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Dermal and Transdermal Delivery

Jonathan Hadgraft
Medway Sciences, NRI, University of Greenwich, Chatham, England

I. DERMAL VERSUS TRANSDERMAL DRUG DELIVERY

There are many similarities, but also differences, in delivering medicinal agents
for dermal as opposed to transdermal use. In the former, uptake into the systemic
circulation is not required and is probably unwanted, whereas in the latter, it is
a prerequisite. In transdermal applications the medicine will be delivered to intact,
healthy skin. In contrast, in dermal applications often the barrier properties are
impaired as the formulation is being used to treat a diseased state. This adds the
complexity that high drug amounts will reach the underlying tissues during the
first applications, but as the disease state is treated and the skin heals, drug perme-
ation becomes more and more difficult and lower concentrations will be reached.
This problem is particularly pronounced in the area of wound healing, as dis-
cussed elsewhere in this book. As our knowledge of the biochemical needs for
treatment of disease advances, it should be possible to provide dermal formula-
tions with programmed delivery that address at least some of these difficulties.

II. THE CHALLENGE

It is rare that the industry produces a new chemical entity specific for dermal or
transdermal use and often, therefore, its inherent physicochemical properties are
not ideally suited to uptake into and through the skin. This means that consider-
able effort has to be expended on the appropriate design of a formulation or a
device to deliver enough of the medicine such that there is sufficient present at
its site of action. The recent advances and development of biotechnology agents

471

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 472 Hadgraft

have increased this problem as these materials are usually large and have proper-
ties that are incompatible with easy transfer through the skin.

III. TRANSDERMAL DRUG DELIVERY

In the late seventies transdermal drug delivery was heralded as a methodology

that could provide blood levels controlled by the device [1]. There was an expec-
tation that it could therefore develop into a universal strategy for the admin-
istration of medicines. For a variety of reasons these hopes have not been
fulfilled. However, this route for drug delivery remains attractive and offers many
benefits.

A. Advantages
The skin offers several advantages as a route for drug delivery [2]. In most cases,
although the skin itself controls drug input into the systemic circulation, drug
delivery can be controlled predictably, and over a long period of time, from sim-
ple matrix-type transdermal patches.
The resultant drug levels are usually constant over the lifetime of the patch,
and the peaks and troughs in plasma levels associated with conventional oral
dosing are avoided.
Programmed delivery from conventional transdermal patches is not easy
but the techniques that use active processes, such as an electric current, can de-
liver the active in a time-dependent manner [3]. This will be particularly impor-
tant where the physiological need can change with time throughout the day. In
the past there has been little recognition of the relative importance of this but
advances in chronopharmacokinetics have highlighted advantages of this ap-
proach to rational therapy [4].
Another advantage of transdermal delivery is the ability to avoid first-pass
metabolism and also to circumvent the hostile environment of the gastrointestinal
tract. How much of a problem exists is very dependent on the properties of the
medicinal agent, but it should be remembered that the skin is capable of metabo-
lizing some permeants [5].
The deeper layers of the skin are metabolically more active than the stratum
corneum. But even in this “dead” layer proteases are present that could degrade
some of the topically applied biotech agents as they diffuse through the skin
[6,7].
Finally, a further advantage of the transdermal route is that patient compli-
ance and the acceptance of transdermal delivery appear to be excellent [8].

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 Dermal and Transdermal Delivery 473

B. Problems
Since the inception of transdermal drug delivery there has only been a very
limited number of products launched onto the market. There are various reasons
for this. The skin is a very effective barrier for the permeation of most xenobiot-
ics. A typical drug that is incorporated into a dermal drug delivery system will
exhibit a bioavailability of only a few percent [9]. Therefore, the active has to
have a very high potency. Considering that topical drug delivery systems typic-
ally are applied at a few mg/cm2 and that they contain only a few percent of the
active, very little drug actually arrives at the site of action. For transdermal deliv-
ery, as a rule of thumb, the maximum daily dose that can permeate the skin is
of the order of a few milligrams. This underscores the need for high-potency
drugs.
The required high potency can also mean that the drug has a high potential
to be toxic to the skin (e.g., irritancy or a sensitization).
If the barrier function of the skin is compromised in any way, some of the
matrix-type delivery devices can deliver more of the active than necessary and
the transdermal equivalent of “dose dumping” can occur.
In all transdermal systems it is recommended that when a patch needs
changing it is applied to a new site. Elevated drug levels can be produced if a
new patch is placed immediately at the old site and there will be the possibility
of enhanced skin toxicity. The skin is a dynamic organ with its surface sloughing
off continuously as new cells are forced up from the basal layer. The dynamics
may be perturbed under the occlusive nature of a transdermal patch and the hydra-
tion levels of the stratum corneum raised. The barrier function of the skin should
be allowed to return to normal before a patch is reapplied to the site.
Finally, the manufacturing costs of the patches or devices have to be taken
into consideration. This is not a simple evaluation, as it will include consider-
ations such as the relative cost of active, quality-of-life assessments, and whether
it will reduce the amount of time a patient is hospitalized [10].

C. The Skin as a Barrier

The first of the two major problems associated with dermal delivery is the excel-
lent barrier property of the skin. This resides in the outermost layer, the stratum
corneum. This unique membrane is only some 20 µm thick but has evolved to
provide a layer that prevents us from losing excessive amounts of water and
limits the ingress of chemicals with which we come into contact. The precise
mechanisms by which drugs permeate the stratum corneum are still under debate
but there is substantial evidence that the route of permeation is a tortuous one
following the intercellular channels. The diffusional pathlength is between 300

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 474 Hadgraft

Figure 1 A schematic of the skin showing the different possible routes of penetration.

and 500 µm rather than the 20 µm suggested by the thickness of the stratum
corneum [11]. However, the tortuosity alone cannot account for the impermeabil-
ity of the skin. The intercellular channels contain a complex milieu of lipids that
are structured into ordered bilayer arrays [12]. It is the combination of the nature
of these and the tortuous route that is responsible. A diffusing drug has to cross,
sequentially, repeated bilayers and therefore encounters a series of lipophilic and
hydrophilic domains. A diagrammatic representation of the various routes of pen-
etration is shown in Figure 1.
The physicochemical properties of the permeant are therefore crucial in
dictating the overall rate of delivery [13]. A molecule that is hydrophilic in nature
will be held back by the lipophilic acyl chains of the lipids, and conversely, a
lipophilic permeant will not penetrate well through the hydrophilic head-group
regions of the lipids. Furthermore, the lipids appear to pack together very effec-
tively, creating regions in the alkyl chains close to the head groups that have a
high microviscosity. This creates multiple layers in which diffusion is compara-
tively slow.

D. Factors Affecting Skin Permeation

Given the excellent barrier property of the skin, it is not surprising that few com-
pounds permeate the skin well. Those that do tend to be relatively small and
have balanced lipid water partition behavior and good solubility in both oils and
water. For this reason compounds such as nitroglycerin and nicotine permeate
the skin well [14]. Even so, the total daily dose that can be delivered over a
reasonable surface area is only of the order of milligrams. As will be seen later
in this chapter, the physicochemical properties that dominate the success of the
technique for passive delivery are predominantly the partition coefficient and
solubility. Where current is used to drive the drug through the skin, charge and
size effects are important. It is possible to perturb these effects. If there are regions
of the permeant that allow it to adsorb onto the “pore” walls through which it

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 Dermal and Transdermal Delivery 475

is moving, the surface potential of the pore can be altered, which in turn can
affect the efficiency of delivery [15].

E. Permeation Enhancement
1. Chemical Approaches
The impermeability of the skin has led to the development of a number of en-
hancement strategies. These can be broadly divided into chemical and physical
approaches.
Chemical methods can be further subdivided. There are methods that pro-
duce the active at a very high thermodynamic activity [16]. This can involve the
loss of a solvent, which may occur as a result of its evaporation or its diffusion
into the skin. Alternatively, the polymer matrix may take up water from the skin,
which can alter the polymer’s solubility properties such that the permeant be-
comes “supersaturated.” The active is often present in the polymer matrix at as
high a loading concentration as possible and is therefore close to saturation. This
can cause stability issues, and permeation rates from devices have been observed
to change with time, especially if the expiration date has been exceeded [17].
The second “chemical” enhancement mechanism is to use solvents that
permeate into the skin and act essentially as a carrier for the active [18]. In some
reservoir-type patches there will be a solvent in the reservoir, such as ethanol,
that can codiffuse with the active facilitating its passage through the stratum
corneum.
The third mechanism is one in which a component of the formulation per-
meates into the intercellular lipids where it intercalates and disrupts their structure
[18]. This creates a region where diffusion is faster and permeation through the
stratum corneum is improved. The molecular structure of this type of enhancer
tends to possess a long alkyl chain and a polar head group; i.e., it is surfactant-
like. It is possible that this type of molecule can also have irritant properties and
it is obvious that materials have to be selected that affect the barrier function in
a reversible manner. They must not disrupt the membranes of the viable cells in
the deeper layers of the skin where they could elicit adverse effects.
It is possible that the enhancement that occurs with transdermal drug deliv-
ery systems is a result of more than one of the above factors. For example, if a
combination of enhancers is used, one that acts as a good solvent and one that
disrupts the lipid structure, a multiplicative effect can be found. There is also the
possibility that the solvents may actually abstract some of the skin lipids making
precise interpretation of the overall mechanism even more complex [19].
Different chemical entities that have been used to enhance transdermal de-
livery are shown in Table 1.

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 476 Hadgraft

Table 1 Typical Enhancers Used in Transdermal

Delivery

Active Patch Enhancer

Fentanyl Duragesic Ethanol

Nitroglycerin Nitrodisc Isopropyl palmitate
Nitrol Lauryl alcohol
Isopropyl palmitate
Estradiol Estraderm Ethanol
Climara Isopropyl myristate
Glyceryl mono-
laurate
Trial Sat Oleic acid
Propylene glycol
Vivelle Oleic acid
Menorest 1,3-Butylene glycol
Lecithin
Dipropylene glycol
Propylene glycol
Testosterone Androderm Glyceryl monooleate
Methyl laurate
Ethanol

2. Iontophoresis
With the development of biotech drugs and the need to deliver peptides and
oligonucleotides (or their analogs) it was clear that the physicochemical proper-
ties of this type of compound precluded transdermal delivery using conventional
enhancer approaches. Most peptides are charged and therefore there was a renais-
sance in iontophoresis [20]. This technique has been known for many years with
some of the pioneering studies conducted as far back as the nineteenth century.
Delivery of charged entities adds a degree of complexity to transdermal delivery.
The process is dominated by the physicochemical properties of the active, and
its charge state as it moves through the strata of the skin has to be considered.
The pH of the stratum corneum varies from the surface (pH 4–5) to physiological
pH at the viable epidermis interface. If the pKa of the permeant is between these
values, charge reversal can occur. The electrode driving the active into the skin
becomes attractive to it and therefore it will not be driven into the deeper tissues
where it is required for systemic absorption. Although predominantly considered
for the delivery of charged entities, iontophoresis can also facilitate the absorption
of uncharged hydrophilic species by the process of electro-osmosis [21].
One of the advantages of using active delivery methods is that it is possible

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 Dermal and Transdermal Delivery 477

to combine delivery with analysis of the blood levels. With the advances in nano-
technology and analytical procedures using appropriate biosensors, either the per-
meant can be measured or a biochemical marker for its activity [22]. As an exam-
ple, it is possible to use reverse iontophoresis to measure glucose levels in the
blood. However, it must be remembered that it is very difficult to deliver insulin
transdermally [23].

3. Other Physical Approaches

The developments of iontophoresis also promoted research into other physical
methods of delivering transdermally; these include electroporation and ultrasound
(or sonophoresis). The barrier function of the skin can also be physically breached
by “shooting” particles through it using high velocities or by ablating the stratum
corneum by precisely controlled laser technology. Microneedles can also be de-
veloped to pierce the skin to allow delivery to carefully controlled depths.

IV. EVALUATING DELIVERY THROUGH THE SKIN

In the development of transdermal drug delivery systems it is important to deter-

mine the effectiveness of delivery of the drug to the site of action, usually the
systemic circulation. Before in vivo work can be conducted it is important to
have some idea of expected plasma levels. To a degree this can be achieved using
in vitro skin models and using the steady-state flux data from these to estimate
the drug input into the body. If this is equated to the clearance kinetics, reasonable
predictions can be made about the expected steady-state plasma levels [24]. Ide-
ally, human skin is used for these experiments as animal skin rarely gives accurate
estimations. In general, animal skin is more permeable than human skin. In vitro
experiments can be misleading if the skin metabolizes the active during its perme-
ation to the blood supply. Guidelines for setting up methodologies for skin perme-
ation studies are readily available in the literature [25]. It is less clear how to
establish reproducible techniques for assessing transdermal delivery when inva-
sive procedures such as laser ablation or needles are involved.

V. REGULATORY ISSUES

The role of any regulatory authority is to ensure a safe and effective medicine.
In the case of transdermal drug delivery a number of issues need to be considered.
They have to take into account the drug, the excipients, and the device. The active
has to be delivered at an adequate rate through the skin and it should have no
adverse effects on the skin. It is surprising how many chemical entities have

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 478 Hadgraft

some degree of skin toxicity, irritancy, or allergenicity. This can be exacerbated

by solvents in the delivery system such as those present to solubilize the medicine
or to enhance its passage through the skin. Enhancers have already been discussed
above, but it is essential to choose agents that are toxicologically safe and do
not alter the barrier function of the skin in an irreversible way. It is possible for
solvents to leach components of the patch, such as plasticizers present in the
polymers/adhesives. The safety of these issues needs to be tested carefully. For
active delivery systems it is important to ensure that the devices are capable of
delivering the drug in a reproducible way to skin sites that may vary considerably
in permeability characteristics.
Stability is also an area of interest. Often transdermal patches have high
drug loads to minimize their surface area. The active is often close to saturation;
care needs to be taken that crystallization on storage does not influence the effec-
tiveness of the medication. In the case of iontophoresis, the drug flux will be
proportional to the current. Tests will need to show that constant current is pro-
vided over a range of conditions and after storage of the devices.

VI. THE FUTURE

The development of medicines is becoming increasingly costly. The active mate-

rials are becoming far more active and selective and need to be delivered in a
carefully controlled manner. This is possible with the types of technology de-
scribed later in this book. The relative costs of using a complex sophisticated
delivery system will become less of a problem in the future. It is possible that
some of the skin toxicity problems will be conquered using biotechnology agents
that can suppress the toxic responses. These biotechnology agents will need to
be delivered carefully and concurrently with the medicine. There are no reasons
why this should not be a successful means of accessing a far wider range of
medicines that otherwise could not be delivered using this attractive route of
administration. Noninvasive monitoring of drug levels or of other biological
markers will become routine and it should be possible to program drug delivery
accurately and only when required. The vision of the seventies, that transdermal
delivery could be universally realizable, is a possibility but requires technological
advances. The following chapters show the different ways in which transdermal
delivery could easily be advanced well into the century.

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