The skin performs a variety of barrier functions, not the least of which is that to the passive, or

insensible, loss of tissue water and that to the ingress of materials contacting its surface. The
latter, of course, plays a crucial role in determining the effectiveness of any topical drug
treatment designed to alleviate skin disease. It follows that the optimization of any
dermatological therapy requires an understanding of the skin's physical barrier and of the
physicochemical mechanisms involved in cutaneous drug uptake and transport.

At the macroscopic level, the skin consists of two principal com ponents: the dermis and the
epidermis. The former, in order of magnitude terms, dermis about 1 mm thick and represents a
connec tive tissue, the main structural components of which are collagen and elastic fibres in an
aqueous glycoprotein gel. The dermis also houses' mechanoreceptors of touch and heat, hair
follicles, sweat and apocrine glands, sebaceous glands, lymphatic vessels and a rich
microcirculation. These blood vessels deliver nutrients to the skin as well as providing a
clearance mechanism by which penetrating xenobiotics are eliminated into the systemic
circulation.
The epidermis is, on average, only 0.1 mm in thickness and is a stratified epithelial membrane
comprising (primarily) proliferating basal and differentiated suprabasal keratinocytes. At the
outermost surface of the epidermis, the cells are terminally dif ferentiated creating the stratum
corneum (SC) or horny layer, the thickness of which is only about 0.01 mm (except on the palms
and soles where it is much more substantial). The epidermis also con tains melanocytes,
Langerhans cells and Merkel cells, but is avas cular, such that transfer of material across this
tissue layer occurs by passive diffusion only.
As the keratinocytes move up through the epidermis, they flatten and their nucleus begins to
degenerate. A complex, lipid mixture of cholesterol, free fatty acids and ceramides is secreted
into the intercellular spaces as the keratinocytes undergo their final
transformation into corneocytes — anucleate flattened cells, filled with keratin —and create the
SC. Microscopically, the SC is often com pared, therefore, to a brick wall, with the corneocytes
representing the bricks and the intercellular lipids the cement (Figure 13.1) [1,2,31. Corneo-
desmosomes act as bridges holding coreocytes together until their controlled enzymatic
degradation towards the SC surface provokes (the roughly daily) desquamation of the outer cell
layer.
Remarkably, it is the SC that represents the skin's principal resistance to molecular diffusion
either from the 'inside-out', as in the case of water, or from the 'outside-in' with respect to
topically contacting drugs or other foreign substances. The effectiveness of the SC to limit
transepidermal water loss (TEWL) is demonstrated easily by measuring the rate of water 'escape'
across the skin as the outer layers of corneocytes are progressively removed by adhesive tape
stripping (Figure 13.2), with TEWL increasing by about an order of magnitude once the barrier
has been fully deranged [4]
The typical, normal value of TEWL across the skin of a human at rest is in the order of 0.5
mg/cm2/h. Given that the surface area of skin in an adult male will approach 2 m2 (or 20 000
cm2), this means that the amount of water lost passively across the skin assuming no active
sweating — is between 200 and 300 mL/day, a remarkably small volume given that the
concentration of water inside the body is about 1 g/mL (i.e. c. 50 mol/L)!
Similar tape stripping experiments have also shown that the SC presents the principal barrier to
drug penetration following topical application. Exceptions to this general rule are limited to very
lipophilic compounds which, although taken up into the SC quite easily, are then limited in their
entry into the underlying, viable epidermal tissue by their unfavourable partitioning and very low
solubility in this predominantly aqueous environment.

Penetration pathways: mechanisms of percutaneous absorption

The 'brick and mortar' model of the SC immediately presents two potential pathways for
penetration across the barrier (Figure 13.3) [5,6]. The first is transcellularly, involving the most
direct route and multiple transfers of the permeant between corneocytes and interstitial lipids.
The other is intercellularly, a tortuous route constraining transport uniquely to the lipid 'cement'
between the bricks. In addition, the opportunity for topically contacting cherni. cals to access
apparent 'shunt' paths, involving the skin appendages (and, in particular, the follicles), represents
a further alternative. As no active transport mechanisms across the SC have been identified, and
accepting therefore that percutaneous absorption involves passive diffusion, it follows that
molecules will follow the path of least resistance across the barrier. At face value, the
transcellular route appears most attractive: it has the largest sur face area and volume available
for transport and the path length is short (c. 0.01 mm). In contrast, the intercellular lipid domains
com prise only about 15% of the SC volume and, given the flattened corneocyte dimensions, the
path length around the cells is closer to 0.5 mm (i.e. 50 times longer than transcellularly).

However, a combination of elegant analytical chemuistry, electron microscopy and biophysics

research in the 1980s and early 1990s has led to a consensus that the intercellular route is, in fact,
the dominant pathway. Unravelling the composition and arrangement of the SC intercelular
lipids was a key first step in reaching this conclusion [12,3. The absence of phospholipids and
the presence of an array of ceramides were important and noteworthy features and their precise
organization, with the approximately equimoar quantites of fatty acids and cholesterol, into two
distinct lamellar phases immediately suggested a more important role for these domains than that
of a simple filler' in between the bricks. It was then noted, in an attempt to visualize chemical
penetration across the SC i situ, that the per meating molecules were indeed localized to the
intercellular spaces reinforcing the impression that transport might be constrained to these lipid-
rich regions. This led to a defining and contirmatory study that demonstrated that water
permeability through the SC was highly correlated with the conformational order of the intercel
lular lipid domains: as the lipids became progressively disordered by increasing temperature, the
permeation of water increased concom tantly. In addition, even as the lipids went through a
phase transition (and became markedly more disordered), the permeation of water was enhanced
in a correspondingly discontinuous way (Figure 13.4) 78]. The inescapable conclusion from
these data was that the path of diffusion for water through the SC was via the intercellular lipids.
I This deduction was reinforced in a further series of experiments that independently assessed the
path length of transport to be more than 50-fold greater than the SC thickness. In terms of
appendageal transport, a variety of experimental data point to two common features: (i) the hair
follicles, in particular, appear to offer more rapid, 'shunt' pathways circumventing the SC barrier;
and (ii) the capacity of the pathway is limited by the low density of follicles on most body sites.
As a result, although the first molecules reaching the viable skin layers after the application of a
topical drug formulation, for example, may well have diffused via the available hair follicles
[1,2,3), the overall contribu tion to delivery at a 'steady state' (when transport across the SC will
have caught up, so to speak) is small.

Factors determining drug permeation into the skin

The absorption of a chemical into the skin depends upon its phys icochemical properties, its
presentation to the skin (i.e, the 'vehicle' in which it is applied), the skin 'environment" (i.e. skin
condition, disease state, etc.) and the duration of exposure.
The inherent permeability of a specific molecule may be expressed in terms of its maximum
potential flux (ma) across the SC [9], defined as: (eqn 13.1) where Cvsat is the solubility of the
compound in the vehicle in which it is applied, and k is its permeability coefficient across the
skin when it is applied in that vehicle. The units of Jmax are amount per unit area per unit time
(e.g. ug/cm•/h). k has units of velocity e.g. cm/h) and depends on the chemical's diffusivity (D)
across the SC, its partition coefficient between the SC lipids and the vehicle in which it is applied
(K/y) and its path length of diffusion across the SC (h):
(eqn 13.3)The permeability coefficients of a large number of drugs and other chemicals from
water have been determined experimentally and this has permitted a simple algorithm to estimate
kn (in units of cm/h) from water to be derived [9] and validated: i logkp=-2.7 + 0.71*logP-
0.0061"MW
where P is the octanol-water partition coefficient of the chemical and MW is its molecular
weight (in Daltons). The log P and MW are readily available physicochemical parameters of the
permeant, the first defining its lipophilicity (a very commonly used metric in pharmaceutical
development to assess a molecule's ability to bei absorbed across lipid barriers), the second
describing its size, and hence the rate at which it is able to diffuse. Equation 13.3 assumes (as is
typically the case) that the SC is the rate-determining barrier for percutaneous absorption. How
ever, as noted above, for very lipophilic compounds, penetration is controlled by their ability to
partition/dissolve into the viable skin layers. In this case, the value of k, predicted by equation
13.3 must be corrected 19
An estimate of Jmax for a chemnical is now possible using equation 13.1, with kpcor determined
from equations 13.3 and 13.4 and its water solubility (i.e. Cwatersa). The latter is frequently
determined in the course of drug development, or (like log P, in fact) can be calculated using any
one of a nuunber of available algorithms. The ranges of water solubilities and log P values
encompassed by 91 drugs, currently approved for topical and transdermal administration, either
in Europe or the USA (or both) are shown in Figure 13.5 as a function of their molecular weight
(MW). Immediately apparent is that the majority of compounds have a MW less than 500
Daltons, that their lipophilicities and aqueous solubilities span many orders of magnitude, and
that, in broad terms, there is an inverse correlation between log P and Cwatersat, the former gen
erally increasing with MW and the latter decreasing.
As anticipated MW and Estimated Jmax values for these drugs are presented in Fig ure 13.6, as
functions of MW. log P and C by equaton 13.3, there are lwo clear patterns of behaviour: first
that drug fux is inversely that wthn a group ot compounds o appfoximately simlar M Jmax
increases with increasing lipophilicity (log P). Notably, the majority of topical and transdermal
drugs manifest rather modest maximum flux rates across the skin (the dotted horizontal lines in
Figure 13.6 signifying a Jmax of only 1 ug/cm2/h), and attest to the considerable
pharmacological potency of these compounds. Validation of the conclusions drawn from this
physicochemical analysis of the percutaneous absorption process is provided in Figure 13.6b, in
which predicted values of /max are compared with published data in the literature (black circles
and stars) for 12 dif ferent drugs. The mean ratio of the experimental to the predicted maximum
flux for these compounds is 2.04, that is, very close to the ideal value of 1.
In sum, therefore, the solubility-diffusion approach to the pre diction of skin penetration provides
a decent "first estimate' of the flux that might be expected. Key parameters that impact on
percutaneous absorption are molecular size (or MW), lipophilicity (as expressed by log P, for
example) and a measure of solubility (most accessibly provided by aqueous solubility). The
criteria for drugs to have good oral bioavailability have been captured in the
so-called Rule of Five: specifically, MW less than 500, log P less than 5, and that the compound
is capable of donating no more than five hydrogen bonds or of accepting no more than 10 (the
latter two conditions being clearly linked to water solubility). The behaviour illustrated in Figure
13.6 fully supports a similar set of criteria for drug delivery across the skin, perhaps with even
morei stringent limits required to confer adequate permeability.