS marketshare (over 50%), followed by oestrogen-based andnicotine patches (each over 15%), analgesics and anti-hypertensives (around 5% each), anti-emetics and an-drogens, with the latter steadily increasing their marketshare. Currently, more than 30 companies and severalhundred academic institutions are investigating TTSdelivery which should ultimately lead to the develop-ment of new commercial products. A list of most ofthese companies is provided in Table 1.

The chief reason for the success of TTS systems to dateis the avoidance of first-pass metabolism, leading to in-creased drug bioavailability. The quasi-first order ki-net ics of transcutaneous del ivery are alsoadvantageous. Improved patient compliance is not soimportant, since all of the current TTS products arecompeting with oral formulations of similar drugs.

The main problems associated with TTS delivery arethat only a small number of agents are suitable for con-ventional transcutaneous delivery approach and

frequent side-effects are experienced. Efforts are nowfocusing on less conventional approaches, such as theadministration of liposomes or other carriers on theskin. Figure 1 illustrates the evolution of TTS prod-ucts, the number of TTS publications in medical jour-nals per annum, the relative proportion of such papersreporting the side-effects of TTS treatment and thenumber of papers dealing with liposome-skin interac-tions.

The first part of this review is intended to be of generalinterest, highlighting the biological and technologicalbackground to transcutaneous drug delivery and dis-cussing its past and present limitations. The secondpart is aimed at the more clinically-oriented reader andwill survey the properties of existing TTS products.Furthermore, several products under developmentwill be evaluated and the rational development of thisdelivery approach will be discussed. Special attentionwill be given to non-conventional TTS methods andthe transcutaneous delivery of large molecules, asthese are most likely to contribute to the long-termsuccess and growth of the TTS market.

Only selected papers will be referenced. Readers arereferred for background information to [1,2], to an ear-lier review of TTS-delivery by Moore & Chien [3] and toa paper by Ridout & Santus [4] for the more clinical re-views. Recent reviews of selected conventional thera-peutic TTS systems include [5-8]; the last of which alsocovers carrier-mediated delivery (liposomes, nio-somes, Transfersomes, etc.). The 1995 issue of Current

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs(1997)6(12)

1888 Drug delivery across the skin - Cevc

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Problems in Dermatology discusses transcutaneousdelivery, to which several books are specifically dedi-cated [9-12].

The use of lipid suspensions on the skin is assessed in[8,13-15] and in a book on liposome dermatics [16].Ample information on phospholipids is given in [17]and liposomes are covered extensively in three vol-umes of [18]. Skin physiology and pathophysiology aredealt with extensively in the series [19], whereas skinbiochemistry is the focus of [20]. The effect of systemdesign on performance variability and the pharma-cokinetics of TTS systems is discussed in [21].Structure-tissue penetration relationships are dealtwith in [22,23] and adverse dermatological reactions toTTS systems are described in the review articles[24,25].

2. The skin

Skin or cutis is one of the best biological barriersknown to man. It is also the largest organ of the humanbody, with a total weight of more than 3 kg and a totalarea of 1.5 - 2 m2.

The efficiency of the skin barrier is chiefly due to thehistological and ultrastructural properties of the outerlayer of this organ. Some approaches consequentlyrely on affecting the skin structure at the subcellularlevel; whilst others attempt to lower the quality of cel-lular organisation. In this section, the overall histologi-cal skin architecture and structural peculiarities of the


Biologicals & Immunologicals - Review 1889

Table 1: Overview of transdermal drug delivery activity.

Company Total no.projects

No. projectsongoing

Stage

3M Medica 1 1 L

Alza 3 2 1 L1 Phase III

Buttler§

Cellegy 1 1 Pre

Cygnus 3 0

Dong Wha 1 1 Pre

Elan 6 4 1 Pre1 Phase III

2 L

Ethical 1 1 PreR

Forest 1 1 L

Fournier 2 2 1 Phase I1L

Hercon 7 0

Hisamitsu 1 1 L

IDEA§

Lec Tec 3 1 L

Medical Devices 1 0

Medtronic 1 0

Merck§

Moleculon 3 0

Non-industrial 1 1 Pre

Novartis§

Noven 1 1 Pre

Pharmed 1 0

Sano 1 1 Phase III

Serastar§

Shin 1 0

SmithKline Beecham 1 0

Techn. Chemicals Prod. 1 0

Teijin 1 0

Transdermal 1 1 Registered

Verex 1 0

Whitby 1 1 PreR

Yamanouchi§

Yissum(non-industrial)

1 0

Total 47 20

L: launched, Pre: preclinical; PreR: preregistration§ Project information for these companies is not available.

Figure 1: Research and marketing developments fortranscutaneous drug delivery. While the number of publications(•) dealing with and products (curve) based on conventionalTTS systems has stabilised, the interest in lipid suspensions onthe skin (o) continues to grow. The number of publicationsdealing with adverse effects (dashed) increased more rapidlyrelative to the number of TTS drugs on the market.

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intercellular pathway in the skin will be discussed. Thelatter is believed to be the major route of material trans-port across this organ [10].

2.1 Anatomical organisation

Skin consists of merely two layers: the outer epidermis[26] and the inner dermis. The epidermis is between 50µm and 200 µm thick and in permanent contact withthe environment. Due to its exposure to the harsh sur-roundings, the epidermis, despite its chemical robust-ness, must be completely renewed at least once everymonth to maintain its optimum protective properties[27].

The dermis is 5 - 20 times thicker than the epidermis,but contains fewer cells. This skin region is mechani-cally stablised by an interwoven network of collagenfibres [28], that normally appear as bundles with inter-spersed cells. The dermis also shelters the blood andlymph capillaries, nerve endings, glands, hair-follicles,etc. Moreover, this part of the skin is responsible forthe biochemical and biological degradation of materi-als transported across the skin [11].

The peripheral blood flow through the skin in the ex-tremities and torsum is 0.3 ml/h/cm3 [29]. The fluxesthrough the skin of the cheeks, front, fingers, foot-soleor palms are somewhat higher. The capillary bed in theskin is concentrated in the papillae of the suprabasallayer (the uppermost part of the dermis). The total sur-face area of the intracutaneous blood vessels, availablefor the direct passage of drugs into the systemic circu-lation, amounts to 100 - 200% of the skin area and isthus lower than that of muscles [30].

The distribution of hair and glands in the human skin isparticularly non-uniform [31]. Hair follicles, for exam-ple, are found over the entire body, but at differentdensities. The hair follicles in man are numerous onthe face and scalp (600 - 800 cm-2), but are 10 timesmore sparse over the rest of the body, with the excep-tion of the chest and armpits. The hair follicles in hu-mans therefore only cover 0.1 - 0.5% of the total skinsurface; in some furry animals this value reaches a fewpercent [32] and may then contribute significantly tothe flow across the skin. The smaller the intrinsic diffu-sivity of a given molecule in the skin, the more impor-tant becomes an appendageal contribution totransport [33,34]. Glands are only found in certainbody regions, such as the face, armpits, chest and pu-bic region.

2.2 Cellular organisation

The stratum corneum, or the horny layer of the skin, isof crucial importance for our survival. This outermost,very thin (1 - 10% of the total) skin layer contributesover 80% to the skin permeability resistance, which is

high enough to keep transcutaneous water loss ataround 0.4 mg/cm2/h under normal conditions. Thisamounts to approximately 150 g per day, transpirationexcluded, and shows that any large scale or extensivelowering of the skin barrier would lead to lethal bodydehydration. This is what happens after major burn in-juries, for example.

The outermost layer of the skin is consequently verydry (≤ 15% water [35]). It consists of a few dozen flatand partly overlapping, largely dead cells, so-calledcorneocytes, that are organised in columnar clusterscomprising groups of 3 - 10 corneocyte stacks [36].

Cells in the inter-cluster region do not overlap laterally.Individual cell clusters are separated by clefts orgorges ≤ 5 - 6 µm wide [37]). The depth of gorges (≤ 3 -5 µm) is also fairly constant, but their length may differconsiderably. The intra-epidermal extension of inter-cluster gorges is 5 - 10 µm thick. This appreciably ex-ceeds the depth of corresponding wrinkles on the skinsurface which is only a few µm. The total estimatedgorge area projected on the surface amounts to ≤ 20%of the entire projected intercellular area, or some ≤ 1%of the total skin surface.

Corneocytes in each cluster are very tightly packedand attached to each other through desmosomes [38],covering 15% of the intercellular space length [39]. Theintercellular spaces contain specialised multi-lamellarlipid sheets with variable ultrastructures that are cova-lently attached to the corneocyte (envelope) mem-branes [40]. Cells in each cluster stack tend to overlapat their edges with the cells in adjacent stacks. Suchtile-like organisation contributes to the tortuosity of theintercellular space in the stratum corneum and im-proves the quality of the skin permeability barrier [10].

Each essentially co-planar corneocyte layer is approxi-mately 0.3 µm thick [41] and gives the impression of asomewhat irregular lattice [42], consisting of cellularhexagons or more rarely, pentagons with an averagecross-section of 25 - 30 µm [36].

The basic features of the stratum corneum resemblethe barrier of the endothelial lining of blood vessels.However, in the horny layer the basic motif is repeateda number of times, which makes the skin a muchtighter barrier than the blood vessel wall. The hornylayer structure was pictorially described in the ‘brickand mortar’ model, in which the corneocytes representthe ‘bricks’ and the intercellular lipids are the ‘mortar’.

Corneocytes originate from the stem cells in the basalepidermal layer. The latter cells divide continuouslyand push their keratinocytic off-spring towards thestratum corneum surface. During keratinocyte differ-entiation into a corneocyte, the cytoplasmatic organ-elles and nucleus degenerate gradually. The products



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of cell biosynthesis, especially keratin, then accumu-late in the cytoplasm. The volume of each corneocytenear the skin surface is consequently relatively small,inert and filled with a stable, elongated macromolecu-lar matrix. The mature and terminally differentiatedcorneocytes finally loose contact and are sheddedfrom the skin surface, approximately one cell layer perday [43].

2.3 Intercellular lipids

Just before they die, keratinocytes give birth to socalled lamellar, or ‘Odland’ bodies [44,45]. These arelysosomes with impaired enzymatic activity and causethe accumulation of certain lipids in the organelle[Sandhoff K; personal communication]. Most lipids inthe horny layer are non-polar [46]. Particularly promi-nent are more than a dozen ceramide species contrib-uting ~ 50% to the total lipid mass, free fatty acids (~15%), cholesterol and cholesteryl-esters (~ 35%), witha total mass of a few mg/cm2 of the stratum corneum.These are all required for normal barrier function [47].However, in deeper strata phospholipids are alsofound [48].

Due to the length and asymmetry of their aliphaticchains and also their low polarity, ceramides crystalliseand spontaneously form lipid multi-lamellae in theskin. The defunct lysosomal vesicles in the older kera-tinocytes are therefore filled with the multilayered,crystalline ceramide plaques. Cell shrinkage and flat-tening, associated with the keratinocyte/corneocytetransformation, provokes the expulsion of such vesi-cles into the intercellular space. Here the vesicles stacktogether and fuse into the ceramide-rich, extendedmulti- lamellae [49], that also contain somecholesterol-esters [46]. The resulting multi-lamellar do-mains are matched together by the domains of poorer

organisations that comprise most of the non-ceramidelipids. Related lipid multi-lamellae are also found inother keratinised barrier tissues, e.g., the oral cavity[39].

In the epidermis, the most frequent lamellar arrange-ments involve 3 (23.5%) or 6 (24.2%) lucent bands withan alternating broad-narrow-broad pattern [39], with aperiodicity of 6 - 13 nm, respectively [50]. Such multi-lamellae are found all around corneocytes, but arenon-uniformly distributed; they are less concentratednear the cell edges and essentially absent in the inter-cluster space where intercellular separation is thegreatest.

Skin lipid composition and structure is reviewed in[46]. High quality electron micrographs are provided in[40,49]; The physiological response of chronically in-flamed and accommodated human skin is dealt with in[59]. The human barrier formation and reactions to irri-tation are discussed in [43].

2.4 The barrier

Generally, the average number of and order in the in-tercellular lipid lamellae increases towards the skinsurface. This is accompanied by a continuous, non-linear decrease in local water content near the surface[35]. This notwithstanding, the peak in the skin barrieris located in the inner half of the stratum corneum [36],where the intercellular lipid seals are already formed,but not yet compromised by the skin desquamation.The intercellular space, which is the important routefor transcutaneous drug delivery, is consequently ex-traordinarily tight in this skin region.

The skin permeability of various animal species/gen-ders is different for some (water, benzopyrene), butnot all (e.g., testosterone) molecules. Table 2 offers acomparison of dorsal animal skin permeability. Skinresistance also differs between sex and race in hu-mans. Female skin is approximately 30% more perme-able than male. Caucasian skin is by approximately thesame factor easier to permeate than black skin. Sitevariations [51,52] and the (patho)physiological state ofthe skin are also important (see Table 2; [53]).

Moreover, hairless mice [54,55] and possibly someother rodents appear to be exceptionally sensitive tothe action of chemical permeation enhancers (see Ta-ble 2), despite the fact that their skin lipid organisationis similar to that of man [50,56]. This is possibly due tothe unusually high lipid concentration in the stratumcorneum of such animals, which may exceed that ofhuman skin by a factor of nearly 4 ([32] and Table 2). Itis also noteworthy that general anaesthesia, in mice at



Table 2: Skin permeability of different species.

Animal Extract. lipidµg/cm2 [57]

Water[57]

Benzopyrene[33]

Guinea-pig 225 4.8

Hairless mouse SKH 273 3.8 1

Hairless mouse HRS 1.5

Sencar mouse 2.2

C3H/DBA2 mouse 3.45

C57BL6/Balbc mouse 4.65

Rabbit 2.7

Nude rat 1.6

Wistar rat 1

Hairless rat 273 1

Human 60 1

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least, is thought to dramatically increase the perme-ability of skin and other transport barriers, such as na-sal mucosa.

3. Transcutaneous transport

Molecules greater than a few hundred Da hardly evercross through the intact skin barrier. Large moleculestherefore do not cross the skin in appreciable quantity[32], even if their solubility is ideal (see [60]; Figure 2).Only after tape-stripping the skin, which completelyeliminates the horny layer (Figure 3; [61]), or by lipidextraction from the organ (e.g., with ethanol or ace-tone [62]) is the transport of at least some moleculesdramatically increased.

The transport rate, or flow, across the skin in the sim-plest approximation is proportional to the barriertransport capability, often called permeability (P) andthe transport driving gradient, ∆c. When several trans-port pathways are available, the various routes areadded together. If several transport-relevant gradientsexist (e.g., ∆ ψ el, ∆ aw, etc.) all of them need to be con-sidered in the flow equation:

Individual transport capabilities are interdependant ifthe underlying principle of motion is the same. Other-wise, basic differences come into play. For example,permeability is proportional to the partition co-efficient and diffusion constant, whereas penetrabilitydepends exponentially on penetrant deformation en-ergy, as will be explained later.

Transport across the skin can be increased by:

• decreasing the skin thickness

• increasing the partitioning of drugs into the skin

• increasing the number and/or the size of defects inthe intercellular lipid seals in the skin

• increasing the drug concentration, or activity gradi-ent, across the skin

• creating additional pathways in the skin

• creating extra forces/gradients which drive materi-als across the skin

Decreasing the skin thickness is used only in excep-tional circumstances [63,64], as it is undesirable tomodify the skin too much. However, some of the oldertopical agents relied on extensive skin abrasion. Drugpartitioning into the skin is normally promoted by pre-paring lipophilic prodrugs, or by complexing drugswith suitable additives. The latter are chosen so as toensure that increased complex partitioning in the skinwill more then compensate the disadvantage of biggercomplex size. This then permits the complexing addi-tive to act as a skin permeation enhancer, even if itdoes not directly interact with the stratum corneum.Choosing the optimum ionisation or salt form of thedrug is a simple way to carry out this approach.

Increasing the extent of the (lipid) excess area in theskin is the most popular approach to date. Simple sol-vents as well as more sophisticated skin permeationenhancers all rely on this principle. The former, whichinclude short-chain alcohols, ethyl acetate, DMSO,etc., acts non-specifically by solubilising and some-times extracting some of the skin lipids. More modernenhancers have a propensity to interact with the leastwell-organised lipids of the skin. The latter offer thebest target for increased diffusivity and partitioning.Azones, long-chain fatty alcohols or fatty acids, acyl oralkyl derivatives of other agents, etc., fall into this cate-gory. They generally solubilise and/or partly expandthe intercellular lipids in the skin, normally outside themulti-lamellar region.

One problem with the above mentioned approach isthat it cannot generate sufficiently stable and large pas-sages (pores) in the skin, owing to the self-sealing



Flow P c P P ael el w w

= + − + ⋅ ⋅ ⋅∆ ∆ ∆ψ

permeation + electromotion + hydrotaxis + ---

Figure 2: Skin permeability to substances of various molarweight (MW) and water-octanol partition coefficient, K,calculated from the equation in the text (curves). The drugs onthe market are shown as bullets. The range of molecules that canbe delivered across the skin by means of ultra-deformablecarriers (penetrants, Transfersomes) is delineated by straightlines.

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tendency of the skin lipid membranes; the observedcut-off is a consequence of this difficulty (Figure 2).The approach is also not well-tolerated.

Increases in drug concentration or activity gradientscan be acheived by several methods. The simplest is tochoose the most soluble ionisation- or salt-form of adrug or to saturate the drug solution on the skin. Adhoc prepared supersaturated solutions are also useful[65]. However, polymers may be included to slowdown drug crystallisation and thus extend the durationof supersaturation.

The third transport enhancement approach will bedealt with in the following sections. This includes ion-tophoresis, electro- and sonoporation, as well as epi-cutaneous drug carrier administration. Each of thesetechniques opens up channels in the skin. Moreover, itrelies on the source of the transport-driving force dif-ferent from the transcutaneous drug concentration gra-dient.

3.1 Permeation

The word permeation in this review exclusively de-scribes the simple diffusion of individual moleculesacross the skin. The permeant is thus assumed to haveno direct effect on the barrier, but the latter may be af-fected by other factors, such as enhancers. The propor-tionality factor between the diffusive flow and its

source is called permeability. It increases with the pro-pensity for molecular partitioning into the skin, typi-cally into the voids in the intercellular lipid layers, andwith the rate of diffusion through such layers. The skinpermeability is inversely proportional to effective bar-rier (stratum corneum) thickness:

The permeant’s motion into the receiver compartmentor through the non-rate limiting tissue, such as the der-mis, plays an important role in permeation.

The partition coefficient Ks depends on the permeant’scompatibility with skin lipids. It is influenced by thepermeant’s molecular size, relative polarity (octanolpartitioning), etc. [66]. The diffusion constant D ischiefly affected by the (relative) excess area availablein the skin [8]. Consequently, this factor is sensitive tothe permeant size and to anything that will affect thelipid packing in the skin. The barrier thickness ds is afunction of mechanical skin pretreatment, physiologi-cal condition, body site, gender, race etc.



Table 3: Skin characteristics at different body sites [58].

Location Stratum corneusthicknessµm

TEWLmg/cm2/h

Diffusivityx 1010/cm2/s

Lag-timemin

Hydrocortisonerelat. uptake

Dorsum 11 0.29 3.5 9 1.7

Abdomen 15 0.34 6.0 11

Forearm, volar 16 0.31 5.9 12 1.0

Forearm, dorsal 1.1

Hand, dorsal 49 0.56 32.0 22

Palm 400 1.14 535.0 83 0.8

Front 13 0.85 13.0 4 6.0

Scrotum 5 1.7 7.4 42 42

Foot-sole 600 3.9 930.0 106 0.1

Foot-ankle 0.4

Armpit 3.6

Scalp 3.5

Chin (ear vicinity) 13

TEWL: Transepidermal water loss

P Skin PermeabilityK D

d

s

s

≡ = ×

Where:Ks= partition coefficient in skin,D = diffusivity in skin andds = skin thickness

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These general considerations explain the success ofthe empirical formula proposed by Guy and Potts [60],to describe the diffusion of biological agents across theskin.

The result of the above formula is illustrated in Figure2 for two different octanol partition coefficient values,Koct. The drugs available on the market as TTS systemsare included as bullets. Increasing MW clearly imposesa very serious constraint on drug diffusion across theskin, and thus on the performance of any conven-tional TTS delivery. In the best case, values around 10-2

cm h-1 and typically values below 10-3 cm h-1 arereached [67]. The main reason for this is the limited ex-cess area in the lipid layers in the skin.

3.1.1Chemical permeation enhancers

Equations 1 and 2 illustrate how the efficiency of drugtransport across the skin can be improved usingchemical skin permeation enhancers.

Chemical skin permeation enhancers promote the de-livery across the skin by increasing the drug solubil-ity/partitioning in the skin lipids and by facilitatingdrug diffusion in and from the barrier.

All chemical skin permeation enhancers are amphi-philes, that is, they have at least one hydrophilic, polarend and at least one hydrophobic part. The two endsneed not be balanced and more often than not the hy-drophobic part prevails. Alcohols, cyclic ketones orsugars, charged carboxylic, sulfate, or (derivatised)amine ions, organic zwitterions etc., all provide exam-ples of hydrophilic ends; alkyl, acyl or alkenoyl, butalso phenyl chains represent examples of hydropho-bic termini. Consequently, all such molecules have anaffinity for the aqueous and lipid surroundings.

When mixed with the skin lipid membranes, permea-tion enhancers partition into the lipid layers and eitherexpand the polar-apolar interface or else formenhancer-rich, partly disordered domains [68-70]; (par-tial) lipid extraction from the skin is also possible. Thisoccurs preferentially in the least well structured skinlipid regions. Enhancers thus enlarge the width and thenumber of hydrophobic pores in the stratum corneumby creating excess lipid area in the lipid matrix. This fa-cilitates the diffusive flow of sufficiently hydrophobicand some amphiphatic drugs across the skin.

A permeation enhancer may also complex with thedrug molecule. The complex is typically held togetherby ionic, hydrophobic or hydrogen bonds, or by someother type of interaction. If this increases the solubilityand activity in the drug reservoir, the driving force is in-creased; if the solubility in the skin is improved [71],the permeability increases. Synergies are thereforepossible. An incomplete, but representative, list ofchemical skin permeation enhancers is given in Table4.

In Table 5 some of the more popular, or recent, per-meation enhancers are presented. Concentrationranges recommended in the literature are also re-ported with the following caveat.

The relative and absolute potency of various skin per-meation enhancers differ [8]. This makes absolutecomparisons, e.g., in Table 5, difficult. In principle, itis the concentration of an enhancer in the skin which



Table 4: Chemical skin permeation enhancers.

Enhancer Reference

1-Acyl-azacycloheptan-2-one (azone) [72,73]

1-Acyl-glucoside [74]

1-Acyl-poly(oxyethylene) [54,75]

1-Acyl-saccharide [76]

2-(n-Acyl)-cyclohexanone [77]

2-(n-Acyl)-1,3-dioxolane (SEPA) [78]

1,2,3-Triacyl-glyceride [79]

1-Alkanol [80-84]

1-Alkanoic acid [85-71]

1-Alkylacetate [87]

1-Alkylamine [88,86]

1-Alkyl-n-alkyl-polyoxyethylene [79]

iso-Alkyl-acylate [79]

n-Alkyl-β-thioglucoside [74]

1-Alkyl-glyceride [89]

1-Alkyl-propyleneglycol [90]

1-Alkyl-poly(oxyethylene) [54,75,91]

(1-Alkyl-)2-pyrrolidones [84,92]

Alkyl-acetoacetate [87]

Alkylene-glycol [93]

Alkyl-methyl-sulfoxide (e.g., DMSO) [94]

Alkyl-propionate [87]

Alkyl-sulfate [94]

Dialkyl-succinate [87]

Diacyl-N,N-dimethylaminoacetate (DDAA) [82,94]

Diacyl-N,N-dimethylaminoisopropionate(DDAIP)

[82]

4-Isopropenyl-1-alkyl-1-cyclohexene [96,97]

Phenyl-alkyl-amine [86]

log . . log .Skin permeability K MWoct

= − + × − ×6 3 0 71 0 0061

Where; Koct:Octanol partition coefficient andMW: Molecular weight

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determines the success of an enhancement. However,it is the nominal enhancer concentration on the skinwhich is typically considered or quoted. The two val-ues often diverge by several orders of magnitude, aresensitive to drug-enhancer association and also mayvary with the application conditions. Too small an en-hancer reservoir on the surface, for example, in thecase of fast enhancer diffusion across the skin orevaporation, leads to substance depletion. It alsochanges the final system properties. The chain-lengthdependence of numerous skin permeation enhancers,listed in Table 4, show an optimum at intermediatechain lengths. The probable reason for this is that ali-phatic chains which are too short do not permit a suffi-ciently strong and persistent interaction with the lipidsin the intercorneocyte space and make the moleculestoo volatile/diffusive. The long chains make enhancerstoo bulky and also anchor them too well in the inter-corneocyte lipid layers. The above illustrates that sup-plementary information that goes beyond skinpermeability values should be considered [98]. Manychemical permeation enhancers disturb the epithelial(epidermal [80,81,94] as well as buccal [82]) barrier in aconcentration- and time-dependent manner. The con-centration dependence is not necessarily linear over alarge range [72,80,81]. Saturation or even a maximum isoften observed. In some cases the drug’s partition

coefficient in the skin is increased [105], whereas inother situations the diffusion coefficient is morestrongly affected by the enhancer.

Irritancy and toxicity are not directly related to the de-gree of skin permeation enhancement [91,105]. Onereason for this is the variability of enhancer-drug inter-actions. The search for the ‘generic’ permeation en-hancer is therefore futile: different drugs or drugclasses prefer dissimilar enhancers, owing to the com-plexity of mutual interactions.

However, the efficacy of many skin permeation enhan-cers depends on the length and degree of unsaturationof the hydrophobic part of the molecule. Quite often,aliphatic chains with 9 - 12 carbons are most efficient[73,105], the latter value being preferred. Polyunsatu-rated substances are better than the monounsaturatedones [106] and double bonds in cis-configuration excelover trans-configuration [103]. Double bonds in themiddle of the chain offer the greatest advantage,probably by mimicking the properties of shorterchains with approximately 10 carbons [107]. Drug lipo-philicity and compatibility with the enhancer also playan important role [108].

Selective inhibition of either cholesterol, fatty acid, orceramide synthesis in the epidermis delays barrier re-covery, since each of these components is required forskin functioning. Lipid synthesis inhibitors, combinedwith skin permeation enhancers (acetone, DMSO) en-hance the delivery of lidocaine or caffeine across thehairless mouse skin [47]. Furthermore reducing essen-tial ion concentrations in the skin, by adding chelators,such as EDTA [74], also lowers the skin barrier.

Recently, it has been suggested that hyaluronan, a gly-cosaminoglycan with a shock-absorbing andstructure-stabilising role in connective tissue, is usefulfor localised delivery of diclofenac through the skin, atleast in vitro. Hyaluronan penetrates the skin at amuch slower rate than the drug, possibly owing tointra-epidermal hyaluronan receptors [109]. However,the mechanism of enhancement is unclear to date.

Water (skin hydration) also increases the transcutane-ous flux by affecting the quality and quantity of defectsin the skin. This occurs preferentially, but not exclu-sively, between, rather than in, the lipid-filled skin re-gion [110].

For alternative permeation enhancement it is impor-tant to know that the barriers in the oral cavity have asimilar, but less perfect structure, than the epidermis[39]. Consequently, the permeation enhancers thatwork in the skin will also increase the transport ofdrugs across the oral mucosa, but to a relativelygreater extent. This means that the cut-off for buccaldrug delivery [111] is higher than the value shown in



Table 5: More recent skin permeation enhancers.

Enhancer Prescribedrange (%)

Reference

1-Capryl-propylene glycol 5 [90]

1-[2-(Decylthio)ethyl]azacyclopentan-2-one (HPE-101)

6 - 10 [99,100]

1-Dodecanol ≤ 10 [82]

1-Dodecyl-azacycloheptan-2-one(azone)

≤ 10 [72,73]

2-n-Nonyl-1,3-dioxolane (SEPA) 10 [78]

2-n-Octylcyclohexanone ≤ 10 [77]

DMSO 20 [101]

Ethanol 40 [81]

Ethylene glycol ≥ 20

Ethyl acetate 30 [87]

Glycerol 6 - 90 [99,102]

Isopropanol ≥ 50 [78]

Isopropyl myristate 1 - 20 [79]

Oleic acid 1 -20 [71,85,86,103]

Oleyl-alcohol 20 [103]

Oleyl-polyoxyethylene-ether ~ 1(?) [54,91]

Propylene glycol 20 - 100 [86,104]

Bold values strongly recommended

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Figure 2, but the efficiency of delivery is often only afew percent [112]. For sufficiently potent and irritating,enhancer combinations, the upper limit may even beat the level of 10 kDa [112]. However, overcoming thisbarrier is difficult, if not impossible, with the non-invasive delivery methods currently available[111-113].

The very nature of skin permeation enhancers and thecharacter of passages which they improve narrowstheir applicability. They are helpful for the delivery oflipophilic molecules, but far less suitable for support-ing the transport of polar molecules across the skin.Improvements are therefore needed for polar drugswhich require less hydrophobic passages across theskin. In the following subsection, various methods forthe activation (opening, creation) of hydrophilic chan-nels in the stratum corneum are described. Amongstthese, controlled skin ‘poration’ is particularly popularfor the delivery of hydrophilic and selected amphi-phatic drugs across the skin.

3.2 Poration

Skin poration is useful for the enhancment of the deliv-ery of molecules across the skin barrier, which are ei-ther too big or too hydrophilic to fit into the voids inthe fluidised lipid layers in the skin.

In addition to classical needles, different devices areused to create suitable hydrophilic passages in the stra-tum corneum. Some of these are macroscopic gadgets.Recent ones are more elegant and (sub)microscopic,essentially acting as self-operating physical enhancersof transcutaneous transport, that is, as drug carriers.Lipid based, but superficially hydrophilic, drug carrierseven offer the advantage of incorporation of hydro-phobic substances, which can be delivered throughthe hydrophilic channels.

3.2.1Acoustic devices (sonoporation)

Skin treatment using an ultrasound of low energy andsuitable frequency, non-selectively opens hydrophilicpassages in the intercellular space in the stratum cor-neum [114,115], probably indirectly through cavita-tions in korneocytes [116]. This principle is calledsonoporation. The term sonophoresis is misleading, asit implies that the flux is driven by ultrasound whereas,in fact, the latter only creates standing waves andopens up channels in the skin.

Post sonoporation, molecules are driven across theskin by a concentration gradient. They traverse thestratum corneum via hydrophilic channels betweenthe lamellar bilayers and via lamellae in sites that dis-played domain separation [115]. This explains why therelative advantage of sonoporation is found to be moreeffective with increasing molecular weight [79].

Channels created by sonoporation remain open for atleast 20 h, but are resealed 2 days following therapeu-tic ultrasound [115].

Relatively low (2 MHz [114]) or too high (> 15 MHz[114,117]) a frequency seem to be inactive or less ac-tive, respectively, than an intermediate ultrasound fre-quency (10 MHz [114]). This effect is apparentlyproportional to the deposition of energy in the stratumcorneum [118]. An ultrasound with a much lower fre-quency (20 kHz) appears not to compromise the skinbarrier for long periods, but nevertheless can promotethe transcutaneous transport by several orders of mag-nitude [119]. Sonoporation with therapeutic ultrasound(1 MHz, around 1 Wcm-2, continuous) and chemicalpermeation enhancers act synergistically, at least forcertain small drugs [79].

The following list (Table 6) gives an impression of thekind of molecules that have been delivered acrossultrasound-treated skin.

3.2.2Impact devices

Microparticles or fine droplets can be propelledthrough the skin in a high velocity jet. If such particlesare loaded with drugs, they can compete with the hy-podermic needle. The corresponding impact devicesare claimed to be painless in practice, but they do trau-matise the skin locally, which releases biological mes-sengers, such as cytokines and histamines. Microjetsare therefore particularly attractive for vaccinations,especially under circumstances where it is difficult tomaintain sterility, or when a large number of peopleare to be treated. Impact devices are unable to entirelyreplace the needle, as they can only deliver drugs to adepth of 250 µm. This allows intradermal, but not im.delivery. Microjets are also unnable to mimic the slow



Table 6: Examples of drugs delivered across the skin by meansof skin sonoporation.

Drug Reference

Caffeine [116]

Nicotine esters [120]

Corticosterone [116]

Physostigmine [121]

Dexamethasone [79]

Progesterone [116]

Diclofenac [122]

Salicylic acid [114]

Oestradiol [79,116]

Testosterone [79,116]

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release kinetics of TTS delivery, except perhaps aftercombination with a suitable sustained-release mate-rial.

3.2.3Electric devices (iontophoresis,electroporation)

Transcutaneous electric potential can widen hydro-philic channels in the skin and drive charged drugsacross the barrier during electrical skin permeation en-hancement. Electrical skin permeation enhancement isprobably somewhat more selective than acoustic skintreatment, as it directly acts in the intercellular space,where the biggest opportunity for transport enhance-ment resides.

An electric current (ideally ≤ 0.4 mAcm-2) activatessome of the originally narrow (≤ 0.5 nm), hydrophilicchannels between the cells in the skin. Such channelsare numerous (≤ 108 cm- 2), but normally rather small(≤ 2.5 nm), when a tolerably low voltage is applied onthe skin ( ≤ 3 V for a 1 cm2 patch). Much higher volt-ages (≥ 150 V) have a more dramatic effect and perfo-rate the skin significantly.

The transcutaneous electrical potential gradient, ∆Ψ,supports the concentration gradient of drugs acrossthe skin i.e., the electromotive term is activated in thetransport equation 1 (see section 3):

This indicates that transcutaneous transport is propor-tional to the concentration of the electrically drivensubstance, ci, with a molar charge Zi x F (valency xFaraday constant) and inversely, but weakly depend-ent on thermal energy, RT . The ion diffusivity, Di andbarrier thickness, ds also continue to play a role. Elec-tric current corresponding to i is the product of i -fluxand Zi x F, but in the total, measured and controlled,current contributions from all migrating charged spe-cies must be included.

One can improve the performance of electromotivedelivery across the skin by using more highly chargeddrugs. For large entities this may involve molecular en-gineering, as has been done for example, by NovoNordisk who used the iontophoretic insulin flowacross the skin.

Iontophoresis opens the stratum corneum rather gen-tly (for reviews see [123-128]). It electrically ‘nanop-orates’ the skin on a time scale of hours by enlargingthe pre-existing, hydrophilic pores with an initial di-ameter around 0.5 nm. When these are negatively

charged, their size is close to 3 nm in hairless mouseskin. Neutral channels are only half as wide and posi-tive channels twice as small [129]. Channel size isthought to increase with increasing electrostatic poten-tial and decrease with increasing supporting electro-lyte concentration. Iontophoretic channels are chargeand molecular weight selective [130], but not very sen-sitive to lipophilicity variation [131] as they appear topass along rather than through, the lipid bilayers. Theflow of current through certain appendages, such assmall hairs, may also be involved [132].

Iontophoretic channels persist in the skin for at least 24h following electrical treatment with a voltage of rea-sonable magnitude [131]. Repeated iontophoretic de-livery on the same skin area therefore gives widelydivergent and typically greater fluxes [133]. However,the maximum permeability for iontophoretic current islimited by physical skin limitations, dissipation of elec-trical energy by currents flowing through the alreadyopened pores puts a limit on the maximum channelsize and number. In the best case, pores up to 20 nmwide are created, concluded from streaming potentialmeasurements [134]. Iontophoretic channels were cal-culated to cover 0.005% of the total treated skin area[135].

Hydrophilic channels in the skin support electro-osmotic flux, that is the flow of water associated withtransported ions, which can also carry uncharged spe-cies. Such flux under the anode typically exceedscathodal values. It reaches steady-state during 10 h ofconstant current iontophoresis (0.36 mA cm-2) at alevel 6 times higher than that found at the beginning (≤3 µL/h/cm-2) [136]. Changes in skin properties aregreatest over the first hour [129,137]. During this time,the resistance drops from ≥ 20 kΩcm-2 to approxi-mately 10% of its starting value. Skin impedance mustnot be overlooked either [138,139]. A very interesting,recent application is reverse electro-osmosis, duringwhich interstitial fluid is extracted to permit non-invasive glucose monitoring [140].

Ionto- or electrophoresis represents the direct flow ofcharged molecules in the electric field under the elec-trode. Its magnitude is proportional to the net numberof charges on migrating molecules and to the appliedpotential. Owing to absolute differences in concentra-tions, iontophoretic current normally comprises adominant contribution of inactive, supporting electro-lyte ions (e.g., Na+, Cl-) and only a minor componentof the active drug. Increasing ion concentration underthe electrodes therefore lowers the useful electropho-retic flow [135,141]. Skin pre-treatment with ethanolmay reduce [142], or increase [124] iontophoretic trans-port, but most other chemical skin permeation



( )P Skin permeability to ions c Z FRT

Ddd el i i

i

s

, ≡ = ×

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enhancers, as well as pH adjustments (often lowering[131,144,143]) increase the electrically driven materialflow.

Iontophoresis requires that the drug is placed on anelectrode with the same polarity as the drug. Electro-motion is then proportional to the applied potential,drug charge, concentration and diffusivity in the skin(see the equation given earlier in this section). A list ofdrugs that were tested for iontophoretic deliveryacross the skin is provided in Table 7.

Electroporation is quasi-catastrophic electrical skinbreak-through, giving rise to relatively wide pores inthe organ. It is performed by applying a high potential(150 - 600 V) on the skin [163,164]. The resulting hy-drophilic passages result largely, but not exclusively[165] between the lipid layers in the stratum corneum.The resulting skin damage is too strong to be rapidlyreversible and increases the transcutaneous flux forsmall fluorescent tracers up to 104-fold [163]. For somemolecules, electrophoresis during the pulse phaseplays the major role [163], but drugs, such as fentanylare transported during, as well as after pulsing [162].



Table 7: Electrically supported drug delivery across the skin.

Drug Clinical application Reference

Electrophoresis (Iontophoresis)

Lidocaine Cutaneous cut-downs in dialysis patients [145]

Lidocaine Eyelid surgery [146]

Lidocaine Pre-injection topical anaesthesia [147]

Lidocaine Biopsies of skin lesions [128]

Lidocaine Pre-myringotomy tympanic anaesthesia [148]

Lidocaine Improving impaired mandibular function [149,150]

Lidocaine Myofascial pain [150]

Lidocaine Laser ablation of ‘port-wine stains’ [151]

Tap water Palmoplantar hyperhidrosis [152]

Indomethacin Postherpetic neuralgia [153]

Benzydamine/diclofenac Neuralgiform facial pains [154]

Dexamethasone phosphate Postherpetic neuralgia [147]

Pilocarpine Cystic fibrosis detection [155]

Experimental

9-desglycinamide, 8-arginine-vasopressin (DGAVP) [137]

Aldosterone (ALDO) [156]

Angiotensin II (A II) [156]

Antibiotics [147]

Atrial natriuretic peptide (ANP) [156]

Calcitonin [130]

Griseofulvin [157]

Insulin [130,158]

Leuprolide (LHRH antagonist) [159]

Luteinising hormone releasing hormone (LHRH) [160]

Nafarelin [161]

Vasopressin (AVP) [130,156]

Phosphorothioate sequence (TAG-6) [142]

Propranolol [157]

Electroporation

Metoprolol [162]

Fentanyl [162]Exp

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For example, metoprolol was transported through fullthickness hairless rat skin in vitro by means of electro-poration [164]. Its flux after 4 h increased linearly withthe pulse voltage (24 - 450 V, duration 620 ms) andpulse duration (80 - 710 ms, voltage 100 V). This sug-gests that drug transport is proportional to the absorp-tion of energy in the skin.

It is doubtful whether any of the treatments describedin previous sections, with the exception of iontophore-sis, will find a wider application. However, further ef-fort is required in order to improve transcutaneousdrug delivery. Carrier-mediated transport offers thebest chance for success (Figure 3). Such transport re-lies on skin penetration.

3.3 Penetration

Skin penetration combines the advantages of skin per-meation and poration, it does not require gadgets orexternal sources of motion and can also mediate theflux of large molecules as it seems to utilise (

hydrophilic) channels in the skin, opened up by thepenetrant. Penetration in this work is used to describethe non-diffusive motion of skin penetrants. The mo-tion of large entities is not driven by a concentrationgradient.

By definition, a simple penetrant is too big to permeatethe skin. If a penetrant is subjected to a strong forceproportional to the nominal penetrant size and actingacross the skin, the penetrant will then make its waythrough the skin, if the exerted force is sufficientlystrong to intercalate the penetrant between the cellsinto a channel wider than the effective penetrant size.

To achieve high rates of penetrant transport, the effec-tive penetrant size has to be much smaller than thenominal penetrant size. Some carriers comply with thisrequirement.

A number of drug carriers were already used to deliverdrugs through the skin: liposomes, niosomes, mixedmicelles, Transfersomes (IDEA). Liposomes, in



Figure 3: Left.Results of Cray simulation of a highly deformable vesicle (quasi-Transfersome), at different stages of penetrating a poresmaller than its own diameter (from ref. [433].)Right. Visualisation of the component’s distribution, in a mixed lipid vesicle upondeformation, is similar to that shown in the left panel, calculated by an analytical membrane model (by courtesy of H. Richardsen): darklipids, with larger polar heads, accumulate in the regions of highest curvature.

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particular, were repeatedly claimed to increase the effi-ciency of drug delivery through the skin [14,166,167],despite the fact that such vesicles exceed in size (≥ 45nm) by more than one order of magnitude the biggestmolecules (≤ 1 nm) to date that have been deliveredacross the skin without gadgets.

It is generally agreed that conventional lipid vesicles,liposomes, do not pass through mammalian skin in sig-nificant quantity [15,168]. Exceptions to this are pilose-baceous units [169,170] and other shunts in the skin.This is understandable, as it is impossible to push alarge, poorly deformable entity through a pore muchsmaller than the ‘permeant’ size [171]. Sterile filtrationprovides an example of this, as can immediately be un-derstood by considering the relationship between vari-ous carrier parameters on skin penetrability [8]:

This empirical, but model supported expression, sug-gests that the efficacy and rate of lipid vesicle transportacross the intact skin increases with lipid bilayer de-formability and with the average pore size in the stra-tum corneum. Both are affected by the optimisation oflipid aggregate composition and by the administrationmode, but the former plays a more important role.

Improving transcutaneous drug transport with con-ventional aggregate carriers, such as liposomes, istherefore non-trivial. It normally results from an in-crease in skin hydration, following the administrationof carrier suspensions [172] and/or due to skin permea-tion enhancement by individual suspension ingredi-ents [8]. To achieve a different and strongerenhancement ultradeformable (lipid based) carriersare needed.

Sufficiently and easily deformable penetrants, such asTransfersomes, overcome the size exclusion principle,which normally prevents non-diffusive flow across theskin. To be extremely deformable, lipid assembliesmust be able to compensate deformation-induced, lo-cal stress (deformation energy). This can be achievedmost naturally by the adjustment in the local composi-tion of the assemblies with at least two components.However, the change must be such that the compo-nent that better sustains the deformation is accumu-lated, while the less adaptable component is diluted atthe maximally stressed site. This represents a transientinstability (metastability) which is not easily controlledand has therefore been avoided or prevented in classi-cal, suspension-based drug delivery systems. In con-trast, Transfersomes were designed specifically tocomply with the ultra-deformability requirements

[8,173], making the membranes of such assembliesflexible enough to pass through a constriction appre-ciably smaller than their own size.

Furthermore, Transfersome can be applied so as to firstfind or create and then utilise the appropriate hydro-philic passages in the skin. This relies on moistureseeking, which originates from the large hydrophilicityof the Transfersome surface. Parallels can be drawnwith iontophoresis, where charged entities are drivenelectrostatically from the high to the low electrostaticpotential site; the driving force is proportional to theirtotal charge and to the electrostatic potential differ-ence. Hydrophilic entities experience a similar fate inthe hydration gradient that enforces their partial hydra-tion at the starting site and ensures complete hydrationat the final site. The resulting hydrotaxis is propor-tional to the effective hydrophilicity of the moving en-tity and to the relative dryness of the starting site. Thepropensity to follow a moisture gradient is thereforeproportional to the number of comigrating amphi-phatic molecules. Large and very deformable Transfer-somes are more strongly driven into the wet skin thanmixed micelles of comparable cross-section, but with asmaller aggregation number.

Transepidermal water activity gradients drive suitabledrug carriers, such as Transfersomes, into and acrossthe skin. The moisture driven transport is observed fol-lowing the non-occlusive administration of Transfer-somes in excess water on the skin. When thesuspending medium gradually dries out a (de)hydra-tion gradient is (re)established across the stratum cor-neum, precipitation of excess Transfersomes’ throughthe skin follows. This happens when the accompany-ing water becomes so sparse that the solubility limit isreached for the suspension on the skin. The provisofor this is the capability of Transfersomes to penetratethe barrier. This is ensured by the high assembly de-formability [174] and the capability to exchange excessvolume without major destruction. Figure 3 illustratesthis process.

Surface hydrophilicity ensures Transfersomes flowinto the skin along the same path as that taken by wa-ter leaving the skin, but in the opposite direction. Thisguides Transfersomes through the intercellular region,where the contacts between the lipid layer surfaces areleast tight. Originally closed, ‘virtual’ hydrophilic chan-nels are thus opened, as during iontophoresis, butmore uniformly and to a greater final width. The pre-cise size distribution of channels in the skin which areused for spontaneous Transfersome migration acrossthe stratum corneum is unknown to date, but the aver-age width appears to be approximately 30 nm.



log( )

(

.

PenetrabilityPore Density Pore Size

Elast∝ × ≥1 25

ic Energy of Carrier Deformation)≤1

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1901Figure 4: A high magnification picture of the preferred route of vesicle penetration between the corneocytes in the stratum corneum (right) suggests that this probably leads between the cellsand lipid multi-lamellae (left; from the textbook). Fluorescence intensity is non-uniform; often parallel and sometimes apparently crossing from one to the next, adjacent corneocyte. This issuggestive of Transfersomes tracking the ‘virtual channels between corneocytes’, that is, the route of lowest penetration resistance between the cells in the skin (from [36].)

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Assymetry of distribution is likely, due to the existenceof two quantitatively different, but qualitatively similarintercellular routes across the skin [36,175].

The first, inter-cluster pathway leads between thegroups of corneocytes. It represents the high-end tailof channel-size distribution and typically starts at thebottom of inter-cluster gorges. It then follows thedense material filling, through the gorges and offersthe lowest resistance to Transfersome penetration atthe junctions of several clusters.

The second, intra-cluster pathway leads between theindividual corneocytes in each cellular cluster. Thisroute typically proceeds along the lipid layer surfaces(Figure 4). In the projection over the outer third of thestratum corneum, such an inter-corneocyte pathwayresembles an interwoven three-dimensional network,including all cells in the organ (Figure 5). At the sub-cellular level, the contacts between envelope mem-branes and the adjacent intercellular lipid membranesappear to be the most easily penetrable, but passagesaway from the cell membrane are also observed. Such

passages are normally parallel to the envelope mem-brane and are often in line with the nearest ‘penetr-ation channel’ [36]. The separation between theparallel channels (≤ 0.1 - 0.2 µm), suggests that they areseparated by many lipid multi-lamellae stacks, whichadhere to each other with less force than the individuallayers in any one multi-lamella (Figure 4).

It seems likely that the opened ‘virtual channels’ util-ised by Transfersomes to cross the skin correspond tothe hydrophilic passages opened by the most gentleskin poration methods, such as iontophoresis or mildsonoporation. These have similar (average/maximum)widths of 20 - 30 nm. However, the total area coveredby the channels opened by Transfersomes appearsmuch bigger in optical micrographs (≤ 4% of skin area)than the total area of iontophoretic channels in the skin(0.005%). This discrepancy can be explained by themore uniform action of transcutaneous hydration vs.electric potential gradient. The fact that Transfersomes,



Figure 5: Low resolution confocal laser scanning micrographs of the skin barrier after non-occlusive administration of fluorescentTransfersomes. Projection of several pictures, taken over the outer half of the stratum corneum, onto each other gives an impression ofthe distribution of putative hydrophilic channels in the skin which are accessible to, and can be crossed by, the skin penetrating drugcarriers. Corneocyte clusters are well recognised.

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unlike ions, feel long-term mutual attraction andtherefore preferentially flow in streams, may also beimportant.

Transfersomes cross through the skin between cellsfollowing the paths of lowest resistance between thepolar lipid layer surfaces and through the widened hy-drophilic ‘virtual channels’. To a lesser extent, the latterare also created by iontophoresis or sonoporation.

3.4Mechanical enhancement

Less elegant approaches have also been taken to over-come the physical skin barrier. A small piece of epider-mis was removed by vacu-suction in order to deliverthe drug via an occlusive patch across the skin

deprived of its barrier [63,64]. A simple mechanical de-vice (Cellpatch) was designed for this purpose [64].Such an approach was used to transport the antidiu-retic peptide, 1-deamino-8-D-arginine vasopressin,across the human skin, which fully recovered 8 weeksfollowing treatment [63].

3.5 Shunts

The role of transcutaneous shunts for the delivery ofagents across the skin is a matter of continued debate.While it would seem logical that at least some mole-cules will use the shunts, such as pilosebaceous unitsor glands in the skin, other weak spots, such as micro-lesions or simply the widest inter-cluster pathways,also provide potential short-cuts across the barrier.



Figure 6: Left. Relative permeation (in % of the average value measured with water,◊) of Transfersomes (•) or liposomes (o) insuspension as a function of pressure difference across the artificial skin with pores smaller than the vesicle diameter (rvesicle / rpore ≥ 2).Right.The efficacy of lipid transfer across murine skinin vivo, as determined with the triturated dipalmitoylphosphatidylcholine invarious aggregates. Inset shows an electron micrograph of a Transfersome, with clearly recognisable thermal undulations indicative ofextreme membrane flexibility (from [171]).

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The absolute importance of trans-follicular transportcan be gauged on the basis of various relative perme-ability values. Hair follicles typically account for 0.1 -0.5% of the total skin surface. Such follicles thereforetake a role in, or even dominate, transcutaneous trans-port, when their permeability is by a factor of 200 (=1/0.005) - 1000 (= 1/0.001) times higher than that of theresidual skin surface. In other cases, non-folliculartransport prevails. To date, the latter condition is onlyfulfilled by Transfersomes. For other kinds of shunts,similar estimates can be made.

In Figure 6 non-optimised lipid vesicles are seen tocross the artificial micro-porous permeability barrierwith an efficiency 104 times below that of water. Theflux of such vesicles through the barrier is therefore in-ferior to the counter-directed flow of water. When theamount of water lost by evaporation from the skin ex-ceeds the out-flow of water across the skin, which is al-ways the case without occlusion, such liposomes dryout and form a crust on the skin. The much smallermixed lipid micelles are also unable to penetrate theskin but probably for different reasons to those de-scribed above: the micelles are too small to open thechannels in the skin permeability barrier.

In contrast to this, the relative penetrability of the skinbarrier to Transfersomes is similar to that for water.Well-optimised particles therefore, compete efficientlywith the opposite flux of water. Under non-occlusiveconditions, the latter is overridden by the evaporativewater loss from the application side. This generatesand maintains a water activity gradient across the bar-rier, which drives the flux of Transfersomes across theskin, as long as such assemblies are present at the ap-plication site. Transfersomes are therefore less shunt-sensitive than standard lipid aggregates, but undersome conditions penetration through the shunts is ob-served [176].

4. Carrier fate on the skin

Lipid vesicles (liposomes, niosomes, Transfersomesetc.) have attracted most attention over the last decade(see Figure 1). Lipid vesicles interact with the skin andvice versa. This ranges from skin-lipid fluidisation,which leads to skin permeability enhancement,through to affecting the biochemical processes in theskin and to compromising the integrity of the cellmembranes; cell lysis and death may arise from this[177]. Vesicle uptake by the viable cells has been seenin vitro [178], but not yet in vivo in large numbers.

Only specially optimised lipid assemblies can pene-trate the skin (see further discussion). Most lipid sus-pensions, upon non-occlusive administration, simply

collapse on [179,180], or into [181,182] the partlydesquamated outermost skin region. This results inmassive fusion between lipid vesicles [180,183-185].Unification with the cell membranes is possible, butunlikely [186].

The first step in material transfer from a conventionalliposome suspension into the skin is vesicle fragmen-tation [184]. Transfersomes appear to be an exceptionto this rule, crossing the skin without breaking, butwith some exchange of internal volume [176]. Defini-tive proof has not yet been published [Gebauer D,Schätzlein A, Cevc G, in preparation].

5. Kinetics

A review that specifically deals with the general as-pects of transcutaneous delivery pharmacokinetics isgiven in [21]; the structure-tissue penetration relation-ship is the topic of [23], whereas the kinetics of per-meation enhancers is covered by [32]; [127] considersthe kinetics of iontophoresis and [187,188] deal withthe role of competing events.

Skin is metabolically highly active [189] and immuno-logically vital [190]. It also carries a rich bacterial flora,the most common commensal being Staphylococcusepidermis. Drug transformation may therefore beginon or in the organ, even before the delivered materialis transported further through the blood circulationand lymph flow. This is especially important whenonly small drug quantities are delivered. If needed,general inhibitors (e.g., taurocholate [74]), skin me-tabolism inhibitors (e.g., puromycin and amastatin[143]) or proteolytic enzyme inhibitors (e.g., aprotinin[144]) are useful. Protein binding was thought to affectthe deep tissue penetration of epicutaneously adminis-tered solutes [191], but this effect might be due to thechanged sink properties.

Normally, the following TTS-specific rates need to beconsidered:

• degradation at the surface

• passage through the device/adhesive

• transport across the stratum corneum

• distribution/binding in the skin

• metabolism in the living skin

• passage into the blood capillaries/lymph vessels

• drug liberation from a carrier, when applicable

• distribution in the tissues under the treated skin



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Typically, transport through the rate-limiting mem-brane in the patch, or else the passage through the stra-tum corneum is the main determinant of thepharmacokinetics of TTS delivery.

Small molecules delivered across the skin, are clearedthrough the blood circulation. This process is fast com-pared to the kinetics of skin crossing, owing to thelower quality and similar area of the blood capillarybarrier compared to the stratum corneum. Drug accu-mulation in deep sc. tissues is seldom important fordiffusion-dominated delivery due to the decrease indrug concentration with depth.

When driving mechanisms other than the concentra-tion gradient dominate, the situation may be different.For example, functioning blood supply significantlyaffects the iontophoresis-mediated solute transportdeep under the skin, but not transepidermal permea-tion [192]. Transcutaneous delivery of luteinising hor-mone releasing hormone (LHRH) by means ofiontophoresis creates a drug depot in the skin which isnearly twice as large as the entire mass of drug deliv-ered systemically [133]. Likewise, the use of drug carri-ers on the skin can shift the distribution largely into thetissue underlying the application site [8] for the follow-ing reason.

Lymph drainage through the fenestrated lymphaticcapillaries provides the main mechanism for the clear-ance of drug carriers from the skin. The reason for thisis that large bodies cannot enter the blood capillariesdirectly, owing to the lack of endothelial gaps (fenes-trations) in such skin capillaries [193]. The number oflymph vessels in the external lymphatic tree seems tobe somewhat lower than that of the blood capillaries.The location of both flow-systems is nearly the samehowever, in the papillae near the epidermal/dermaljunction [27].

The relatively small total area of lymphatic fenestra-tions, compared to the total area of the blood andlymph vessels and the difference in absolute sizes, ex-plains the slowness of carrier clearance compared tothe single molecule (drug) elimination from the site ofadministration.

The physio-pathological responses of the skin can in-duce changes in the chemical structure and composi-tion of lipids and proteins in the skin. Therefore, thepossible role of physio-pathological responses of theskin, leading to enhanced skin permeability should al-ways be taken into account.

5.1 Conventional TTS systems

All transdermal delivery systems share the same phar-macokinetic characteristics, including time lag, a pe-riod of steady-state plasma levels and a decline phase

(see Figure 7). The lag period is a consequence of thefinite time needed for crossing the skin. Typically, it isof the order of a few hours and seldom less than onehour. Constant plasma levels reflect the balance be-tween the continuous transcutaneous input and drugelimination from the tissue.

Transport across skin appendages, especially pilose-baceous units, may give rise to an initial pulse of mate-rial until the steady state is established and/or the drugreservoir in the vicinity of appendages is empty.

More complex temporal profiles result from interac-tions with enhancers, or removal of the system beforesteady-state conditions are achieved [21]. Clinically,these systems are used to achieve multiple peak serumoestradiol concentrations, e.g., after application oftransdermal oestradiol, or an initial peak systemic con-centration, such as after application of transdermal tes-tosterone.

Multiple-dose, dose proportionality and skin site bioe-quivalence studies are needed for the full pharmacoki-netic characterisation of a transdermal delivery system,which may even differ between people, gender andrace [21]. The size of the drug molecule and its oc-tanol/water partition coefficient with conventionalTTS also plays a dominant role and often contributes tointer-patient variability [23].

A combination of different types of skin permeationenhancers can give synergistic effects. Supersaturationprovides another means for enhancing the transport ofdissolved substances across the skin, but may be asso-ciated with stability problems [2].

The physiological status of the skin and underlying tis-sues often plays an important role in the pharmacoki-netics and pharmacodynamics of TTS delivery.Abnormal skin typically has impaired barrier proper-ties: the transepidermal water loss is 10 times the nor-mal for psoriatic skin, 9 times higher in the case ofeczema or erythrodermis and 3-fold increased in ich-thyosis [19,30,53]. Higher tissue concentrations of sol-utes are found in the upper tissue layers of sacrificedrats with no blood supply compared to those in anaes-thetized rats [192]. Even greater differences are ob-served with Transfersomes, owing to their largeassembly size. Solute concentration following 2 h ion-tophoresis is highest in the epidermis, the dependenceon the solute’s size being similar to that previously re-ported for excised human skin [192].

A great variability in the kinetics of delivery is observedin patients as well. Circulating levels of 17-β-oestr-adiol, following the administration of fixed drug doses,vary by up to 1000% [194]. This depends upon the



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product administered, the routes of administration andthe individual variations in absorption and metabolism[195]. The season may also play some role [250].

5.2 Carrier-based systems

Lag time between the epicutaneous drug applicationof a carrier that can cross the skin (Transfersomes) andthe biological action of the transported drug is affectedby the drug as well as carrier properties [176]. The vol-ume of the suspension medium, which must firstevaporate for the dehydration force to become fullyoperative, is also important. This explains why occlu-sion of the application site [196] or the use of very di-lute suspensions hampers, or slows down, the skinpenetration process. The rate of carrier passage acrossthe skin is, however, chiefly determined by the activa-tion energy for carrier deformation [8,173,176].

The time required for the highly deformable carrierpenetration through the skin may be as short as 15min, if the rapidly exchanging agents, such as local an-algesics are detected right under the skin permeabilitybarrier [197]. Agents which do not leave the carrier asfast are typically detected in the serum 2 - 6 h after, de-pending on the drug formulation [176]. A considerableproportion of more lipophilic drugs may be releasedfrom the carrier before the assembly reaches theblood, if only a small quantity of agent is used, owingto drug binding to the cells.

6. Passive devices

A list of transdermal products on the market is given inTable 8.

6.1 Hormones

Female hormone replacement therapy is reviewed in[198-204]. Fifteen products are on the market includingEstraderm TTS, Menorest and Oesclim, to name but afew.

Original epicutanous oestradiol delivery relied onspreading the drug in a gel over a large area. For exam-ple, a daily dose of 2.5 g of 17-β-oestradiol adminis-tered on the skin for four weeks in gel form gives riseto a significant systemic oestradiol level (≥ 60 pg/mL),which is sometimes lower after the application on theabdominal region [205]. A sufficiently high amount ofoestradiol (3 mg/day) in a conventional cream alsorapidly reduces bone turnover in post-menopausalwomen [206].

More recent approaches (e.g., Estraderm, Systen, Me-norest, etc.) focus on patch technology. The beneficialeffects of such oestradiol formulations on plasmagonadotrophins, maturation of the vaginal epithelium,

metabolic parameters of bone resorption and meno-pausal symptoms (hot flushes, sleep disturbance, geni-tourinary discomfort and mood alteration) [198], butalso on insulin-like growth factor and growth hormoneproduction [207], appear to be comparable to those oforal and sc. oestrogens. However, epicutaneous hor-mone replacement therapy has relatively fewer effectson insulin metabolism than oral drug delivery [208].Neither form of oestrogen completely reverses theknown age-related reductions in spontaneous, orgrowth hormone releasing hormone (GHRH)-stim-ulated, secretion of these hormones [209], but the pre-vention of osteoporosis by transcutaneous drugdelivery in postmenopausal women is now proven[199-201,211].

Advances in transdermal delivery continue to emerge.For example, low-dose systems and patches that main-tain serum oestradiol levels for a full 7-day period havebeen developed [204]. Such patches are bioequivalentto twice weekly transdermal administration of oestra-diol [212] and deliver a nominal oestradiol dose of 0.02mg every 24 h during the intended ‘wear’ period [213].Dose lowering was also advocated (e.g., the replace-ment of Estraderm 50 by Estraderm 25) [211], but cau-tion is necessary since serum levels of oestradiol mayvary by up to 1000%, when a fixed oestradiol dose isused [194].

The epicutaneous drug administration results in alower 17-β-oestradiol level, lower oestrone level and adecrease in some liver proteins, possibly due to thelack of first pass effect. Thyroid, carbohydrate or bloodcoagulation metabolism are sometimes unaffected[201]; in other cases, conjugated oestrogen, alone orcombined with progestin therapy, reduces blood lev-els of plasminogen activator inhibitor type-1 (PAI-1),an essential inhibitor of fibrinolysis in humans, by ap-proximately 50% in postmenopausal women. The drugalso enhances systemic fibrinolysis [214].

Oral and transcutaneous oestradiol delivery exert dif-ferent effects on prostanoids, prostacyclin and throm-boxane A2: while oral drug administration stimulatesexcretion of the latter, no such increase is observed af-ter epicutaneous drug delivery [215]. Moreover, themean ambulatory blood pressure is reduced in nearly2/3 of normotensive, oophorectomised women fol-lowing epicutaneous oestrogen delivery [216].

A limited number of studies suggest that transcutane-ous oestradiol may have less of an effect on plasmalipoproteins than oral drug administration [217] andthat the former creates relatively low cholesterol andatherogenic low density lipoprotein-cholesterol(LDL-C) levels [201,218]. The reports on lowering theconcentrations of high density lipoprotein-cholesterol(HDL-C) levels are conflicting [201]. Transdermal



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oestrogen can also [210], but not always [201], lowertriglycerides, whereas oral oestrogen increases them[210]. The risk of thrombosis [219] appears to be thesame in either case [218].

As with oral or injectable oestrogen replacement ther-apy, concomitant sequential progestogen is recom-mended for patients with an intact uterus duringtransdermal oestradiol administration, in order to re-duce endometrial stimulation [198]. Progestin additionto oestradiol also prevents an increase in HDL2 choles-terol levels, but lowers triglyceride concentration [210].Novel progestins, with minimal HDL cholesterol low-ering effects and the possible anti-oxidative propertiesof oestrogen, should be explored further [218]. Todate, it is clear that TTS oestradiol preserves the con-tent of α-tocopherol and β-carotene in LDL particlesand thus maintains the LDL in a reduced anti-oxidantstate [220]. It is also known that nortestosterone-

derived progestins are more efficient than progester-one derivatives when used in conjunction with TTSoestradiol [218].

Hypersensitivity to oestradiol may be specific to skinadministration. Adverse systemic events are reportedin 4% of cases, as after oral drug uptake [201]. Transcu-taneous oestradiol/norethisterone (e.g., Estragest TTS)is well-tolerated, except for local irritation at the site ofapplication in 3 - 7% of patients [201]. This notwith-standing, compliance is not very good: only a minorproportion of women starting the treatment continue itfor more than 5 years [194]. Unfortunately, the preven-tion of cardiovascular diseases and osteoporosis de-pends on long-term treatment [194]. The recentintroduction of once-weekly patches will perhaps im-prove the situation [212].

With respect to the improvement in quality of life, thetransdermal delivery of 17-β-oestradiol combined withan oral progestin offers no advantage over the oral



Table 8: Transdermal products on the market.

Drug Molecularweight (Da)

Indication/ action TTS(mg)

Oral(mg)

Introduced No. ofproducts

No. ofPublications

Systemic action(patches)

Clonidine 267 Hypertension 0.1 0.5 09/85 1 140

Oestradiol 272 Hormonereplacement therapy

0.01 2 11/85 15 381

Fentanyl 336 Generalised pain 2 0.2 (iv.) 04/91 1 131

Nicotine 162 Smoke cessation 5 25 03/90 4 278

Nitroglycerine 277 Hypertension 5 12/81 7 362

Norethisterone 298 Hormonereplacement therapy

0.25 0.25 94 32

Scopolamine 303 Motion sickness 0.5 1 09/80 1 138

Testosterone 288 Hormonereplacement therapy

3 50 03/94 3 62

Local action (patches, gels, etc.)

Diclofenac 318 Inflam./local pain 150 13

Flurbiprofen 244 Inflam./local pain 200 6

Ibuprofen 228 Inflam./local pain 1200 5

Indomethacin 358 Inflam./local pain 150 34

Ketoprofen 254 Inflam./local pain 300 12

Lidocaine 234 Localised pain 100 (iv.) 77

Lidocaine/prilocaine 257 Localised pain 100 (iv.) 77

Naproxen 252 Inflam./local pain 1500 7

Prilocaine 257 Localised pain 100 (iv.) 40

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conjugated equine oestrogen [221]. However, fromseveral human studies it was concluded that if agonadotrophin-releasing hormone (GnRH) antagonistis considered the treatment of choice, (transcutane-ous) hormone replacement therapy should be used incombination [222].

Combination of transdermal oestradiol and a GnRHantagonist, medroxyprogesterone acetate, fully trans-formed the endometrium of women in spontaneousmenopause; periods were thus heavier, but regular.Low doses of medrogestone often add to transdermaloestradiol-induced incomplete transformation of en-dometrium and oligo-amenorrhea, but also increasethe chances of irregular bleeding [223].

With regards to the progestins, the type of moleculesprescribed appears to be more relevant than the routeof administration, with the beneficial effects of oestro-gens being unaffected by the non-androgenic proges-togens [224].

Treatment with oral hormone replacement therapy sig-nificantly suppresses plasma insulin-like growthfactor-type 1 (IGF-1) levels and increases plasma insu-lin like growth factor binding protein type-1(IGFBP-1), while transdermal treatment has no influ-ence. As plasma oestradiol levels show little differencebetween groups, the effect of oral oestrogens onIGFBP-1 seems to be attenuated by progestins [225].Transdermal delivery of oestroprogestins (50 µg of17-β-oestradiol daily in a patch) vs. transdermal oestro-gen plus transdermal/oral (norethisterone acetate/di-hydrogesterone) replacement in menopause alsoprovides no significant therapeutic benefit [226].

Male hormone replacement therapy was introduced 14years after than female treatment. This was chiefly dueto the much higher daily doses required, which wasonly recently overcome by wearing a patch on mostpermeable part of the body, the scrotum (Androderm),or by using several very potent enhancers at one time(as in TheraDerm MTX system) in 2 simultaneously ap-plied patches (Andropatch).

Male ageing impairs testicular function. This decreasesthe bioavailable testosterone by approximately 1% peryear between the ages of 40 and 70 years. This is be-lieved to affect musclesunfavourably, adipose tissue,bone, haematopoiesis, fibrinolysis, insulin sensitivity,central nervous system, mood and sexual function andmight be treated by an appropriate androgen supple-mentation, with some risk for prostate abnormalities. Adaily percutaneous treatment with dihydrotestoster-one for nearly 2 years created high plasma levels of di-hydrotestosterone (> 8.5 nmol/L), with a slightlyreduced prostate size [227].

Following the success of female hormone replacementtherapy across the skin, male hormone replacementproducts therefore became fashionable [228-230], de-spite the fact that the daily demand of testosterone (3 -5 mg) exceeds the daily requirement for oestradiol byseveral orders of magnitude. To overcome this prob-lem, the first patch on the market was worn on thescrotum, taking advantage of the high resorption capa-bility of the organ. Newer products use more potentenhancers.

The AUC and cumulative release of testosterone fromtransdermal patches, containing several permeationenhancers, are linearly related to the number of ap-plied systems on hypogonadal men [231]. A peak indrug concentrations in a Phase III study was observedapproximately 8 h after the application of 2 patches,independent of the administration site. However,baseline-subtracted time-average-steady state concen-trations decreased in the following manner: back >thigh > upper arm > abdomen > chest > shin and gavean averaged daily input of 4 - 5 mg at best [232]. Thiswas sufficient for physiological testosterone replace-ment in hypogonadal men and restored prostate sizeto normal. In the men treated with testosterone epicu-taneously, prostate-specific antigen (PSA) levels werewithin the normal range [233]. Testosterone deliverythrough the skin also improved sexual function in menwith hypogonadism [234]. Figure 7 illustrates the per-formance of a modern testosterone patch in vitro andin vivo. Recent experiments using enhanced testoster-one delivery across the skin [116] revealed synergisticeffects of chemical enhancers and ultrasound [235].

6.2 Antihypertensives

Nitroglycerin (Glyceryl Trinitrate) is probably the mostwidely used nitric oxide donor. and was introduced inpatch form to prevent angina. Unfortunately, the useof long-acting nitrates, such as a 24 h patch, induces ni-trate tolerance and creates a therapeutic problem inmost patients with stable angina [236]. In particular,continuous transdermal drug delivery leads tocounter-regulatory responses associated with sodiumretention and probable plasma volume expansion[237]. To minimise these difficulties, intermittent use isrecommended, during the day only, when angina at-tacks are most frequent [21]. This selectively changesβ-adrenoceptor density and vascular response, whichmay partly contribute to the phenomenon of pharma-cological tolerance following chronic nitrate admini-stration [238]. Nitroglycerin given as a transdermallong-acting system also influences portal haemody-namics in liver cirrhosis [239] and appears to be activeagainst tendinitis [240].



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Nitroglycerin (25 mg) in a tape (Millisrol tape) inducesrapid coronary vasodilation within the first 15 min fol-lowing topical use, causing small blood pressure andno heart rate changes [241]. In dogs, nitroglycerin (2.5mg/kg) decreases systolic blood pressure by 10 - 15%,while diastolic blood pressure and heart rate are unaf-fected 30 min post-application and for at least the fol-lowing 8 h.

Administration of a nitroglycerin patch with nifedipinedecreases systolic blood pressure, as well as heart rateand coronary blood flow, more than the use of glyceroltrinitrate only [242].

Nitroglycerin used epicutaneously at a dose of 10mg/day does not alleviate the myocardial ischaemiaproduced by balloon inflation during coronary angio-plasty, in contrast to intracoronary glyceryl trinitrate

[243]. Limited drug permeation across the skin is in-ferred by the observation that transcutaneous admini-stration of nitrite increases the methaemoglobinconcentration in the blood in the case of abraded, butnot of normal skin [244].

The route of delivery influences the prevalence of indi-vidual nitroglycerin metabolites [21]. Transdermal ni-troglycerin ultimately induces drug tolerance and maysignificantly lower haematocrit [245]. Allergic reactionsto local nitroglycerin administration are detected in ap-proximately 13% of patients, but only in 3.4% has thetherapy had to be discontinued. Changing to a differ-ent transdermal system reduces the incidence of localreactions [246].

Clonidine as a patch (e.g., Catapres-TTS) deliverstherapeutically effective drug doses for 7 days. It wasshown to reduce blood pressure in patients with mild-to-moderate hypertension as effectively as oral clo-nidine, but regulates blood pressure more effectively[247]. Blood pressure in patients with more severe hy-pertension and those receiving multiple antihyperten-sive agents is not significantly reduced byCatapres-TTS [248].

Most patients find the transdermal system more con-venient than oral treatments and compliance may beimproved. Dry mouth, drowsiness and sedation,which are the most common side-effects of orally ad-ministered clonidine, also result from transcutaneousdrug administration, but possibly at a lower incidencethan during oral treatment [247,248]. Up to 50% of pa-tients suffer from adverse skin reactions [25], black pa-tients being less sensitive than whites [248].

Clonidine has recently been used in tape form(M-5041T). The antihypertensive effects of this formu-lation were investigated in various rat hypertensionmodels. Therapeutic effects without adverse effectswere observed with 1.5 mg of the drug per kg bodyweight on the skin [249]. Plasma concentrations of clo-nidine, administered with such medication on humansduring the winter, was not affected by bathing. How-ever, plasma drug concentration as a whole was sig-nificantly higher in the summer [250]. The continuousinfusion of clonidine (250 µg/kg/24 h) and epicutane-ous administrations (1.5 and 4.5 mg/kg in a M-5041Tpatch) both lower blood pressure for 12 h or more, butdiuresis followed by antidiuresis is only significantwith the former treatment [251].

A combination of central α-adrenergic antagonists,such as clonidine, with calcium channel blockers (e.g.,nifedipine or propranolol) is expected to ensure themost favourable overall effects on hypertension-related end-organ damage [252]. Several attempts were



Figure 7: Correlation between thein vitro and in vivodetermination of testosterone flux across the human skin from aTTS patch (15 cm2) over 24 h. A: Cumulative drug input; arrowon right denotes the totalin vivo input (per 2 patches), based onanalysis of residual material in the patch. B: Baseline adjustedin vivo pharmacokinetic profile andin vitro simulation (from[434]). Reproduced from Journal of Controlled Release,Volume 19, pages 347-362. Copyright 1992, Elsevier.Reprinted with permission.

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therefore made to either combine clonidine with anoral α-blocker [252], or to develop TTS formulations ofsuch blockers [253,254].

Nifedipine from two microemulsions tested in vitro (≤20 µg/h/cm2) [253] was absorbed across the skin at amuch higher rate than from reference gels (≤ 0.5µg/h/cm2) [253,254]. Matrix dispersion-type nifedipinepatches gave an intermediate delivery rate (∼ 10µg/h/cm2) [255]. However, systematic attempts to de-velop transdermal nifedipine formulations alone, or incombination with the permeation enhancers sodiumlauryl sulfate (1%) and propylene glycol (20%) in a so-dium carboxymethylcellulose 3% gel base, have failedto date [254]. Use of mixed solvents or supersaturationwere also ineffective, if an aqueous receiving phasewas used [254].

The oral nifedipine-TTS-clonidine combination pro-vided good blood pressure control and also combinedthe protective effects of the two agents against compli-cations of the hypertensive syndrome [252].

Propranolol is also interesting from the pharmacody-namic viewpoint. This widely used β-adrenoceptorblocker suffers from a high degree of first-pass me-tabolism, leading to a very low bioavailability (< 10%)of conventional oral formulations. TTS propranolol,consequently, would be very attractive.

Early experiments with propranolol ointments, con-taining macrogol and Carbopol, revealed that the per-cutaneous drug absorption in rabbits depends on thepresence of skin permeation enhancers, such as azone[256], or intermediate chain-length fatty acids [257], butis typically low. Lipophilic prodrugs were synthesizedto address this problem [258]. Interestingly, only the(R) but not the (S) isomers of lipophilic prodrugs areconverted to propranolol in the epidermis and thenpass through the dermis, resulting in stereoselectivepenetration [258]. However, these may not be neces-sary since the transdermal patch, based on acarboxymethylcellulose-sodium gel, already appearsto provide 66% permeation efficiency in the excised,hair-free rat skin model over a 24 h period. The zero-order permeation profile in this latter case was charac-terised by a permeation rate of 52.87 ± 11 63 µg cm-2

h-1. In the rabbit, plasma levels of 11.75 ± 3.40 ngdrug/mL were achieved during the same time period[259]. However, concomitant skin irritation was signifi-cantly strong. Similar problems in pigs [260] and rats[259] suggest that the skin erythaema is due to the cu-mulative amount of propranolol permeating throughthe stratum corneum and thus may be difficult to over-come. On the other hand, topical propranolol did notinduce psoriasis-like lesions in (guinea-pig skin), un-like oral propranolol [261].

6.3 Scopolamine

Scopolamine (hyoscine) is an anticholinergic agentfrequently used to prevent non-specific dizziness (e.g.,motion sickness) and vestibular disorders [262]. Trans-dermal scopolamine offers the advantage of a 12-timeslonger duration of action (72 h) compared to oral or in-jected drugs, but shares with the latter the deleteriousside-effects on the autonomic and central nervous sys-tem cholinergic functions. Biological responses totranscutaneous scopolamine vary appreciably, bothbetween individuals and between different patch ap-plications on the same individual [262].

Transcutaneous scopolamine was compared to pla-cebo in the prevention of postoperative nausea andvomiting, but offered no significant benefit within a 48h interval [263]. However, transdermal scopolaminepatches were claimed to reduce postoperative emesisin paediatric patients undergoing strabismus surgery[264] and were found to increase vagal tone in patientswith severe coronary heart disease [265]. The drug de-livered through the skin had an anti-ischaemic effect insuch patients [265], was shown to be useful in the treat-ment of detrusor instability [266] and increased para-sympathetic tone in healthy volunteers [265].Scopolamine was also reported to act transiently as aweak antidepressant and nocturnal rapid eye move-ment inhibitor [267].

The main side-effects of epicutaneously administeredscopolamine are xerostomia and blurred vision due toreduced visual accommodation [268]. Visual problemsincrease following repeated patch applications, withhypermetropic (‘long sighted’) individuals particularlyat risk. Central nervous system effects comprise re-duced memory for new information, impaired atten-tion and lowered feelings of alertness [262].Sometimes, subtle dependency and outright addictionmay develop to the point where hospitalisation is nec-essary to treat physiological chemical dependency[268]. This may be one of the reasons why TTS sco-polamine has been withdrawn from certain markets.

6.4 Nicotine

Nicotine in patch form (e.g., Nicoderm) is used for avariety of indications, but most often to facilitate smok-ing cessation.

Smoking cessation and its dependence on systemicnicotine availability was reviewed in a number of pa-pers [5,269-276]. Epicutaneous nicotine administrationwas reported to increase the chances of smoking ces-sation by a factor of 20 after 6 weeks [269], by a factorof 10 after 6 months [272] but only 2-fold after a year[274], concomitant supportive treatment being of greatimportance [272,273]. These relative numbers aresomewhat misleading, since an increase of 50% in



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relative terms only corresponds to approximately 5%in absolute terms [277]. According to more recent stud-ies, time to relapse is longer, but quit rates at one yearare not significantly different after the use of nicotinepatches [278]. This may be due to the fact that with-drawal discomfort often persists despite the use ofnicotine patches [279]. The low-dose nicotine or pla-cebo patches are both inefficient [276].

Nicotine patches are therefore only recommended forsmokers willing, but unable, to quit by simpler meansand those likely to suffer severe nicotine withdrawalsymptoms. Nicotine patch therapy seems safe in ado-lescent smokers, but placebo-controlled trials areneeded to establish the efficacy of such therapy [280].

Skin reactions to transdermal nicotine are the mostcommon adverse event. In a recent study, erythaemawas observed in 55%, erythaema and oedema in 5%and erythaema and vesicles in 9% of patients; 32% ofyoung subjects had no skin reactions. Other reportedadverse events were headaches (41%), nausea andvomiting (41%), tiredness (41%), dizziness (27%) andarm pain (23%) [280]. Sleep disturbances were ob-served in up to 13% of patients [274]. No cardiac ad-verse effects were seen in healthy volunteers [281], butmultiple transdermal patches of nicotine and someother drugs were used by several dozen suicidal adultsin the USA [282].

Transdermal nicotine administered at the highest toler-ated dose for 4 weeks is efficacious for controllingclinical manifestations of mild-to-moderate active ul-cerative colitis [283,284]. Consequently, nicotinepatches may represent a good alternative to steroids inselected patients with mild to moderate relapses of ul-cerative colitis. The precise mechanism of action re-mains unknown [284].

Transdermal nicotine was also used to potentiate neu-roleptics in Tourette’s syndrome [285,286].

6.5 Pain

6.5.1Systemic analgesics

Fentanyl applied on the skin is effective in the controlof chronic and postoperative general pain [287,288].The success of medication is nearly twice as good as inthe placebo-treated group and permits the reductionof concomitant parenteral morphine dose by approxi-mately 30% [287]. The cost of analgesic therapy withfentanyl transdermal delivery is higher than that of par-enteral opioid analgesia, but less than patient-controlled analgesia. The pharmacokinetics of transcu-taneous fentanyl, as well as its effects and therapeuticconsiderations, are similar to those common to other

opioids [287]. The recent experiments withelectroporation-facilitated delivery of fentanyl acrossthe skin are therefore poorly justified [162].

A conventional, epicutaneous fentanyl administration(Duragesic) at doses ranging from 25 - 300 µg/h, ac-cording to one study [288], provided good analgesia in80% of a heterogeneous group of 44 patients with vari-ous terminal diseases. Pain reduction was seen in a dif-ferent study after 24 h and satisfactory analgesia wasachieved within 48 h. To maintain this effect, the dosehad to be adjusted during weeks 1 through to 4, innearly 50% of adult patients [289]. The dose require-ments for juvenile patients is less well known [290]. Inorder to reduce the lag time before reaching steady-state and allow variable drug release rate, iontopho-retic delivery of opioids (fentanyl, sufentanil) could beused [291].

Transdermal fentanyl used at a relative dose of 1/70provides similar pain relief as sustained release mor-phine, but significantly more patients require supple-mental medication with liquid morphine duringtransdermal fentanyl therapy [292]. Conversely, consti-pation and medication with laxatives decrease signifi-cantly during fentanyl therapy [289,292].

In general, the side-effects of transdermal fentanyl aresimilar to those of conventional opioids, but normallypatient compliance is good [288]. The most commonadverse effects to fentanyl in patch form are nausea (45- 85%), pruritus (14 - 60%) and sedation (40 - 59%)[287]. In one study, the treatment was discontinued inless than 20% of patients due to intractable nausea, di-arrhoea, adherence problems, or poor analgesia. Inanother study, over 90% of the patients chose to con-tinue the transdermal fentanyl therapy due to the bet-ter performance in comparison with oral morphine[292]. The reduction in side-effects was also confirmedby others [289,293], but the issue of withdrawal symp-toms was discussed repeatedly [294-296].

Clonidine delivered across the skin prophylactically,safely prevents withdrawal symptoms in paediatric pa-tients who have undergone single-stage, laryngotra-cheal reconstruction and who require prolonged (≥ 7days), deep sedation [297].

Other opiates and narcotic drugs that were tested inTTS formulations include morphine, hydromorphine,codeine, sufentanyl and meperidine, [298]. Whereasthe latter two had comparable permeabilities throughthe skin as fentanyl, codeine was delivered less effi-ciently by a factor of ≥ 2, whereas hydromorphine andmorphine were worse, by one or two orders of magni-tude, respectively [298].



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6.5.2Regional anaesthetics

Mexiletine was used in an open-label study to evaluateits effectiveness in the treatment of phantom pain.Close to 50% of patients had favourable results withmexiletine alone. A further 35% responded to a combi-nation of mexiletine and clonidine. 10% had intoler-able persistent nausea, even at low mexiletine doses[299].

6.5.3Local anaesthetics

EMLA (eutectic mixture of local analgesics) combineslidocaine and prilocaine in a patch or cream [300]. Bothare equally effective in alleviating the pain associatedwith lumbar puncture, but the patch offers better dosecontrol and is easier to use [301]. However, the result-ing local analgesia has a limited depth. In patientstreated with extracorporal shock-wave lithotripsy,EMLA cream only improves the pain sensation in 10%of cases, but does not replace the need for analgesic

sedation [302]. In neonates, a 78.8% lower reaction isseen in the relatively superficial venopuncture vs. arte-rial puncture [303]. Typically, a low pain score is deter-mined in around 60% of such children treated topicallywith EMLA, in comparison with 15 - 18% in the controlgroup [303].

Simple lidocaine solutions may require a large applica-tion area to act, if they act at all. For example, post-herpetic neuralgia is relieved by 5% lidocaine in up to3 patches, covering a maximum of 420 cm2, 4 - 12 hpost-drug administration [304], with minimal systemicabsorption (≤ 0 1 µg.mL-1). A much longer action of5% lidocaine gel (8 h on the cranium non-occlusively,or 24 h under occlusion for limb or torso) reduces thepain of postherpetic neuralgia, following herpes zosterin all patients [305]. Conversely, a more dilute 2% lido-caine solution used topically does not attenuate thepain of drug infiltration more than saline [306].

Topical lidocaine may induce allergic contact dermati-tis which, in turn, results in severe localised reactionsfollowing drug injections [307]. Another side-effect ofone of the constituents of EMLA cream is mild methae-moglobinaemia [303].

With 4% amethocaine gel, clinically acceptable anaes-thesia was achieved faster in 92% of children. Whereasin grown-ups, the success rate after 40 min applicationtime was 85%, compared to 66% in the 5% EMLA group[308]. 37% of children treated with amethocaine gelshowed localised erythaema at the application site, butno more serious adverse effects were noted [308].

Systemic absorption is often greater for the topicallyused nonsteroidal anti-inflammatory agents (NSAIDs),which also suppress local pain.

6.5.4NSAIDs

NSAIDs are widely used for the management of localand systemic pain. Probably the best known exampleis Voltaren, which contains the cyclo-oxygenase an-tagonist, diclofenac, as an active ingredient. VoltarenEmulgel also contains several skin permeation enhan-cers and thickening agents to make the formulationsuitable for local administration on the skin. Other ex-amples include ketoprofen [309-311] and ibuprofen[312,313]. Only 6% of all adverse drug reactions relatedto NSAIDs refer to topical formulations and only 5% ofthese reactions are of a general nature [314].

Diclofenac has very limited permeation depth in ani-mals (4 mm [315]) and in humans [316], when adminis-tered in commercial hydrogel. In patients, only smallerjoints, such as those on the fingers and wrist, can there-fore be treated adequately. Drug concentration in the



Table 9:Chemical enhancer supported drug delivery across theskin - experimental studies.

Drug Action/indication Ref.

6-Mercaptopurine(6-MP)

[105]

Alniditan Migraine(5 HT1D antagonist)

[341]

Aspirin Herpetic neuralgia [329,331]

Codeine Pain treatment [298]

Cyclosporin PsoriasisImmunomodulation

[99]

Diclofenac Pain [342,343]

Dehydroepiandrosterone(DHEA)

HormoneImmunomodulation

[337]

Ebiratide Adrenocorticotropicanalogue

[74]

Elcatonin Hypocalcaemic peptide [74]

Hydromorphine Narcotic [298]

Levonorgestrel Hormonal treatment [338]

Meperidine Narcotic [298]

Mexiletine Phantom pain [299]

Metaproterenol sulfate(orciprenaline)

Bronchodilator [71]

Methimazole Thyroid suppression [344]

Minoxidil Hair growth [78]

Morphine Narcotic [298]

Pilocarpine Glaucoma [334]

Sufentanyl Pain treatment [298]

Tacalcitol Psoriasis [345,346]

Tazarotene Psoriasis [347]

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muscle is nearly the same as in the plasma [315,317]. Ifthe plasma concentration is too low, which is normallythe case, no therapeutic success is expected.

Diclofenac hydroxyethylpyrrolidine (DHEP) was in-corporated in a plaster [318] containing 180 mg DHEPin an auto-adhesive, medicated gauze pad of standarddimensions (10 x 15 cm2). The steady-state measure-ments with such a pad on animals indicated thesustained-release (12 h) of the drug [319], with an esti-mated absorbed dose of 5 - 10 mg per application; thiscorresponds to a bioavailability of 2.5 - 5.5% [319],which is not sufficient for the successful treatment ofmost NSAID-sensitive diseases [318,320].

Diclofenac in a submicron emulsion was 40% more ac-tive than diclofenac in a gel (Voltaren Emulgel) [321].However, the validity of the animal model used issomewhat doubtful [322].

Penetration profiles achieved with diclofenac, usingthe highly deformable carriers Transfersomes, in a ratand pig model, come close to the desired therapeuticeffects [8]. The transfersomal formulation of diclofenacgets into and across the skin approximately ten timesmore efficiently than the drug from commercial hydro-gel, administered at an intermediate dose (2 mg/kgbody weight). It is also accumulated to a much greaterextent in the tissue proximal to the site of administra-tion, probably owing to the inability of the carrier asso-ciated drug to get cleared directly through the bloodcirculation. Drug concentration in the treated patellaexceeds the systemic level by a factor of 5 (in rats) tomore than 30 (in pigs). In either case, it is in the thera-peutic range. Diclofenac in Transfersomes thereforehas the potential to compete successfully with thecombined oral/ topical treatment of this drug [323].

Owing to the therapeutic and commercial importanceof NSAIDs, novel skin permeation enhancers werealso tested in conjunction with this group of drugs. Forexample, a 5 % solution of polyol fatty acid monoesters(sefsols), with the exception of glyceryl monoester,was recently shown to enhance the absorption of di-clofenac sodium across rat skin. Propylene glycolmonocaprylate gave the best effect [90]. Hyaluronanwas also found to be useful for localised delivery of di-clofenac into the skin in vitro [109] and in vivo.

Ketoprofen in a topical formulation, received daily at adose of 375 mg over 750 cm2 on the back, is initiallyabsorbed with an apparent half-life of ~ 3 h. The totalamount of drug excretion in urine from healthy volun-teers is ≤ 3% with a half-life of ∼ 28 h for the first doseand 17 h after 10 days [309]. The peak plasma concen-tration is around 150 ng ml-1 after the first administra-tion [309]. The percutaneous absorption of a loweramount of ketoprofen (30 mg/100 cm2) is marginally

higher when applied to the back or arm (5 - 10%), butis lower when applied to the knee [310]. The efficacy ofketoprofen delivery through rat skin correlates withthe concentration of co-applied ethanol and D-l-imonene (4-isopropenyl-1-methyl-1-cyclohexene)[324], as well as other conventional [104] and novelpermeation enhancers [77]. Ketoprofen, with rare ex-ceptions [325], does not sensitise human volunteers,but photosensitisation to this drug is quite common af-ter topical use. This suggests that some local or individ-ual factors, at present unknown, facilitate thedevelopment of allergy [326,327].

Ibuprofen concentrations in sc. tissue, tendon, mus-cles and joint capsules after topical application of a gelcontaining 5% of the drug (Trauma-Dolgit) werelargely within therapeutic ranges. The drug concentra-tion in plasma was several orders of magnitude lowerhowever, even after repeated application [312]. A com-parison between tissue concentrations of ibuprofen,following topical or oral administration, has also beenmade [313].

Indomethacin in a submicron, emulsion topical vehi-cle was reported to be 50% more active, in the unreli-able, carrageenan-induced paw oedema rat model,than the drug in a regular cream form [321].Indomethacin in a plaster was also tested against backpain [328], whereas indomethacin/ether mixture wasfound to be useful for the treatment of (weak) herpeticneuralgia [329].

Naproxen administered on the skin in gel form ispoorly reabsorbed over a 96 h period. The transcuta-neous drug uptake, as estimated from serum concen-trations and cumulative urinary metabolite excretiondata, is ∼ 1% for the 10% drug formulation and ∼ 2% forthe 5% drug concentration. Despite the small amountof naproxen absorbed, a potential pharmacological ef-fect, due to cutaneous accumulation of the drug, maybe suggested from the course of the serumconcentration-time curves [330]. However, accumula-tion also occasionally leads to contact and photocon-tact allergy to drugs [326].

Salicylic acid was reported to be absorbed through theskin by a considerable absolute (175.2 mg/24 h/10cm2), but only by relatively low amount (3%) aftertopical application of methyl salicylate products, espe-cially after multiple applications [331]. The sc. tissuewas only filled up with the drug to a depth of 3 - 4 mm,independent of the mode of administration (passive,iontophoretic), the concentration in the body beingthe same as in the blood [332]. This notwithstanding,the topically applied aspirin/diethyl ether mixture wasproven useful for the treatment of acute, but not toostrong, herpetic neuralgia [329,331] and postherpetic



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neuralgia [331]. Transdermal aspirin was also dis-cussed in conjunction with gastric ulcer healing aftercoronary artery stent placement [333].

Transdermal nitroglycerin can suppress shoulder painsyndrome, caused by supraspinatus tendinitis [240].Similar approaches could also prove useful in the treat-ment of other tendon musculoskeletal disorders.

6.6 Various drugs

Pilocarpine was delivered across the skin in order tolower intraocular pressure. Results showed that sub-stantial uptake in the skin was detectable. However,low systemic drug levels were achieved and no thera-peutic effect was observed [334].

Systemic absorption of minoxidil and a high sensitivityto minoxidil of the follicular apparatus in the treatedareas was suggested to cause diffuse hypertrichosis af-ter topical treatment with the drug [335]. On the otherhand, minoxidil was shown to promote hair growth inbalding monkeys when applied with a suitable skinpermeation enhancer and alcohol [78].

Terbutaline has some potential to prevent nocturnalwheezing. A formulation of this drug was thereforetested on animal and human skin in vitro and shown todeliver the drug transdermally at a rate of a few µg cm-2

h-1 and to a greater extent in the presence of skin per-meation enhancers [336].

DHEA administered twice daily for one week on thedorsal skin of the rat exhibits 33% of the efficacy seenwith sc. DHEA injections. The calculated oral bioavail-ability of this drug compared to injection is only 3%[337].

Levonorgestrel delivered across the rabbit skin withthe aid of ethyl acetate, with or without ethanol as theskin permeation enhancer, was evaluated in rabbits.Typically, erythaema and oedema were observed asside-effects [338].

Photodynamic therapy, based on topically applied∆-aminolaevulinic acid and a filtered short arc xenonlamp as a light source, gave good results in the treat-ment of superficial basal cell carcinoma [339].

Ebiratide (an adrenocorticotropic analogue) and elca-tonin (a hypocalcaemic peptide) were absorbedthrough rat skin in the presence of enhancers, withpharmacological availability ≤ 4.1%, assessed via hy-pocalcaemic effect [74]. In combination with vitaminD3, elcatonin also improved some osteoporotic pa-rameters in rat [340].

7. Iontophoretic devices

Iontophoresis can increase the rate of small, chargeddrug permeation across the skin up to 50-fold.

Iontophoresis is therefore a good method for the ad-ministration of certain local anaesthetics and perhaps,small polypeptides. In the therapy of hyperhidrosis it iseven therapeutically active on its own [125,152]. For arepresentative list of the drugs delivered across theskin by this method see Table 7.

For example, to bring lidocaine to a depth of 1.0 cm ormore below the skin, the drug is normally applied ion-tophoretically (for reviews see [332,348,349]). Vaso-constrictors are typically included to slow down drugelimination from the site of delivery [350]. While goodeffects were reported for different local therapies (seeTable 7), the systemic drug availability is too low for ageneralised treatment [332], irrespective of drug con-centration used [351]. In this context, the following ob-servation is also interesting: lidocaine is the only drugavailable that suppresses tinnitus when given intrave-nously. Iontophoretic delivery of this drug throughoutthe tympanic membrane into the middle ear does notprovide any therapeutic advantage in human trials[352,353].

Combination with other drugs may be advantageous.The co-administration of calcium channel antagonists(nicardipine, verapamil, diltiazem) with iontophoreti-cally delivered lidocaine did not change the painthreshold, but did prolong the duration of the analge-sic action compared with lidocaine alone [354].

8. Carriers

Some enthusiastic reports on the topical use of naturalphospholipid suspensions (liposomes, [14,355-357]),or dispersions of synthetic non-ionic amphiphiles (nio-somes, [358-360]) loaded with various drugs have beenpublished. In some cases, an improved transcutaneousdelivery was claimed [14,166,167,361], whereas inother publications, better retention on the skin surfacewas appraised [362-365].

Liposomes are (phospho)lipid vesicles, often mixedwith cholesterol, in a thermodynamically stable state[366], but originally the word described any closed andwater-filled body consisting of lipids [367]. From thepharmaceutical point of view, a liposome has to bemaximally stable against leakage and disaggregation inserum [18]. Cholesterol, typically in a 1/1 ratio with thephospholipid (which in most cases is phosphatidyl-choline), prevents the above. Charged lipids (such as



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anionic phosphatidic acid or, more rarely, phosphati-dylglycerol) increase the colloidal stability of themixed lipid suspension.

Submicron emulsion (SME) vehicles are oil droplets,colloidally stabilised with a surface layer of lipids. Afterdispersion in water, they have a mean size of approxi-mately 100 nm and have been tested in epicutaneousadministration. Hydrophobic drugs incorporated intothe oil phase of the SME were proposed to cross theskin better than more conventional formulations. Thiswas shown with NSAIDs [321], but experiments withmore discriminating, larger molecules remain to bedone.

Niosomes are mixtures of non-ionic surfactants, typi-cally of alkyl-polyoxyethylene ethers (Brij) and cho-lesterol [368]. The latter component, often used in the3/2 to 5/1 molar ratio, is needed to make vesicles fromthe normally micelles-building detergents. Owing tothe relatively high toxicity of many Brij-subtypes to theskin, gel phase vesicles are preferred for practical ap-plications [369].

Amongst the above mentioned carrier systems, drugloaded liposomes have the longest history of medici-nal (experimental) application. A list of examples isgiven in Table 10.

In most cases, following ‘in vesicle’ administration ofthe drug, the agent remained confined to the upperepidermis, or even to the upper half of the stratum cor-neum. In the few studies which have achieved deeperpenetration, local bioavailability of a few percent, atbest, was reached [381]. Part of this success was due tothe trans-follicular shunts [169,403] and part to the in-creased skin hydration effect, which acted as a trans-port promoter [172]. An exception to this are thespecially optimised, highly deformable carriers, whichreportedly have delivered more than 50% of an epicu-taneously administered dose across the stratum cor-neum barrier [370-372,378] (see the discussion ofTransfersomes).

The liposome-mediated delivery of retinoic acid in theepidermis and upper dermis was found to increase byapproximately a factor of 2 [181], but was dependenton the delivery approach [404-406]. Furthermore, theliposomal retinoic acid was effective at a dose 5 - 10times smaller than with conventional alcoholic gels[405].

Commercially available, liposome-based transfectionkits permitted topically-applied DNA/liposome com-plexes to be expressed genetically in several cell typesin the skin after epicutaneous administration [395]. Theroute of DNA entry is unclear to date, but could betransfollicular as postulated by a different group [403].Epicutaneously administered tetracaine with multi-lamellar liposomes and permeation enhancers main-tained local anaesthesia for at least 4 h [375]. Lidocainein a similar formulation was more effective than in thecream form [376].

Liposomes, containing T4 endonuclease V, were foundto stimulate the removal of UV-generated cyclobutanepyrimidine dimers in human epidermis in vitro [406].Even phospholipids alone (Natipide II) were seen todecrease the UV-B induced erythaema in patients withskin Type II and III [407], supposedly due to the sup-pression of peroxide formation by phosphatidylcho-line.



Table 10:A list of drugs in lipid vesicle suspension marketed ortested for epicutaneous administration.

Drug Reference

Therapeutic (marketed liposomes)

Econazole

Miconazole

Heparin

Tested liposomes

Analgesics [197,374-376]

Antibiotics [377]

Clindamycin [379]

Anti-micotics [167,355,380]

Cyclosporin [363,381]

Antiinflammatory agents [382,383]

Corticosteroids [384-389]

Related hormones [390]

Psoralenes [391]

Porphyrins [391]

Calcitonin [392]

Heparin [393]

High molecular weight DNA [394,395]

Interferon [172,362,396-398]

Melanin [169, 501]

Superoxide desmutase [399,400,401]

Tested Transfersomes (disclosed)

Calcitonin [176]

Cyclosporin [8]

Diclofenac [8]

Gap junction protein [370]

Insulin [171,371-373]

Interferon-γ [8]

Lidocain [197]

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©A

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ublicationsLtd.A

llrightsreserved.

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Figure 8: Transcutaneous delivery of various (model) drugs across intact murine skin into the blood circulationin vivo,by means of Transfersomes. Carrier-mediated delivery, performedunder comparable, non-occlusive conditions, results in similar pharmacokinetic characteristics for all substances with reasonable residence time in/on Transfersomes. The final labelconcentration does not define efficiency of delivery, however, as blood is only a transient compartment for Transfersomes.

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Lipid vesicles were loaded with the epidermal growthfactor [408] or hyaluronic acid [409] and this was foundto improve the healing process, but such success isbased on a different working principle.

The partial success of some of the liposome suspen-sions explored in the past could be due to the skinpermeation-enhancing effect of additives or impuritieswhich, in exceptional cases, might even have im-proved the membrane deformability to some extent.

Analysis of published information on the skin penetra-tion by liposomes suggests the following conclusion:vesicles with at least some capability to reach the epi-dermis were either made up from the mixtures of bio-logical components (e.g., skin), or else from themixture of not very pure lipids (≤ 90% or, more often, ≤80) . The successful preparations often contained sol-vents (such as ethanol or propylene glycol) or otherpermeation enhancers (such as lyso-phospholipids orfatty acids). Some skin penetrating and drug-carryingcapability was also measured with lipid suspensionsprepared by relatively harsh processes (such as the re-verse phase evaporation or sonication). Liposomesmade from lipids (such as synthetic long-chain phos-phatidylcholines) or lipid blends (such as phosphati-dylcholine/cholesterol mixture) with a highmembrane rigidity did not penetrate the skin [8].

Owing to the postulated involvement of hydrotaxis incarrier penetration across the skin, the data collectedfrom suspensions under occlusion, should not be com-pared with those of an open administration. In theformer case, only skin permeation enhancement andperhaps, improved contact between the drug and theskin is expected. An open administration of very de-formable lipid assemblies offers at least two moretransport-enhancing mechanisms: the lipid-dependentskin (de)hydration and the direct lipid assembly pene-tration into the skin.

In the first published account of the iontophoresis ofliposomes loaded with [Leu5]enkephalin across humancadaver skin, successful penetration of the carrier wasdemonstrated. The drug was partly electro-degraded,but less so after the association with liposomes [402].

Transfersomes are mixtures of at least two compo-nents. The first component is often a phospholipid(such as phosphatidylcholine) in the fluid-lamellarphase; the second ingredient is frequently a membranesoftening, edge-active agent (such as a bile salt, an al-kyl- or acyl-polyethoxylene derivative, a polysorbate,a glycolipid, etc.). The former makes liposomes on itsown, the latter can act directly as the skin permeationenhancer, but this is only important for some drugs. Itis by judicious choice of components and their properbalance that Transfersome assemblies are made

exceptionally deformable (Figure 3), thereby ensur-ing the delivery of large molecules across the skin (Fig-ures 3, 6 and 8).

To achieve maximum assembly deformability, thecomposition must be optimised for each drug sepa-rately. Consequently, no general ‘Transfersome recipe’exists [502], but a 3.75/1 mol/mol mixture of soy-beanphosphatidylcholine (SPC) and sodium cholate, pH7.2, with 10% total lipid will work on its own [171]. An-other transfersome composition, which has been usedin Leiden by J. Bouwstra and colleagues as skin pene-trating ‘liposomes’, is a mixture of dilauroylphosphati-dylcholine (DLPC) and lauryl-polyoxyethylene ether(C12EO8).

Transfersomes can be loaded with different kinds ofmolecules to achieve the desired therapeutic effect.When administered on intact skin, these carriers de-liver molecules into the blood with good reproducibil-ity and efficiency over a vast range of molecular sizesand lipophilicities. Figure 8 illustrates the transcutane-ous delivery of various (model) drugs.

Transfersomes have already been used to deliver insu-lin transcutaneously (Figure 9). When administered tothe intact skin, such formulations gave the first sign ofsystemic hypoglycaemia after 90 - 180 min, dependingon the specific carrier composition [171,371,373]. Theeffect of insulin in Transfersomes was nearly the samein mice, pigs or humans. Epicutaneously appliedmixed micelles or liposomes carrying the sameamount of drug had no hypoglycaemic effects duringthe investigated time period. This shows that drug en-hancement was not due to the action of individualcomponents [171].

Transfersome penetration across the stratum corneumcan be controlled sufficiently to permit selective deliv-ery of drugs into the skin. This can be achieved bychoosing the correct vesicle type or, more importantly,by selecting the number of carriers used. One can thendeposit close to 100% of the total carrier/agent mass tothe organ. Figure 10 illustrates this for corticosteroidsin one of the transfersomal formulations.

The use of tetracaine or lidocaine in Transfersomeswithout any conventional permeation enhancers, pro-longed pain suppression to a significant extent com-pared to the injection of a drug [197], but directcomparison with the results of previous experimentswith liposomes is impossible in light of the differentdrug doses and formulations used. The comparison ofcumulative injected, or epicutaneously applied drugaction in this latter study suggests that the relative effi-cacy of lidocaine in Transfersomes reached nearly 50%of the total injected drug action, amounting to nearly100% of the encapsulated agent activity. The potency



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was less than 50% of an injection however, probablyowing to the very fast drug clearance from the site ofadministration [197].

Drug incorporation into Transfersomes and their sub-sequent use on the skin prolongs the drug’s biologicalaction. The duration of this effect depends on the

amount of drug applied as well as on carrier character-istics. On the one hand, this was shown for topicallyadministered corticosteroids, which gained an order ofmagnitude in cumulative therapeutic effect after asso-ciation with Transfersomes [411]. On the other hand, asubstantially longer duration of action was seen with



Figure 9: The average glucose concentration change in the blood of mice (upper panel, in %) or humans (lower panel, in mg/dL) as afunction of the time after an epicutaneous administration of Transfersulin (at t = 0). Thick curves give the mean value and thin, dashed ordotted lines define the corresponding 95% confidence limits. Transfersomes (•) elicit a significant hypoglycaemic response in contrastto standard liposomes(o) or the mixed-lipid micelles(¤) with identical insulin concentration.

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‘fast-acting’ insulin after association with Transfer-somes. Such an association effectively transformed thedrug into long acting insulin [171].

9. Macromolecules

References [130,412,413] provide reviews of non-parenteral delivery of macromolecules. In review arti-cles [124,130,414,415], iontophoresis of large mole-cules is focused on. Buccal delivery is surveyed in[416].

The transcutaneous delivery of peptides would bevery attractive from the pharmacotherapeutical andpatient compliance point of view. Unfortunately, thehigh molecular mass and hydrophilicity of such mole-cules are difficult obstacles to overcome with simpleskin permeation enhancement.

To date, only iontophoresis and some drug carriershave efficiently delivered peptides through the skin,except when ultrapotent, relatively small substanceswere used. In fact, it has been speculated for sometime that electrical delivery of macromolecules across

the skin should be possible [415]. However, it is un-likely that this will be possible in the near future, de-spite some encouraging results. A few examples aregiven in Table 7.

An example of the iontophoretic transport of thera-peutic proteins is that of Leuprolide driven across theskin iontophoretically (0.2 µA), reaching the systemwith a lag time of approximately 1 h, relative to the on-set of action following injection [159]. The AUC for thefirst 150 min in such cases amounts to 42% in the non-invasive case [159]. Luteinizing hormone releasing hor-mone seems to retain its immunological, as well as bio-logical activity after epicutaneous iontophoreticdelivery [160]. Iontophoretic delivery of vasopressin,calcitonin and insulin, using hydrogel-based devices,is possible as well, but less efficient for the larger mole-cules [130].

Combination with chemical skin permeation enhan-cers permits a small, but significant quantity of des-enkephalin-γ-endorphin to be delivered across theskin iontophoretically [414]. The somatostatin ana-logue, SMS 201-995, mixed with permeation enhancer,



Figure 10: Carrier-mediated regiospecificity of transcutaneous drug delivery: absolute dexamethasone concentration in the blood ortreated skin, as deduced from the[3H]-derived radioactivity, changes with the administered dose, when Transfersomes are used ascarriers (injection: open symbols or columns; epicutaneously in Transfersomes: full symbols) and dose of application. 0.015 mg/kg:∇,left-dashed; 0.15 mg/kg:◊, hatched; 1.5 mg/kg:∆, right-dashed.

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N-decylmethylsulfoxide, also successfully crosses theskin in vitro under the influence of electromotion, at arate of 20 µg/cm2/24 h [417]. pH adjustments (usually alowering) may also increase the iontophoretic flow ofproteins across the skin [131,143,144]).

For example, the phosphorothioate sequence,5′-d(TAGGG)-3′ (TAG-6), which mimics the repeat se-quence of the telomere, has been delivered acrosshairless mouse skin using iontophoresis. The flux wasstrongly affected by pH and salt concentrationchanges, as expected [142].

Furthermore, it was shown that injected melanocortin(α-MSH) and an ACTH-(4-9) analogue (ORG.2766)both accelerate functional recovery from sciatic nervedamage. The latter agent appears to be active after oc-clusive administration of the peptide-impregnated,biodegradable gelatine foam-matrix surrounding thesite of injury on rats [418], but this may be due to an im-paired skin barrier. Interestingly, topical application of[Nle4, D-Phe7]α-MSH, a superpotent analogue ofα-melanocyte stimulating hormone, induces a darken-ing of follicular melanocytes, but can only be deliveredacross murine [419] or human [420], but not rat skin invitro [419]. It is very likely that these peptides are onlysuccessfully transported through hair follicle shunts.

The delivery of proteins by electrical means across theskin can be improved by suitable enhancers (e.g., N-decylmethyl sulfoxide), pH adjustment (often acidic[131,143,144]) and inhibitors [143]. However, some in-hibitors of proteolysis appear to act differently in skinhomogenates and in living skin [143]. Others may betoo large to cross the skin together with the drug. Forexample, the proteolytic enzyme inhibitor, aprotinin(MW 6500 Da), was found to enhance theiontophoresis-dependent hypocalcaemic effects cre-ated by the delivery of salmon calcitonin across theskin [144]. In contrast to this, the bulkier soybean tryp-sin inhibitor (MW 8000 Da) was ineffective under simi-lar conditions [144].

Owing to its inferior barrier properties, the buccal mu-cosa is easier to cross, especially with large molecules,than the stratum corneum [39]. Strategies to controltransbuccal drug absorption have employed mucoad-hesive devices, to shorten the diffusion pathways andprolong administration and structural and chemicalmodulation of the device, with the aim of shifting therate-limiting transport step from the tissue to the de-vice [416]. Local irritation and unpleasant taste remainproblematic to date.

The percutaneous delivery of insulin was studied by agroup from Japan. The permeation through rat skin invitro was small, but nevertheless a significant hypogly-caemic response was measured over a 10 h period.

This was greatest for a suspension of liposomal insulin,in the presence of D-limonen and taurocholate, or for acombination of n-octyl-β-D-thioglucoside (OTG), ci-neol and deoxycholate or of D-limonen and octylglu-coside [97]. This may have been due to partial lipidextraction from the skin, demonstrated in a differentstudy from the same group [96].

We have recently performed a series of studies withepicutaneously applied insulin, in several differentTransfersome formulations [171,371,373]. In all casesthe glucose concentration in animal or human bloodwas significantly suppressed by the non-invasively ap-plied drug (see Figure 9). Comparison of C-peptideand insulin concentrations in the blood directly con-firmed the systemic availability of the agent [373].

A recent study using carrier-mediated transport usedtopically administered, non-ionic liposomes to transfergrowth hormone releasing peptide into the skin [421].An earlier study with diabetic patients and epicutane-ous insulin, combined with triglycerides and oral sul-fonylurea was ineffective [422].

Repeated skin exposure to ovalbumin for 7 days, evenin the absence of an adjuvant, sensitised mice and in-duced a predominant Th2-like response. Repeated ad-ministrations sustained elevated levels of specific IgE,but IgG2a concentrations were negligible, comparedto those elicited by two injections [423]. A faster andmuch higher level of protein antibody presentation onthe skin was achieved with Transfersomes [370,378].The antiprotein (serum albumin or gap junction pro-tein) titres were nearly as high as after the correspond-ing antigen injections, but the resulting antibodyclasses differed. Especially prominent was the relativeincrease in IgA levels and the relatively low inductionof IgG1a.

10. Adverse side-effects

Cutaneous adverse side-effects are frequent with con-ventional TTS systems (for reviews see [25,424]) andsometimes necessitate discontinuation of therapy [24].Most cutaneous reactions are limited to localised der-matitis, but occasionally generalised systemic effectsoccur. Reactivation of the dermatitis via oral medica-tion, following sensitisation to the patch, is rare [25].Side-effects are often observed with clonidine (50%)[25] and testosterone (≥ 70%). Alkyl chain derivativesof certain enhancers, such as azones [105] or lipo-polyoxyethylenes [91], are more irritant than thosewith alkenyl chains. This is probably to be the casewith other enhancers as well, owing to the slower bio-degradation of fatty-ethers compared to -esters.



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Electric or acoustic transport enhancers may cause se-vere problems if they are not carefully employed.Overall iontophoresis, is a safe procedure. Its mainside-effect is first-degree burns, caused by electrolysis[145,152,425] and pH effects. The likelihood of theseeffects increases with increasing currents or when theapplication medium is inadequately buffered, but ex-treme pH can also be harmful on its own [426].Current-induced hyperaemia [427], occasionally con-tact eczema [428] and shocks are possible under cer-tain circumstances [429]. A good understanding of thetechnique, proper device operation and patient co-operation are all essential in order to minimise the oc-currence of these problems [429]. The application ofhigh voltage pulses, for example during electropora-tion, is painful. Therapeutic ultrasound is gentler andsafer, but also less versatile in its application.

Sensitivity problems vary between drugs. Changingthe site of drug administration minimises these reac-tions. Eczematous reactions are treated well with mod-erately potent topical steroids [424]. Systemic allergicreactions were reported to result from the topical ap-plication of glyceryl trinitrate [246] or resorcinol [430].Sensitisation was also reported with the repeated ad-ministration of a strong proteinaceous antigen, inpatch form on animal skin [423], possibly owing to theprotein penetration through follicular shunts. Drugspecific side-effects are listed in previous sections.

11. Transdermal delivery commercialisation

According to a recent professional survey, 47 productsare or were in development for transdermal delivery.Table 11 indicates the stage of development of these(potential) products. A list of the main organisationsresearching TTS delivery is provided in Table 1 (datataken from a survey performed in 1996).

Tables 1 and 11 are informative, but incomplete. Theysuggest that amongst the 47 original projects, only 6products are still under development. However, 34TTS products were on the market at the end of 1996,excluding topical patches of nonsteroidal anti-inflammatory agents. The list of companies active inthe TTS field can also be extended.

Merck, Novartis and Yamanouchi are not properlylisted in Table 1 despite their activity in the TTS arena.In fact, Ciba-Geigy (now part of Novartis) was the firstcompany to bring a TTS product (Estraderm TTS) tothe market. Alza has developed 7 transdermal prod-ucts and has iontophoretic transdermal devices(‘E-TRANS’) in the late stages of development. Buttleris actively investigating TTS delivery. Cellergy special-ises in low molecular weight dermatologicals and has8 products (preclinical) and 3 (Phase III). Cygnus has 4active transdermal delivery projects/products. Elan isfocusing on the development of electro-transportacross the skin (ETDAS/Panoderm) and has at least 2corresponding products in the pipeline. IDEA (Innova-tive dermal applications) in Munich is working on sev-eral innovative therapeutics based on drug carriers(Transfersomes). Ethical has at least 3 dermal patchesin the pipeline and Hercon is working on 10 products(preclinical), 4 (Phase II) and 2 (Phase III) and has a to-tal of 4 products in the pre-registration phase, or regis-tered. Serastar has developed its own patch based onskin permeation technology. TheraTec has designed avery potent testosterone patch and Teijin has an oes-tradiol patch.

The best known companies developing or using im-pact devices are Powderjet, Bioject, Medi-ject and Wes-ton Medical. Powderjet relies on solid particles, whilstthe latter companies use liquid formulations.

12. Competing delivery approaches

Sites/techniques, other than the skin, that were sug-gested to offer some potential for the non-invasive de-livery of high molecular weight substances areillustrated in Table 12. In all cases, the drug is typicallyapplied as a solution (with transport enhancers) or in-corporated in suitable vehicles (nanoparticles, gels,emulsions, suspensions), with or without permeationenhancers and with or without suitable coating/em-bedding.

The drug delivery approaches listed in Table 12 allshare the problem of poor efficiency and reproducibil-ity. Local irritation, which results in poor patient com-pliance, is also often a problem. Furthermore, specialgadgets must be used to deliver the drug trans-nasallyor trans-bronchially (intra-pulmonary). Rectal or vagi-nal, as well as ocular, administration is fairly



Table 11: The stage of development of transdermal productsaccording to a recent survey.

Stage Number of projects

No reported development 10

Discontinued 17

Preclinical stage 5

Phase I 1

Phase III 3

Pre-registration 2

Registered 1

Launched 8

Total 47

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inconvenient and will not be accepted by a large pro-portion of patients. Oral formulations, which would bepreferred by the majority of patients, are far from clini-cal use. The oral administration of large drugs is un-likely to become sufficiently reliable for general use,owing to variability in dietary uptake and digestion/GIuptake. To provide a more quantitative picture, therelative performance of various techniques for non-invasive delivery of insulin is compared in Table 13.

13. Conclusions

All current transdermal products and those in develop-ment rely on:

• skin permeation enhancers

• transdermal delivery gadgets (iontophoresis, highvelocity impact)

• carrier mediated delivery (liposomes, Transfer-somes)

The simplest approach to transcutaneous drug deliv-ery for systemic medication is the modification of thedrug, thereby increasing the drug partitioning and dif-fusivity in the skin, or the use of skin permeation en-hancers, which reduce the skin barrier, or both.

In general, material flux across the skin relies on mo-lecular permeation or aggregate penetration. In theformer case, it is mainly driven by the generatedtranscutaneous solute concentration, or by other man-made potential differences, such as the electric poten-tial across the skin. A naturally occurring water con-centration gradient across the skin may take the role ofa carrier locomotor.

The flow of the drug across the skin stops with the dis-sipation of transcutaneous permeant concentration. Incontrast to this, the transcutaneous moisture gradient

persists and constantly drives the water molecules outand the (sufficiently penetration capable) carriers intothe body.

Passive skin permeation enhancers are typically em-ployed in various combinations under occlusion in apatch. They lower the skin barrier by partially fluidis-ing the lipids in the organ and thus ‘creating voids’.Only small enough molecules can enter the bodythrough these hydrophobic ‘pores’. Skin permeationenhancers cannot promote the transport of large mole-cules across the skin. The reason for this is that suchmolecules would require more free space to move inthe intercorneocyte matrix than the permeation en-hancers, partitioned in the skin, create. Skin permea-tion enhancers are therefore not useful for thetranscutaneous delivery of molecules > 400 Da. Moreoften than not they are also poorly tolerated.

Active transcutaneous transport promoters are basedon the enforced electric current or (micro)jets of parti-cles/droplets through the skin. The iontophoretic fluxof a charged solute is chiefly affected by the electro-chemical potential gradient across the skin, increasedskin permeability for passive transport accompanyingiontophoresis and by current-induced water flux(electro-osmosis); the latter two phenomena also al-low the transport of uncharged solutes across the skinand biological marker extraction from the body.Electro-osmosis is the least important amongst thethree factors [124]. Iontophoretic flow can be en-hanced by skin permeation enhancers and can then in-clude even small, sufficiently charged polypeptidesdriven across the skin [124,414,415].



Table 13:Comparison of insulin delivery techniques.

Medication State Cumulative action(‘bioavailability’)

Insulin injection iv. 100 %

Insulin injection sc. Hyperglycaemic ∼ 85%

Insulin injection sc. Normoglycaemic ≤ 60%

Transfersulin ec. Normoglycaemic,8 h

≥ 12%

Hyperglycaemic,16 h

≥ 25%

Insulin intranasal Hyperglycaemic ≤ 15%Insulin intrapulmonal ≤ 5%Insulin Oral ≤ 0.1%

sc.: subcutaneous, according toJ. Clin. Endocrinol. Metab.(1988)67:551-9.ec. epicutaneous; data from a small number of volunteersrequiring further confirmation.Intranasal fromDiabetologia(1995)38:680-684.Oral data by Protein Therapeutics.Intrapulmonal from Inhale Therapeutics.

Table 12:Alternative non-invasive drug delivery routes.

Administrationroute

Disadvantage

Ocular Low efficiency and poor tolerance

Nasal Low efficiency and reproducibility;irritation

Pulmonal(bronchial)

Low efficiency and sometimes poorreproducibility

Oral Low efficiency and reproducibility

Rectal Low efficiency and reproducibility

Vaginal Low efficiency and reproducibility

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Small permeants typically move across the skin via dif-fusion. The skin permeability is proportional to drugpartitioning and diffusion in the skin and to the con-centration gradient. The efficacy of transcutaneoustransport, consequently, can be improved with the aidof skin permeation enhancers which increase the drugsolubility, activity or diffusivity in the system.

With the exception of iontophoretic delivery of macro-molecules, the progress in this field was sparse untilvery recently, owing to the inadequacy of chemicalskin permeation enhancement approaches. Electro-and sonoporation of the skin have not yet been shownto be useful for the delivery of macromolecular thera-peutics. In principle, these instrument-based skintreatments damage the mechanical and electrical bar-rier of the skin sufficiently to permit even molecules >500 Da to cross the resulting channels. Furthermore,the cost of devices and batteries needed, the limited ef-ficacy and/or the low potency of delivery, togetherwith poor local tolerance to treatment, will severely re-strict the practical use of either of these approaches.

Over the last 17 years numerous attempts have beenmade to control the delivery of drugs via the skin bymeans of lipid vesicles. Despite considerable experi-ence with transdermal drug delivery, a consensus hasnot yet been reached on whether or not the admini-stration of lipid suspension results in whole vesiclepenetration across the skin [15]. However, it is gener-ally agreed that conventional liposomes remain con-f ined to the skin surface. The concept ofvesicle-driving pressure based on the transepidermalhydration gradient [196] is now accepted by the re-search community. The first promising data are beingreported by independent groups (still using the word‘liposome’ to describe the multi-component vesicles,consisting of phospholipids and single-chain,membrane-softening amphiphiles). But general con-sensus on when, where and whether, vesicles cross theskin without fragmentation has not yet been reached.Both these issues have been addressed in this reviewand it has been concluded that circumstantial data sug-gest that Transfersomes, but not other types of lipidvesicles, achieve this.

Standard lipid-based carrier suspensions on the skinsometimes enhance transport across the skin by in-creasing skin hydration or through the indirect actionof their components, acting as skin permeation enhan-cers. Conventional liposomes collapse colloidally onthe skin after partial local dehydration. Very few lipidvesicles cross the skin directly, except through shuntssuch as pilosebaceous units. A notable exception areTransfersomes which are sufficiently deformable to fitinto the hydrophilic ‘virtual channels’, which theyopen in the skin after non-occlusive administration.

To transport large entities through the skin, variousskin poration methods have proven useful. The mostunderstood, but not the most versatile, is iontophore-sis. This opens hydrophilic passages between the skincells via electrically-enforced transcutaneous ioniccurrents. Drugs with a molecular weight up to 4 kDacan be delivered across the stratum corneum in thisfashion. Larger pores are opened by high-voltage elec-troporation or perhaps by sufficiently strong mechani-cal skin agitation (e.g., during ultrasound treatmentwith high enough intensity). However, sonoporationusing therapeutic ultrasound only facilitates the deliv-ery of small molecules across the skin.

Highly deformable lipid vesicles, applied non-occlusively on the skin, also activate hydrophilic chan-nels in the stratum corneum due to their moistureseeking tendency. Owing to the uniform nature oftranscutaneous hydration pressure, Transfersome-mediated channel opening is more uniform and effi-cient than electro- or sonoporation.

The focus on the weakest spots in the intercellular re-gion in the stratum corneum, which are the result ofhighly deformable vesicles acting as hydrotacticallyguided, extremely gentle, submicroscopic ‘needles’,makes transfersomes very attractive. They perforatethe skin painlessly and reversibly during passageacross the barrier. In so doing, they deform enough tofit into the constrictions of virtual channels in the skin.The carriers then act as non-invasive delivery vehicles,transporting high molecular weight substances acrossthe skin.

Carrier distribution in and beyond the skin reliesstrongly on first, lymphatic and, second, blood flow.This explains why in vitro experiments underestimatethe efficacy of transcutaneous penetration by ultra-deformable carriers in vivo by several orders of magni-tude. In contrast, skin permeation enhancers demon-strate the opposite effect.

Liposomal drug formulations may be advantageous incomparison to hydrogels, creams or ointments, whenthe drug retention on or in the upper skin is desired.However, conventional lipid vesicles are unsuitablefor systemic therapy via the skin.

Classical skin permeation enhancement relied heavilyon affecting skin resistivity. The prerequisite to main-tain at least a rudiment of the skin barrier has limitedthe success of chemical permeation enhancement, todrugs with molecular weights below 400 Da. The intro-duction of highly deformable drug carriers has in-creased this boundary to > 105 Da. This has led to newand unprecedented therapeutic opportunities for thedelivery of drugs across the skin.



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Acknowledgements

I would like to thank my students and (ex) collabora-tors: G Blume, D Gebauer, A Paul, A Schätzlein and JStieber, all of whom have contributed greatly to the ex-perimental progress in the field of Transfersomes. HRichardsen was helpful in technically preparing thismanuscript.

Bibliography

Papers of special note have been highlighted as:• of interest•• of considerable interest

1. HADGRAFT J: Advances in transdermal drug delivery.Practitioner (1996) 240:656-658.

2. HADGRAFT J: Recent developments in topical and trans-dermal delivery. Eur. J. Drug. Metab. Pharmacokinet.(1996) 21:165-173.

• A scholarly review article by an expert in the field.

3. MOORE L, CHIEN YW: Transdermal drug delivery: a re-view of pharmaceutics, pharmacokinetics and phar-macodynamics. Crit. Rev. Ther. Drug. Carrier. Syst. (1988)4:285-349.

4. RIDOUT G, SANTUS GC, GUY RH: Pharmacokinetic con-siderations in the use of newer transdermal formula-tions. Clin. Pharmacokinet. (1988) 15:114-131.

5. ROBBINS AS: Pharmacological approaches to smokingcessation. Am. J. Prev. Med. (1993) 9:31-33.

6. GUY RH: Percutaneous absorption: physical chemistrymeets the skin. Curr. Probl. Dermatol. (1995) 22:132-138.

7. GUY RH: Current status and future prospects of trans-dermal drug delivery. Pharm. Res. (1996) 13:1765-1769.

8. CEVC G: Transfersomes, liposomes and other lipid sus-pensions on the skin: permeation enhancement, vesi-cle penetration and transdermal drug delivery. Crit.Rev. Ther. Drug Carrier. Syst. (1996) 13:257-388.

•• An extensive review outlining the basic theoretical back-ground to skin penetration.

9. Transdermal Controlled Systemic Medications. Chien YW(Eds.), Marcel Dekker, New York (1987).

10. Transdermal Drug Delivery. Developmental Issues and Re-search Initatives. Hadgraft J, Guy RH (Eds.), Marcel Dekker,New York (1989).

11. Pharmaceutical Skin Penetration Enhancement. Walters KA,Hadgraft J (Eds.), Marcel Dekker, New York (1993):383-408.

12. Percutaneous Absorption. Bronough RL, Maibach HI (Eds.),Marcel Dekker, New York (1993).

13. PATEL HM, MOGHIMI SM: Liposomes and the skin per-meability barrier. Drug Targ. Deliv. (1993) 2:137-148.

14. MEZEI M: Liposomes and the skin. In: Liposomes in DrugDelivery. Gregoridadis G, Florence AT, Patel H (Eds.), Har-wood Academic Publishers, Switzerland (1993):124-135.

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• Useful account of adverse effects associated with TTS sys-tems.

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65. AF DAVIS, HADGRAFT J: Effect of supersaturation onmembrane transport: 1. Hydrocortisone acetate. Int. J.Pharmaceut. (1991) 76:1-8.

66. SURBER C, WILHELM KP, HORI M, MAIBACH HI, GUY RH:Optimization of topical therapy: partitioning of drugsinto stratum corneum. Pharm. Res. (1990) 7(12):1320-1324.

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• The most complete survey of skin permeability data pub-lished to date.



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70. POTTS RO, MAK VHW, GUY RH, FRANCOEUR ML: Strate-gies to enhance permeabilitiy via stratum corneumlipid pathways. Adv. Lipid Res. (1991) 24:173-210.

71. ELYAN BM, SIDHOM MB, PLAKOGIANNIS FM: Evaluationof the effect of different fatty acids on the percutaneousabsorption of metaproterenol sulfate. J. Pharm. Sci.(1996) 85(1):101-105.

72. LAMBERT WJ, HIGUCHI WI, KNUTSON K, KRILL SL: Dose-dependent enhancement effects of azone on skin per-meability. Pharmaceut. Res. (1989) 6:798.

73. BODDE HE, PONEC M, IJZERMAN AP: In vitro analysis ofqsar in wanted and unwanted effects of azacyclohep-tones as transdermal penetration enhancers. In: Phar-maceutical Skin Penetration Enhancement. Walters K,Hadgraft J (Eds.), Marcel Dekker, New York (1993).

74. OGISO T, PAKU T, IWAKI M, TANINO T, NISHIOKA S: Per-cutaneous absorption of physiologically active pep-tides, ebiratide and elcatonin, in rats. Biol. Pharm. Bull.(1994) 17(8):1094-1100.

75. HOFLAND HEJ, BOUWSTRA JA, SPIES F, TALSMA H, JUNG-INGER HE: Non-ionic surfactant vesicles: a study of vesi-cle formation, characterization and stability. J. ColloidInterf. Sci. (1992) 161:366.

76. VERMEIRE A, DE C, MUYNCK G, VANDENBOSSCHE, W: Su-crose laurate gels as a percutaneous delivery system foroestradiol in rabbits. J. Pharm. Pharmacol. (1996)48(5):463-467.

77. AKITOSHI Y, TAKAYAMA K, MACHIDA Y, NAGAI T: Effectof cyclohexanone derivatives on percutaneous absorp-tion of ketoprofen and indomethacin. Drug. Des. Deliv.(1988) 2(3):239-245.

78. DIANI AR, SHULL KL, ZAYA MJ, BRUNDEN MN: The pene-tration enhancer sepa augments stimulation of scalphair growth by topical minoxidil in the balding stump-tail macaque. Skin Pharmacol. (1995) 8(5):221-228.

79. JOHNSON ME, MITRAGOTRI S, PATEL A, BLANKSCHTEIND, LANGER R: Synergistic effects of chemical enhancersand therapeutic ultrasound on transdermal drug deliv-ery. J. Pharm. Sci. (1996) 85(7):670-679.

80. KRILL SL, KNUTSON K, HIGUCHI WI: The influence ofiso-propanol, n-propanol and n-butanol on stratumcorneum lipid phase behavior. J. Control. Rel. (1993)25:31-42.

81. FRANCOEUR ML, GOLDEN GM, POTTS RO: Oleic acid: itseffects on stratum corneum in relation to (trans)der-mal drug delivery. Pharm. Res. (1990) 7:621-627.

82. TURUNEN TM, URTTI A, PARONEN P, AUDUS KL, RYTTINGJH: Effect of some penetration enhancers on epithelialmembrane lipid domains: evidence from fluorescencespectroscopy studies. Pharm. Res. (1994) 11(2):288-294.

83. GOATES CY, KNUTSON K: Enhanced permeation of po-lar compounds through human epidermis. I. Perme-ability and membrane structural changes in thepresence of short chain alcohols. Biochim. Biophys. Acta(1995) 1195:169-179.

84. YONETO K, GHANEM AH, HIGUCHI WI, PECK KD, LI SK:Mechanistic studies of the 1-alkyl-2-pyrrolidones asskin permeation enhancers. J. Pharm. Sci. (1995)84(3):312-317.

• Description of a new type of skin permeation enhancer.

85. AUNGST BJ: Structure/effect studies of fatty acid iso-mers as skin penetration enhancers and skin irritants.Pharmaceut. Res. (1989) 6:244.

86. AUNGST BJ, BLAKE JA, HUSSAIN MA: Contributions ofdrug solubilization, partitioning, barrier distruptionand solvent permeation to the enhancement of skinpermeation of various compounds with fatty acids andammines. Pharmaceut. Res. (1990) 7:712-718.

87. CATZ P, FRIEND DR: Alkyl esters as skin permeation en-hancers for indomethacin. Int. J. Pharm. (1989) 55:17.

88. TAKEUCHI Y, YASUKAWA H, YAMAOKA Y et al.: Destabili-zation of whole skin lipid bio, liposomes induced byskin penetration enhancers and ft, ir/atr (fourier trans-form infrared/attenuated total reflection) analysis ofstratum corneum lipids. Chem. Pharm. Bull. (1992)40:484-487.

89. OKUMURA M, NAKAMORI Y, SUGIBAYASHI K, MORI-MOTO Y: Enhanced skin permeation of papaverine by amedium chain glyceride. Drug Des. Deliv. (1991) 7:147-157.

90. TAKAHASHI K, MATSUMOTO T, KIMURA T et al.: Effect ofpolyol fatty acid esters on diclofenac permeationthrough rat skin. Biol. Pharm. Bull.(1996) 19(6):893-896.

91. KADIR R, TIEMESSEN HLGM, PONEC M, JUNGINGER HE,BODDE HE: Oleyl surfactants as skin penetration en-hancers: effects on human stratum corneum perme-ability and in vitro toxicity to cultured human skincells. In: Pharmaceutical skin penetration enhancment.Walters K, Hadgraft J (Eds.), Marcel Dekker, New York(1993):215-227.

92. BARRY BW, SOUTHWELL E, WOODFORD R: Optimizationof bioavailability of topical steroids: penetration en-hancers under occlusion. J. Invest. Dermatol. (1984)82:49-52.

93. COOPER ER: Alterations in skin permeability. In: Trans-dermal Controlled Systemic Medications. Chien YW (Ed.),Marcel Dekker, New York (1987):83-91.

94. GOODMAN M, BARRY BW: Action of skin penetrationenhancers on human stratum corneum as assessed bydifferential scanning calorimetry. In: Percutaneous Ab-sorption. Bronough RL, Maibach HI (Eds.), Marcel Dekker,New York (1993):567-593.

95. FLEEKER C, WONG O, RYTTING JH: Facilitated transportof basic and acidic drugs in solutions through snake-skin by a new enhancer-dodecyl n,n-dimethylaminoacetate. Pharm. Res. (1989) 6(6):443-448.

96. OGISO T, NIINAKA N, IWAKI M: Mechanism for enhance-ment effect of lipid disperse system on percutaneousabsorption. J. Pharm. Sci. (1996) 85(1):57-64.

97. OGISO T, NISHIOKA S, IWAKI M: Dissociation of insulinoligomers and enhancement of percutaneous absorp-tion of insulin. Biol. Pharm. Bull. (1996) 19(8):1049-1054.



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98. POTTS RO, GOLDEN GM, FRANCOEUR ML, MAK VHW,GUY RH: Mechanism and enhancement of solute trans-port across the stratum corneum. J. Contr. Rel. (1991)15:249-260.

99. NAKASHIMA M, ZHAO MF, OHYA H et al.: Evaluation of invivo transdermal absorption of cyclosporin with ab-sorption enhancer using intradermal microdialysis inrats. J. Pharm. Pharmacol. (1996) 48:1143-1146.

100. MATSUYAMA K, NAKASHIMA M, NAKABOH Y et al.: Appli-cation of in vivo microdialysis to transdermal absorp-tion of methotrexate in rats. Pharm. Res. (1994)11(5):684-686.

101. BARRY BW: Optimizing percutaneous absorption. In:Percutaneous Absorption. Bronough RL, Maibach HI (Eds.),Dekker, New York (1993):531-554.

102. ALBERY WJ, HADGRAFT J: Percutaneous absorption: invivo experiments. J. Pharm. Pharmacol. (1979) 31:140-147.

103. BRAIN KR, WALTERS KA: Molecular modeling of skinpermeation enhancement by chemical agents. In: Phar-maceutical Skin Penetration Enhancement. Walters KA,Hadgraft J (Eds.), Marcel Dekker, New York (1993):383-408.

104. SINGH SK, DURRANI MJ, REDDY IK, KHAN MA: Effect ofpermeation enhancers on the release of ketoprofenthrough transdermal drug delivery systems. Pharmazie(1996) 51(10):741-744.

105. OKAMOTO H, HASHIDA M, SEZAKI H: Structure-activityrelationship of 1-alkyl- or 1-alkenylazacycloalkanonederivatives as percutaneous penetration enhancers. J.Pharm. Sci. (1988) 77(5):418-424.

• One of the first studies investigating the relationship betweenthe chemistry of an enhancer and its effect on skin permeabil-ity.

106. AUNGST BJ, ROGERS NJ, SHEFETER E: Enhancement ofnolaxone penetration through human skin in vitro us-ing fatty acids, fatty alcohols, surfactants, sulfoxidesand amides. Int. J. Pharm. (1986) 33:225-234.

107. CEVC G: How membrane chain-melting phase transi-tion temperature is affected by lipid chain asymmetryand the degree of unsaturation: analysis and predic-tions based on the effective chain-length model. Bio-chemistry (1991) 30/29:7186-7193.

108. HORI M, SATOH S, MAIBACH HI, GUY RH: Enhancementof propranolol hydrochloride and diazepam skin ab-sorption in vitro: effect of enhancer lipophilicity. J.Pharm. Sci. (1991) 80(1):32-35.

109. BROWN MB, MARRIOTT C, MARTIN GP: The effect of hya-luronan on the in vitro deposition of diclofenac withinthe skin. Int. J. Tissue. React. (1995) 17(4):133-40.

110. BEHL CR, FLYNN GL, KURIHARA T et al.: Permeability ofthermally damaged skin: I. Immediate influences of60°C scalding on hairless mouse skin. J. Invest. Dermatol.(1980) 75:340-345.

111. HOOGSTRAATE AJ, CULLANDER C, NAGELKERKE JF et al.:Diffusion rates and transport pathways of FITC-labeledmodel compounds through the buccal epithelium.Pharm. Res. (1994) 11(1):83-89.

112. HOOGSTRAATE AJ, VERHOEF JC, TUK B: In-vivo buccaldelivery of fluorescein isothiocyanate-dextran 4400with glycodeoxycholate as an absorption enhancer inpigs. J. Pharm. Sci. (1996) 85(5):457-460.

113. HOOGSTRAATE AJ, COOS VERHOEF J, PIJPERS A et al.: Invivo buccal delivery of the peptide drug buserelin withglycodeoxycholate as an absorption enhancer in pigs.Pharm. Res. (1996) 13(8):1233-1237.

114. BOMMANNAN D, OKUYAMA H, STAUFFER P, GUY RH:Sonophoresis. I. The use of high-frequency ultrasoundto enhance transdermal drug delivery. Pharm. Res.(1992) 9(4):559-564.

115. MENON GK, BOMMANNAN DB, ELIAS PM: High-frequency sonophoresis: permeation pathways andstructural basis for enhanced permeability. Skin. Phar-macol. (1994) 7(3):130-139.

116. MITRAGOTRI S, EDWARDS DA, BLANKSCHTEIN D, LAN-GER R: A mechanistic study of ultrasonically enhancedtransdermal drug delivery. J. Pharm. Sci. (1995)84(6):697-706,

• A scholarly paper which describes the effect of ultrasound onthe skin.

117. MENON GK, PRICE LF, BOMMANNAN B et al.: Selectiveobliteration of the epidermal calcium gradient leads toenhanced lamellar body secretion. J. Invest. Dermatol.(1994) 102(5):789-795.

118. BOMMANNAN D, MENON GK, OKUYAMA H, ELIAS PM,GUY RH: Sonophoresis. II. Examination of the mecha-nism(s) of ultrasound-enhanced transdermal drug de-livery. Pharm. Res. (1992) 9(8):1043-1047.

119. MITRAGOTRI S, BLANKSCHTEIN D, LANGER R: Transder-mal drug delivery using low-frequency sonophoresis.Pharm. Res. (1996) 13(3):411-420.

120. BENSON HAE, MCELNAAY JC, HARLAND R, HADGRAFT J:Influence of ultrasound on the percutaneous absorp-tion of nicotinate esters. Pharm. Res. (1991) 8:204-209.

121. LEVY D, KOST J, MESHULAM Y, LANGER R: Effect of ultra-sound on transdermal drug delivery to rats and guineapigs. J. Clin. Invest. (1989) 83:2074.

122. VYAS SP, SINGH R, ASATI RK. Liposomally encapsulateddiclofenac for sonophoresis induced systemic deliv-ery. J. Microencapsul. (1995) 12(2):149-154.

123. SINGH J, ROBERTS MS: Transdermal delivery of drugs byiontophoresis: a review. Drug. Des. Deliv. (1989)4(1):1-12.

124. SRINIVASAN V, HIGUCHI WI, SIMS SM, GHANEM AH, BEHLCR: Transdermal iontophoretic drug delivery: mecha-nistic analysis and application to polypeptide delivery.J. Pharm. Sci. (1989) 78(5):370-375.

• Good, review article written by opinion leaders.

125. THEISS U, KUHN I, LUCKER PW: Iontophoresis: is there afuture for clinical application? Methods Find. Exp. Clin.Pharmacol. (1991) 13(5):353-359.

126. GREEN PG, FLANAGAN M, SHROOT B, GUY R: Iontopho-retic drug delivery. In: Pharmaceut. Skin Penetration En-hancement. Walters K, Hadgraft J (Eds.), Marcel Dekker,New York (1993):297-319.

127. SINGH P, MAIBACH HI: Transdermal iontophoresis:pharmacokinetic considerations. Clin. Pharmacokinet.(1994) 26(5):327-334.

128. COSTELLO CT, JESKE AH: Iontophoresis: applications intransdermal medication delivery. Phys. Ther. (1995)75(6):554-563.



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129. PIKAL MJ, SHAH S: Transport mechanisms in ionto-phoresis. II. Electroosmotic flow and transferencenumber measurements for hairless mouse skin. Pharm.Res. (1990) 7(3):213-221.

130. BANGA AK CHIEN YW: Hydrogel-based iontotherapeu-tic delivery devices for transdermal delivery of pep-tide/protein drugs. Pharm. Res. (1993) 10(5):697-702.

• Good paper.

131. GREEN PG, HINZ RS, KIM A, SZOKA FC JR, GUY RH: Ionto-phoretic delivery of a series of tripeptides across theskin in vitro. Pharm. Res. (1991) 8(9):1121-1127.

132. CULLANDER C, GUY RH: Sites of iontophoretic currentflow into the skin: identification and characterizationwith the vibrating probe electrode. J. Invest. Dermatol.(1991) 97(1):55-64.

133. HEIT MC, MONTEIRO-RIVIERE NA, JAYES FL, RIVIERE JE:Transdermal iontophoretic delivery of luteinizing hor-mone releasing hormone (LHRH): effect of repeated ad-ministration. Pharm. Res. (1994) 11(7):1000-1003.

134. AGUIELLA V, KONTTURI K, MURTOMÄKI L, RAMIREZ P:Estimation of the pore size and charge density in hu-man cadaver skin. J. Contr. Rel. (1994) 32:249-257.

135. PIKAL MJ: Transport mechanisms in iontophoresis. I. Atheoretical model for the effect of electroosmotic flowon flux enhancement in transdermal iontophoresis.Pharm. Res. (1990) 7(2):118-126.

• Important paper discussing the factors that contribute to ion-tophoretic flow.

136. KIM A, GREEN PG, RAO G, GUY RH: Convective solventflow across the skin during iontophoresis. Pharm. Res.(1993) 10(9):1315-1320.

137. CRAANE VAN HINSBERG WH, BAX L, FLINTERMAN NH etal.: Iontophoresis of a model peptide across humanskin in vitro: effects of iontophoresis protocol, pH andionic strength on peptide flux and skin impedance.Pharm. Res. (1994) 11(9):1296-300.

138. POTTS RO, GUY RH, FRANCOEUR ML: Routes of ionic per-meability through mammalian skin. Solid States Ionics(1992) 53-56:165-169.

139. KALIA YN, GUY RH: The electrical characteristics of hu-man skin in vivo. Pharm. Res. (1995) 12(11):1605-1613.

140. RAO G, GUY RH, GLIKFELD P et al.: Reverse iontophore-sis: noninvasive glucose monitoring in vivo in humans.Pharm. Res. (1995) 12(12):1869-1873.

141. PIKAL MJ, SHAH S: Transport mechanisms in ionto-phoresis. III. An experimental study of the contribu-tions of electroosmotic flow and permeability changein transport of low and high molecular weight solutes.Pharm. Res. (1990) 7(3):222-229.

142. BRAND RM, IVERSEN PL: Iontophoretic delivery of a telo-meric oligonucleotide. Pharm. Res. (1996) 13(6):851-854.

143. CHOI HK, FLYNN GL, AMIDON GL: Transdermal deliveryof bioactive peptides: the effect of n-decylmethyl sul-foxide, pH and inhibitors on enkephalin metabolismand transport. Pharm. Res. (1990) 7(11):1099-106.

144. MORIMOTO K, IWAKURA Y, NAKATANI E, MIYAZAKI M,TOJIMA H: Effects of proteolytic enzyme inhibitors asabsorption enhancers on the transdermal iontopho-retic delivery of calcitonin in rats. J. Pharm. Pharmacol.(1992) 44(3):216-218.

145. ZELTZER L, REGALADO M, NICHTER LS et al.: Iontophore-sis versus subcutaneous injection: a comparison of twomethods of local anesthesia delivery in children. Pain.(1991) 44(1):73-78.

146. MEYER DR, LINBERG JV, VASQUEZ RJ: Iontophoresis foreyelid anesthesia. Ophthalmic. Surg. (1990) 21(12):845-848.

147. GANGAROSA LP, Sr., OZAWA A, OHKIDO M, SHIMOMURAY, HILL JM: Iontophoresis for enhancing penetration ofdermatologic and antiviral drugs. J. Dermatol. (1995)22(11):865-875.

148. CARRASCO VN, PRAZMA T, BIGGERS WP: A safe, effectiveanesthetic technique for outpatient myringotomy tubeplacement. Laryngoscope (1993) 103(1):92-93.

149. SCHIFFMAN EL, BRAUN BL, LINDGREN BR: Temporoman-dibular joint iontophoresis: a double-blind random-ized clinical trial. J. Orofac. Pain (1996) 10(2):157-165.

150. LARK MR, GANGAROSA LP Sr: Iontophoresis: an effectivemodality for the treatment of inflammatory disordersof the temporomandibular joint and myofascial pain.Cranio. (1990) 8(2):108-119.

151. KENNARD CD, WHITAKER DC: Iontophoresis of lido-caine for anesthesia during pulsed dye laser treatmentof port-wine stains. J. Dermatol. Surg. Oncol. (1992)18(4):287-294.

152. HOLZLE E, ALBERTI N: Long-term efficacy and side ef-fects of tap water iontophoresis of palmo-plantar hy-perhidrosis - the usefulness of home therapy.Dermatologica (1987) 175(3):126-135.

153. MORIMOTO M, HAKUTO T, MORIMOTO E et al.: Ionto-phoretic administration of indomethacin in the treat-ment of postherpetic neuralgia. Masui (1991)40(8):1256-1260.

154. BREMERICH A, WIEGEL W: The treatment of neuralgi-form facial pains with the combined therapy oftranscutaneous electric nerve stimulation (tens) andthe iontophoresis of nonsteroidal antiphlogistics.Dtsch. Zahn. Mund. Kieferheilkd. Zentralbl. (1992)80(2):81-84.

155. COURY AJ, FOGT EJ, NORENBERG MS, UNTEREKER DF:Development of a screening system for cystic fibrosis.Clin. Chem. (1983) 29(9):1593-1597.

156. THORNTON SN, NICOLAIDIS S: Blood pressure effects ofiontophoretically applied bioactive hormones in theanterior forebrain of the rat. Am. J. Physiol. (1993) 265(4):826-833.

157. RITSCHEL WA, SABOUNI A, HUSSAIN AS: Percutaneousabsorption of coumarin, griseofulvin and propranololacross human scalp and abdominal skin. Methods Find.Exp. Clin. Pharmacol. (1989) 11(10):643-646.

158. RAO VU, MISRA AN: Enhancement of iontophoretic per-meation of insulin across human cadaver skin. Phar-mazie (1994) 49(7):538-539.

159. MEYER BR, KREIS W, ESCHBACH J et al.: Transdermal ver-sus subcutaneous leuprolide: a comparison of acutepharmacodynamic effect. Clin. Pharmacol. Ther. (1990)48(4):340-345.

160. HEIT MC, WILLIAMS PL, JAYES FL, CHANG SK, RIVIERE JE:Transdermal iontophoretic peptide delivery: in vitroand in vivo. J. Pharm. Sci. (1993) 82(5):240-243.



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161. RODRIGUEZ BAYON AM, GUY RH: Iontophoresis of na-farelin across human skin in vitro. Pharm. Res. (1996)13(5):798-800.

162. VANBEVER R, MORRE ND, PREAT V: Transdermal deliv-ery of fentanyl by electroporation. II. Mechanisms in-volved in drug transport. Pharm. Res. (1996)13(9):1360-1366.

163. PRAUSNITZ MR, BOSE VG, LANGE R, WEAVER JC: Electro-poration of mammalian skin: a mechanism to enhancetransdermal drug delivery. Proc. Natl. Acad. Sci. (USA)(1993) 90:10504-10508.

164. VANBEVER R, LECOUTURIER N, PREAT V: Transdermaldelivery of metoprolol by electroporation. Pharm. Res.(1994) 11(11):1657-1662.

165. PRAUSNITZ MR, GIMM JA, GUY RH et al.: Imaging regionsof transport across human stratum corneum duringhigh-voltage and low-voltage exposures. J. Pharm. Sci.(1996) 85(12):1363-1370.

166. MEZEI M, GULASEKHARAM V: Liposomes - a selectivedrug delivery system for the topical route of admini-stration, lotion dosage form. Life Sci. (1980) 26:1473-1477.

167. MEZEI M: Liposomes in the topical application of drugs:a review. In: Liposomes as Drug Carriers. Gregoriadis G(Ed.), John Wiley & Sons, New York (1988):663-677.

168. HOFLAND HE, BOUWSTRA JA, BODDE HE, SPIES F, JUNG-INGER HE: Interactions between liposomes and humanstratum corneum in vitro: freeze fracture electron mi-croscopical visualization and small angle X-ray scatter-ing studies. Br. J. Dermatol. (1995) 132(6):853-866.

169. LI L, LISHKO VK, HOFFMAN RM: Liposomes can specifi-cally target entrapped melanin to hair follicles in histo-cultured skin. In vitro Cell Dev. Biol. (1993) 29A:192-194.

170. LAUER AC, LIEB LM, RAMACHANDRAN C, FLYNN G, WEI-NER ND: Transfollicular drug delivery. Pharm. Res.(1995) 12:179-186.

171. CEVC G, GEBAUER D, GOMPPER G, KROLL DM: Transportof highly deformable vesicles through narrow pores.Biochim. Biophys. Acta (1997) (In Press.)

172. SHORT SM, RUBAS W, PAASCH BD, MRSNY RJ, Transportof biologically active interferon-γ across human skin invitro. Pharm. Res. (1995) 12:1140-1145.

173. CEVC G, BLUME G, SCHÄTZLEIN A, GEBAUER D, PAUL A:The skin: a pathway for the systemic treatment withpatches and lipid-based agent carriers. Adv. Drug Del.Rev. (1996) 418:349-378.

174. GOMPPER G, KROLL DM: Driven transport of fluid vesi-cles through narrow pores. Phys. Rev. (1995) 52:4198-4208.

175. SCHÄTZLEIN A, CEVC G: Skin penetration by phos-pholipid vesicles, Transfersomes, as visualized bymeans of the confocal laser scanning microscopy. In:Phospholipids: Characterization, Metabolism and Novel Bio-logical Applications. Cevc G, Paltauf F (Eds.), AOCS Press,Champain, Illinois (1995):191-209.

176. CEVC G, SCHÄTZLEIN A, BLUME G: Transdermal drugcarriers: basic properties, optimization and transfer-efficiency in the case of epicutaneously applied pep-tides. J. Contr. Rel. (1995). (In Press.)

177. BODDE H‚ OESTMANN-KNEISSL E: Measuring skin irrita-tion: biophysical techniques versus the naked eye.(1991) 1-31.

178. KORTING HC, SCHMID MH, HARTINGER A et al.: Evidencefor the phagocytosis of intact oligolamellar liposomesby human keratinocytes in vitro and consecutive intra-cellular disintegration. J. Microencapsul. (1993) 10:223-228.

179. HOLMAN BP, SPIES F, BODDE HE: An optimized freezefracture replication procedure for human skin. J. Invest.Dermatol. (1990) 94:332-335.

180. SCHUBERT R, JOOS M, DEICHER M, MAGERLE R, LASCH J:Destabilization of egg lecithin liposomes on the skin af-ter topical application measured by perturbed gammagamma angular correlation spectroscopy (pac) with111in. Biochim. Biophys. Acta (1993) 1150:162-164.

181. MEYBECK A: Past, present and future of liposome cos-metics. In: Liposome Dermatics. Braun-Falco O, Korting HC,Maibach HI (Eds.), Springer, Berlin (1992):341-345.

182. LASCH J, LAUB R, WOHLRAB W: How deep do intact lipo-somes penetrate into human skin? J. Contr. Rel. (1991)18:55-58.

183. SCHUBERT R, JOOS M, DEICHER M, LASCH J: Mode of ac-tion of topically applied liposomes in dermatology andcosmetics. Proceedings of MOBBEL (1992).

184. BOUWSTRA JA, HOFLAND HE, SPIES F, GOORIS GS, JUNG-INGER HE: Changes in the structure of the stratum cor-neum induced by liposomes. In: Liposome Dermatics.Braun-Falco O, Korting HC, Maibach HI (Eds.), Springer, Ber-lin (1992):121-136.

185. LASCH J, ZELLMER S, PFEIL W, SCHUBERT R: Interactionof liposomes with the human skin lipid barrier:HSCLLS as model system - DSC of intact stratum cor-neum and in situ CLSM of human skin. J. Lipos. Res.(1995) 5:99-109.

186. ZELLMER S, PFEIL W, LASCH J: Interaction of phosphati-dylcholine liposomes with the human stratum cor-neum. Biochim. Biophys. Acta (1995) 1237:176-182.

187. GUZEK DB, KENNEDY AH, MCNEILL SC, WAKSHULL E,POTTS RO: Transdermal drug transport and metabo-lism. I. Comparison of in vitro and in vivo results.Pharm. Res. (1989) 6:33.

188. POTTS RO, MCNEILL SC, DESBONNET CR, WAKSHULL E:Transdermal drug transport and metabolism. II. Therole of competing kinetic events. Pharm. Res. (1989)6:119.

189. STEINSTRASSER I, MERKLE HP: Dermal metabolism oftopically applied drugs: pathways and models recon-sidered. Pharm. Acta. Helv. (1995) 70(1):3-24.

• A good introductory paper.

190. BOS JD, KAPSENBERG ML: The skin immune system:progress in cutaneous biology. Immunol. Today (1993)14:75-78.

191. CROSS SE, WU Z, ROBERTS MS: The effect of proteinbinding on the deep tissue penetration and efflux ofdermally applied salicylic acid, lidocaine and diazepamin the perfused rat hindlimb. J. Pharmacol. Exp. Ther.(1996) 277(1):366-74.



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192. CROSS SE, ROBERTS MS: Importance of dermal bloodsupply and epidermis on the transdermal iontopho-retic delivery of monovalent cations. J. Pharm. Sci.(1995) 84(5):584-592.

193. The Dermal Lymphatic Capillaries. Daróczy J (Ed.), Springer,Berlin (1989):2.

194. TUIMALA RJ, VIHTAMAKI T: Individual hormone re-placement therapy. Maturitas (1996) 23(Suppl.):87-90.

195. REGINSTER JY, ALBERT A, DEROISY R et al.: Plasma con-centration of estradiol following transdermal admini-stration of systen 50 or menorest 50. Scand. J.Rheumatol. Suppl. (1996) 103:94-100.

196. CEVC G, BLUME G: Lipid vesicles penetrate into intactskin owing to transdermal osmotic gradients and hy-dration force. Biochim. Biophys. Acta (1992) 1104:226-232.

197. PLANAS ME, GONZALEZ P, RODRIGUEZ L, SANCHEZ S,CEVC G: Noninvasive percutaneous induction of topicalanalgesia by a new type of drug carrier and prolonga-tion of local pain insensivity by anesthtic liposomes.Anesth. Analg. (1992) 75:615-621.

198. BALFOUR JA, HEEL RC: Transdermal estradiol. A reviewof its pharmacodynamic and pharmacokinetic proper-ties and therapeutic efficacy in the treatment of meno-pausal complaints. Drugs (1990) 40(4):561-582.

• Good summary of a decade of experience with TTS oestra-diol.

199. BALFOUR JA, McTAVISH D: Transdermal estradiol. A re-view of its pharmacological profile and therapeutic po-tential in the prevention of postmenopausalosteoporosis. Drugs. Aging (1992) 2(6):487-507.

200. CORSON SL: A decade of experience with transdermalestrogen replacement therapy: overview of key phar-macologic and clinical findings. Int. J. Fertil. (1993)38(2):79-91.

201. RUNNEBAUM B, SALBACH B, VON HOLST T: Oral ortransdermal estrogen substitution therapy in climac-teric? Geburtshilfe Frauenheilkd. (1994) 54(3):119-30.

202. WISEMAN LR, MCTAVISH D: Transdermal estra-diol/norethisterone. A review of its pharmacologicalproperties and clinical use in postmenopausal women.Drugs Aging (1994) 4(3):238-256.A survey of TTS hormone replacement therapy.

203. LOBO RA, ETTINGER B, HUTCHINSON KA et al.: Estrogenreplacement: the evolving role of transdermal delivery.J. Reprod. Med. (1996) 41(Suppl. 10):781-796.

204. JEWELEWICZ R: New developments in topical estrogentherapy. Fertil. Steril. (1997) 67(1):1-12.

205. ARAYA V, CONTRERAS P, AGUIRRE C, FORADORI A: Effectof a 17-β-estradiol gel preparation on hormone levelsin menopausal women. Rev. Med. Chil. (1995)123(9):1116-1121.

206. CICINELLI E, CANTATORE FP, GALANTINO P et al.: Effectsof continuous percutaneous estradiol administrationon skeletal turnover in post-menopausal women: a 1-year prospective controlled study. Eur. J. Obstet. Gynecol.Reprod. Biol. (1996) 69(2):109-113.

207. FRIEND KE, HARTMAN ML, PEZZOLI SS, CLASEY JL, THOR-NER MO: Both oral and transdermal estrogen increasegrowth hormone release in postmenopausal women -A clinical research center study. J. Clin. Endocrinol. Me-tab. (1996) 81(6):2250-2256.

208. GODSLAND IF, GANGAR K, WALTON C et al.: Insulin re-sistance, secretion and elimination in postmenopausalwomen receiving oral or transdermal hormone re-placement therapy. Metabolism(1993) 42(7):846-853.

209. BELLANTONI MF, VITTONE J, CAMPFIELD AT et al.: Effectsof oral versus transdermal estrogen on the growth hor-mone/ insulin-like growth factor I axis in younger andolder postmenopausal women: a clinical research cen-ter study. J. Clin. Endocrinol. Metab. (1996) 81(8):2848-2853.

210. STEVENSON JC, CROOK D, GODSLAND IF, LEES B, WHITE-HEAD MI: Oral versus transdermal hormone replace-ment therapy. Int. J. Fertil. Menopausal. Stud. (1993)38(Suppl.1):30-35.

211. SHARP CA, EVANS SF, RISTELI L et al.: Effects of low andconventional-dose transcutaneous HRT over 2 years onbone metabolism in younger and older postmeno-pausal women. Eur. J. Clin. Invest. (1996) 26(9):763-771.

212. BARACAT E, HAIDAR M, CASTELO A et al.: Comparativebioavailability study of an once-a-week matrix versus atwice-a-week reservoir transdermal estradiol deliverysystems in postmenopausal women. Maturitas (1996)23(3):285-291.

213. BOYD RA, ZEGARAC EA, ELDON MA, SEDMAN AJ,FORGUE ST: Characterization of a 7 day 17-β-estradioltransdermal delivery system: pharmacokinetics inhealthy postmenopausal women. Biopharm. Drug. Dis-pos. (1996) 17(6):459-470.

214. KOH KK, MINCEMOYER R, BUI MN et al.: Effects ofhormone-replacement therapy on fibrinolysis in post-menopausal women. New. Engl. J. Med. (1997)336(10):683-690.

215. VIINIKKA L, ORPANA A, PUOLAKKA J, PYORALA T, YLIK-ORKALA O: Different effects of oral and transdermalhormonal replacement on prostacyclin and thrombox-ane A2. Obstet. Gynecol. (1997) 89(1):104-107.

216. AKKAD AA, HALLIGAN AW, ABRAMS K, AL AZZAWI F: Dif-fering responses in blood pressure over 24 hours innormotensive women receiving oral or transdermal es-trogen replacement therapy. Obstet. Gynecol. (1997)89(1):97-103.

217. CROOK D, STEVENSON JC: Transdermal hormone re-placement therapy, serum lipids and lipoproteins. Br. J.Clin. Pract. Symp. (1996) 86 (Suppl.):17-21.

218. TIKKANEN MJ: The menopause and hormone replace-ment therapy: lipids, lipoproteins, coagulation and fi-brinolytic factors. Maturitas (1996) 23(2):209-216.

219. SCARABIN PY: Risk of venous thrombosis with hor-mone replacement therapy. Lancet (1996)348(9042):1668.

220. CLEMENTE C, CARUSO MG, BERLOCO P et al.: β-Toc-opherol and β-carotene serum levels in post-menopausal women treated with transdermal estradioland oral medroxyprogesterone acetate. Horm. Metab.Res. (1996) 28(10):558-561.

221. HILDITCH JR, LEWIS J, ROSS AH et al.: A comparison ofthe effects of oral conjugated equine estrogen andtransdermal oestradiol-17-β combined with an oralprogestin on quality of life in postmenopausal women.Maturitas (1996) 24(3):177-184.



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222. EDMONDS DK: Add-back therapy in the treatment ofendometriosis: the european experience. Br. J. Obstet.Gynaecol. (1996) 103(Suppl. 14):10-13.

223. PANSINI F, DE PAOLI D, ALBERTAZZI P et al.: Sequentialaddition of low dose of medrogestone or medroxypro-gesterone acetate to transdermal estradiol: a pilot studyon their influence on the endometrium. Eur. J. Obstet.Gynecol. Reprod. Biol. (1996) 68(1-2):137-41.

224. SITRUK WARE R: Comparative evaluation of oral versusnon-oral hormonal treatments in menopause. J. Gyne-col. Obstet. Biol. Reprod. (1996) 25(7):688-93.

225. HELLE SI, OMSJO IH, HUGHES SC et al.: Effects of oral andtransdermal estrogen replacement therapy on plasmalevels of insulin-like growth factors and IGf bindingproteins 1 and 3: a cross-over study. Clin. Endocrinol.(1996) 45(6):727-732.

226. MARCHESONI D, DAL POZZO M, DAL MAGRO L et al.:Transdermal estroprogestins versus transdermal es-trogen plus oral dihydrogesterone replacement inmenopause. J. Endocrinol. Invest. (1996) 19(5):268-272.

227. DE LIGNIERES B: Transdermal dihydrotestosteronetreatment of ‘Andropause’. Ann. Med. (1993) 25(3):235-241.

228. NIESCHLAG E: Testosterone replacement therapy:something old, something new... Clin. Endocrinol. (1996)45(3):261-262.

229. PORCHE DJ: Treatment review. Testosterone (testo-derm). J. Assoc. Nurses. AIDS. Care (1995) 6(4):43-45.

230. EVANS I: Amorous inclinations. Lancet (1996)348(9024):352.

231. BROCKS DR, MEIKLE AW, BOIKE SC et al.: Pharmacoki-netics of testosterone in hypogonadal men after trans-dermal delivery: influence of dose. J. Clin. Pharmacol.(1996)36(8):732-739.

232. MEIKLE AW, ARVER S, DOBS AS et al.: Pharmacokineticsand metabolism of a permeation- enhanced testoster-one transdermal system in hypogonadal men: influ-ence of application site. A clinical research centerstudy. J. Clin. Endocrinol. Metab. (1996) 81(5):1832-1840.

233. MEIKLE AW, ARVER S, DOBS AS et al.: Prostate size in hy-pogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology(1997) 49(2):191-196.

234. Arver S, Dobs AS, Meikle AW et al.: Improvement of sexualfunction in testosterone deficient men treated for 1year with a permeation enhanced testosterone trans-dermal system. J. Urol. (1996)155(5):1604-1608.

235. JOHNSON ME, MITRAGOTRI S, PATEL A, BLANKSCHTEIND, LANGER R: Synergistic effects of chemical enhancersand therapeutic ultrasound on transdermal drug deliv-ery. J. Pharm. Sci. (1996) 85(7):670-679.

236. TODD PA, GOA KL, LANGTR. HD: Transdermal nitroglyc-erin (glyceryl trinitrate). A review of its pharmacologyand therapeutic use. Drugs (1990) 40(6):880-902.

237. PARKER JD, FARRELL B, FENTON T, COHANIM M, PARKERJO: Counter-regulatory responses to continuous and in-termittent therapy with nitroglycerin. Circulation(1991) 84(6):2336-2345.

238. BAUER JA, FUNG HL, ZHENG W et al.: Continuous versusintermittent nitroglycerin administration in experi-mental heart failure: Vascular relaxation and radio-ligand binding to adrenoceptors and ion channels. J.Cardiovasc. Pharmacol. (1993) 22(4):600-608.

239. ZOLI M, MAGALOTTI D, GHIGI G, MARCHESINI G, PISI E:Transdermal nitroglycerin in cirrhosis. A 24-hourecho-doppler study of splanchnic hemodynamics. J.Hepatol. (1996) 25(4):498-503.

240. BERRAZUETA JR, LOSADA A, POVEDA J et al: Successfultreatment of shoulder pain syndrome due to supraspi-natus tendinitis with transdermal nitroglycerin. A dou-ble blind study. Pain (1996) 66(1):63-67.

241. HARA M, SAIKAWA T, TSUNEMATSU Y et al.: Rapid coro-nary vasodilation by nitroglycerin tapes. Jpn. Heart J.(1996) 37(5):603-610.

242. KANDAA, YOSHIDAM, KANOU M, YAMAGUCHI K, KYUKIK: Cardiovascular effects of nt-1, a new patch form ofnitroglycerin, alone and in combination with nifedip-ine in conscious dogs. J. Pharm. Pharmacol. (1995)47(12A):1021-1024.

243. RAMAMURTHY S, MEHAN V, KAUFMANN U et al.: Effect ofpre-treatment with transdermal glyceryl trinitrate onmyocardial ischaemia during coronary angioplasty.Heart (1996) 76(6):471-476.

244. SAITO T, TAKEICHI S, NAKAJIMA Y, YUKAWA N, OSAWAM: Experimental studies of methemoglobinemia due topercutaneous absorption of sodium nitrite. J. Toxicol.Clin. Toxicol. (1997) 35(1):41-48.

245. PARKER JD, PARKER AB, FARRELL B, PARKER JO: The ef-fect of hydralazine on the development of tolerance tocontinuous nitroglycerin. J. Pharmacol. Exp. Ther. (1997)280(2):866-875.

246. KOUNIS NG, ZAVRAS GM, PAPADAKI PJ, et al.: Allergic re-actions to local glyceryl trinitrate administration. Br. J.Clin. Pract. (1996) 50(8):437-439.

247. LANGLEY MS, HEEL RC: Transdermal clonidine. A pre-liminary review of its pharmacodynamic propertiesand therapeutic efficacy. Drugs (1988) 35(2):123-142.

• An early review of the performance of TTS clonidine in thepraxis.

248. CHEN SW, VIDT DG: Patient acceptance of transdermalclonidine. A retrospective review of 25 patients. Cleve.Clin. J. Med. (1989) 56(1):21-26.

249. ISHII R, TAGAWA T, ISHIDA T, NARUSE T: Antihyperten-sive effects of a new transdermal delivery system forclonidine in genetic and experimental hypertensiverats. Arzneimittelforschung (1996) 46(3):261-268.

250. FUJIMURA A, SASAKI, M HARADA K et al.: Influences ofbathing and hot weather on the pharmacokinetics of anew transdermal clonidine, m-5041t. J. Clin. Pharmacol.(1996) 36(10):892-896.

251. NARUSE T, ISHIDA T, ISHII R, TAGAWA T: Preclinical as-sessment of a new transdermal delivery system for clo-nidine (m-5041t). Fundam. Clin. Pharmacol. (1996)10(1):47-55.

252. HOUSTON MC HAYS L: Transdermal clonidine as an ad-junct to nifedipine-gits therapy in patients with mild-to-moderate hypertension. Am. Heart. J, (1993)126(4):918-923.



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253. BOLTRI L, MOREL S, TROTTA M, GASCO MR: In vitrotransdermal permeation of nifedipine from thickenedmicroemulsions. J. Pharm. Belg. (1994) 49(4):315-320.

254. MCDAID DM, DEASY PB: An investigation into the trans-dermal delivery of nifedipine. Pharm. Acta. Helv. (1996)71(4):253-258.

255. RUAN LP, ZHENG JM: Research on nifedipine patch. Yao.Hsueh. Hsueh. Pao (1991) 26(4):286-292.

256. OGISO T, ITO Y, IWAKI M, SHINTANI A: The percutane-ous absorption of propranolol and prediction of theplasma concentration. J. Pharmacobiodyn. (1988)11(5):349-355.

257. OGISO T, SHINTANI M: Mechanism for the enhance-ment effect of fatty acids on the percutaneous absorp-tion of propranolol. J . Pharm. Sci , (1990)79(12):1065-1071.

258. AHMED S, IMAI T, OTAGIRI M: Evaluation of stereoselec-tive transdermal transport and concurrent cutaneoushydrolysis of several ester prodrugs of propranolol:mechanism of stereoselective permeation. Pharm. Res.(1996) 13(10):1524-1529.

259. KRISHNA R, PANDIT JK: Carboxymethylcellulose-sodium based transdermal drug delivery system forpropranolol. J. Pharm. Pharmacol. (1996) 48(4):367-370.

260. KOBAYASHI I, HOSAKA K, UENO T, Relationship be-tween the amount of propranolol permeating throughthe stratum corneum of guinea pig skin after applica-tion of propranolol adhesive patches and skin irrita-tion. Biol. Pharm. Bull. (1996) 19(6):839-844.

261. TUZUN B, TUZUN Y, GUREL N et al.: Psoriasis-like lesionsin guinea pigs receiving propranolol. Int. J. Dermatol.(1993) 32(2):133-144.

262. PARROTT AC: Transdermal scopolamine: a review of itseffects upon motion sickness, psychological perform-ance and physiological functioning. Aviat. Space. Envi-ron. Med. (1989) 60(1):1-9.

• A useful review of the, somewhat disputed, anti-emetic treat-ment TTS.

263. EBERHART LHJ, HOLZRICHTER P, ROSCHER R: Transder-mal scopolamine for prevention of post-operative nau-sea and vomiting: no clinically relevant result in spiteof reduced postoperative vomiting in general surgicaland gynecologic patients. Anaesthetist (1996) 45(3):259-267.

264. HORIMOTO Y, NAIDE M: Transdermal scopolaminepatches reduce postoperative emesis in pediatric pa-tients undergoing strabismus surgery. Can. J. Anaesth.(1990) 37(4):94.

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• State of the art report.

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• Good introduction to this rapidly developing field.

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419. DAWSON BV, HADLEY ME, KREUTZFELD K et al.: Trans-dermal delivery of a melanotropic peptide hormoneanalogue. Life Sci. (1988) 43(14):1111-1117.

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• Complements [25].

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426. BERNER B, WILSON DR, STEFFENS RJ et al.: The relation-ship between pKa and skin irritation for a series of ba-sic penetrants in man. Fundam. Appl. Toxicol. (1990)15(4):760-706.

427. GROSSMANN M, JAMIESON MJ, KELLOGG DL JR et al.: Theeffect of iontophoresis on the cutaneous vasculature:evidence for current-induced hyperemia. Microvasc.Res. (1995) 50(3):444-452.

428. LAPORTE M: Contact eczema and drug ionization. Acta.Belg. Med. Phys. (1984) 7(3):97-99.

429. Lesions and shocks during iontophoresis. Health Dev.(1997) 26(3):123-125.

430. BARBAUD A, MODIANO P, COCCIALE M, REICHERT S,SCHMUTZ JL: The topical application of resorcinol canprovoke a systemic allergic reaction. Br. J. Dermatol.(1996) 135(6):1014-1015.

431. GOMPER G, KROLL DM: Driven transport of fluid vesi-cles thruogh narrow pores. Phys. Rev. E. (1995)52(4):4198-4208.

432. MAZER NA, HEIBER WE, MOELLMER JF et al.: Enhancedtransdermal delivery of testosterone: a new physiologi-cal approach for androgen replacement in hypogona-dal men. J. Control. Rel. (1992) 19:347-362.

Patents

101. AGIN PP, EP-386680 (1990).

102. CEVC G, EP-111416 (1991).

Gregor CevcMedizinische Biophysik, Klinikum r.d.I., Technische UniversitätMünchen, Ismaninger Str. 22, D-81675 München, Germany



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expert opinion on investigational drugs volume 6 issue 12 1997 [doi 10.1517%2f13543784.6.12.1887]...

Documents

skin barrier

chemical skin

skin iontophoresis

skin hydrationandor

skin lipids

tts delivery

skin tts therapeutic

driven skin poration