11
PA RT
Therapeutics
Topical Therapy
Chapter 214 :: Principles of Topical Therapy
:: Aieska De Souza & Bruce E. Strober
PRINCIPLES OF TOPICAL THERAPY
AT A GLANCE
The efficacy of a topically applied drug
depends on its inherent potency and on its
ability to penetrate skin.
Some factors that affect penetration include:
concentration of medication, thickness and
integrity of the stratum corneum, frequency
of application, occlusiveness of the vehicle,
and compliance.
Topical formulations (vehicles) are meant
to enhance the beneficial effects of the
medication.
Either the vehicle or its active ingredient(s)
may cause local toxicity.
Topical medications may induce systemic
toxicity.
Sensible topical drug therapy involves not only the
selection of an appropriate agent, but also a thought-
ful consideration of the areas of the body affected, the
state of the diseased skin, the concentration of the drug,
the type of vehicle (e.g., ointment, cream, lotion), the
method of application, and a defined duration of use
that both maximizes efficacy and minimizes adverse
side effects. Behind each of these considerations are
basic principles that help guide the practitioner toward
a rational plan of therapy.
CUTANEOUS DRUG DELIVERY
The therapeutic efficacy of a topical drug relates to
both its inherent potency and the ability of that drug to
penetrate the skin.1 In fact, many potent agents, such as
hydrocortisone and fluocinolone acetonide, are quite
poorly absorbed after topical application. Conversely,
many well-absorbed agents with weak potency have
negligible therapeutic use. Percutaneous absorption
necessitates passage through the stratum corneum,
epidermis, papillary dermis, and into the bloodstream.
(See Chapter 215 for information on the pharmacoki-
netics of topical therapy.)
In contrast to many orally administered drugs that
are nearly completely absorbed within a few hours,
topical medicines generally have a poor total absorp-
tion and a very slow rate of absorption. For example,
less than 2% of a topically applied corticosteroid such
as hydrocortisone is absorbed after a single applica-
tion left on the skin for more than 1 day. Furthermore,
peak rates of absorption are reached up to 1224 hours
after application. Fortunately, low absorption does not
necessarily translate into low efficacy. Drugs such as
topical corticosteroids are effective because of their
inherent potency and can exert clinically significant
effects in spite of low absorption. In this light, absorp-
tion represents only one of many facets of efficacy.
36 OTHER FACTORS THAT AFFECT
ABSORPTION
STRATUM CORNEUM
The stratum corneum is the rate-limiting barrier to per-
cutaneous drug delivery. This cornified layer is com-
posed of ceramides, free fatty acids, and cholesterol
in a 1:1:1 molar ratio. By weight, the stratum corneum
consists of 50% ceramides (acylceramides being the
most abundant), 35% cholesterol, and 15% free fatty
acids. The stratum corneum thickness and, thus, drug
penetration will vary depending on body site.2 Box
Section 36
214-1 lists varying body sites and their relative resis-
tance to percutaneous absorption.
There are two main routes for permeation through the
stratum corneum: (1) the transepidermal and (2) the trans-
appendageal pathways. The transappendageal, or shunt
::
route, involves the flow of molecules through the eccrine
glands and hair follicles via the associated sebaceous
Topical Therapy
glands.3 In the transepidermal route, molecules pass
between the corneocytes via the intercellular micropath-
way, or through the cytoplasm of dead keratinocytes and
intercellular lipids, defined as the transcellular micropath-
way.3,4 The intercellular pathway is considered the most
important route for cutaneous drug delivery.
An important consideration in topical therapy is
that diseased skin may have an altered (increased,
decreased, or absent) stratum corneum, thus changing
the body sites barrier function. Abraded or eczema-
tized skin presents less of a barrier. Solvents, surfac-
tants, and alcohols can denature the cornified layer
and increase penetration; as a result, topical medica-
tions with these components may enhance absorption.
Importantly, simple hydration of the stratum corneum
enhances the absorption of topically applied steroids
by four to five times.5
OCCLUSION
Occlusion via closed, airtight dressings or greasy oint-
ment bases increases the hydration and temperature
BOX 214-1 REGIONAL DIFFERENCES IN
PENETRATIONa
1. Mucous membrane
2. Scrotum
3. Eyelids
4. Face
5. Chest and back
6. Upper arms and legs
7. Lower arms and legs
8. Dorsa of hands and feet
9. Palmar and plantar skin
10. Nails
a
Most penetration with number 1 and less penetration with
increasing numbers.
2644
of the stratum corneum, limits rub-off/wash-off of the
drug and, consequently, enhances drug penetration.
Occlusion techniques range from application under an
airtight dressing such as vinyl gloves, plastic wrap, and
hydrocolloid dressings to occlusion with cotton gloves
or socks at night for treatment of hands and feet, to
application of a medication already impregnated into
an airtight dressing, as seen in flurandrenolide tape. To
derive the greatest benefit from occlusion, the patient
should hydrate the skin by immersion in water for
approximately 5 minutes before the application of a
cream or ointment. Clinically, this may correspond to
application immediately after bathing and before dry-
ing completely. With many drugs, occlusion increases
drug delivery by 10100 times the amount of drug
delivered when not occluded.6 This approach can lead
to more rapid onset times and increased efficacy when
compared with topical application alone. On the other
hand, occlusion may also lead to a more rapid appear-
ance of the drugs adverse effects, such as the ability
of topical corticosteroids to induce local skin atrophy
or suppression of the hypothalamuspituitaryadrenal
axis. Occlusion may promote infection, folliculitis, or
miliaria. In the case of topical anesthetics such as lido-
caine and prilocaine, occlusion hastens absorption into
both the skin and the bloodstream, which has led in
rare cases to cardiac complications from lidocaine tox-
icity or methemoglobinemia from prilocaine toxicity.
FREQUENCY OF APPLICATION
The frequency of drug application likely has little
effect on increasing a topical drugs overall efficacy.6,7
One daily application is enough for most topical gluco-
corticoids, for example, but the nonspecific emollient
or protective effect of creams and ointments are likely
enhanced by more frequent applications. Regardless,
increasing the contact time for a topical drug augments
its total absorption.
QUANTITY OF APPLICATION
The quantity of the drug applied likely has a negli-
gible effect on drug absorption. Obviously enough
drug must be dispensed and spread to cover the
affected areas. Further, the quantity of drug applied
might affect patient adherence to the prescribed regi-
men. For example, too much applied drug might
negatively alter the subjective experience of having a
medication on the skin, i.e., the drug may feel wrong
(greasy, caked, chalky, etc.) or is cosmetically unat-
tractive (shiny, white color). Regardless, the amount
prescribed must be adequate to treat the affected body
surface area for the necessary length of time. In this
regard, patient education is critical to prevent waste-
ful overuse or ineffective underuse of the medica-
tion. The amounts of topical medications to dispense,
based on the estimated body surface area, frequency of
application, and duration of therapy, are presented in
Table 214-1. For topical medications like sunscreens that
are used over large areas, underapplication is a problem
 TABLE 214-1
36
Suggested Amounts of Topical Medications to DispenseCream or Ointment

Estimated% Body Single Twice a Day for Three times a Day

Area Treated Surface Area Application (g) 1 Week (g) for 1 Week (g)
Face 3 1 15 20
Scalp 6 2 30 45
One hand 3 1 15 20
One arm 7 3 45 60
Anterior trunk 14 4 60 90
Posterior trunk 16 4 60 90

Chapter 214
One leg including foot 20 5 70 100
Anogenital area 1 1 15 20
Whole body 100 3040 450500 6001,000

From New York Universitys Dermatologic FormularySkin and Cancer Unit.

for most patients. However, for smaller areas, patients
may apply a large amount of an ointment, for example,
leading to complaints of greasiness or rubbing off on
clothing, which can be minimized by using an appro-
priate amount.
ADHERENCE
Topical medication adherence is a critical although
often overlooked aspect of medication efficacy. Gen-
erally, adherence to a treatment regimen is associated
with female gender, employment, being married, and
low prescription costs. Lower adherence is seen for
patients with extensive disease, and paradoxically,
disease on the face.8 One 8-week survey using elec-
tronic monitoring showed that adherence to treatment
for a twice-daily topical prescription decreased from
84% the first week to 51% during the eighth week,
with topical nonadherence being especially notable
on weekends.9 Furthermore, adherence is negatively
affected by depression, which is common in people
with chronic skin conditions and found in up to 20% of
patients with psoriasis.10
::
Principles of Topical Therapy
the duration of time between applications of the topi-
cal drug might prevent the rebound effect.
MISCELLANEOUS FACTORS
Vigorous rubbing or massaging of the drug into the
skin not only increases the surface area of skin covered,
but also increases blood supply to the area locally, aug-
menting systemic absorption. It may cause a local exfo-
liative effect that will also enhance penetration. The
presence of hair follicles on a particular body site also
enhances drug delivery, with the scalp and beard areas
presenting less of a barrier when compared with the
relatively hairless body sites. Although having a thin-
ner stratum corneum, the skin of older individuals is
poorly hydrated, with fewer hair follicles and, there-
fore, may impede drug delivery.
Reducing the particle size of the active ingredi-
ent increases its surface areavolume ratio, allowing
for a greater solubility of the drug in its vehicle. This
forms the basis for the increased absorption of certain
micronized drugs.12

TACHYPHYLAXIS. Defined as the decrease in drug CLASSIFICATION AND CLINICAL

response when used over a prolonged period of time,
tachyphylaxis is commonly observed during cortico-
steroid topical therapy. It is now thought that adher-
ence may be a contributing factor, rather than loss of
corticosteroid receptor function.5,11 Increase in adher-
ence may be achieved by asking patients to use it only
on weekends (weekend therapy) or specific days of the
week (pulse therapy).5
REBOUND EFFECT. Worsening of preexisting der-
matoses can occur in patients who have been using
topical potent corticosteroids for prolonged regimens.5
Either tapering down the corticosteroid strength to
moderate- or low-potency corticosteroids or increasing
APPLICATION OF TOPICAL
FORMULATIONS
The vehicle is the inactive part of a topical preparation
that brings a drug into contact with the skin. Before the
mid-1970s pharmaceutical companies performed lim-
ited testing of the impact of the vehicle on the potency
of a given formulation. The lack of a scientific analy-
sis of the vehicle led to the marketing of topical drugs
that, while having different concentrations of the same
active ingredient, nevertheless exhibited similar bio-
availability and potency. For example, older prepa-
rations of triamcinolone acetonide showed no real 2645
36 BOX 214-2 VEHICLE INGREDIENTS COMMONLY USED IN TOPICAL PREPARATIONS
Emulsifying agents Diisopropyl adipate
Cholesterol Glycerin
Disodium mono-oleamidosulfosuccinate 1,2,6-Hexanetriol
Emulsifying wax Isopropyl myristate
Polyoxyl 40 stearate Propylene carbonate
Polysorbates Propylene glycol
Sodium laureth sulfate Water
Sodium lauryl sulfate Thickening agents
Auxiliary emulsifying agents/emulsion stabilizers Beeswax
Carbomer Carbomer
Catearyl alcohol Petrolatum
Section 36

Cetyl alcohol Polyethylene

Glyceryl monostearate Xanthan gum
Lanolin and lanolin derivatives Emollients
Polyethylene glycol Caprylic/capric triglycerides
Stearyl alcohol Cetyl alcohol
::

Stabilizers Glycerin
Topical Therapy

Benzyl alcohol Isopropyl myristate

Butylated hydroxyanisole Isopropyl palmitate
Butylated hydroxytoluene Lanolin and lanolin derivatives
Chlorocresol Mineral oil
Citric acid Petrolatum
Edetate disodium Squalene
Glycerin Stearic acid
Parabens Stearyl alcohol
Propyl gallate Humectants
Propylene glycol Glycerin
Sodium bisulfite Propylene glycol
Sorbic acid/potassium sorbate Sorbitol solution
Solvents
Alcohol

differences in potency among the 0.025%, 0.1%, and
0.5% concentrations. By contrast, modern drug devel-
opment attempts to maximize drug bioavailability by
optimizing vehicle formulation. Additionally, during
the current drug development process, dose-response
studies determine the maximal effective concentra-
tion within a given vehicle, above which any further
increase in concentration serves no therapeutic benefit.
The vehicle of a topical formulation often has ben-
eficial nonspecific effects by possessing cooling, pro-
tective, emollient, occlusive, or astringent properties.
Rational topical therapy matches an appropriate
vehicle that contains an effective concentration of the
drug. The vehicle functions optimally when it is stable
both chemically and physically and does not inacti-
vate the drug. The vehicle also should be nonirritat-
ing, nonallergenic, cosmetically acceptable, and easy
to use. Additionally, the vehicle must release the drug
into the pharmacologically important compartment
of the skin. Finally, the patient must accept using the
vehicle or else compliance will be poor. For example,
although ointments are often pharmacodynamically
2646 more effective than creams, patients generally prefer
creams to ointments, and thus, it is no surprise that
more prescriptions are written for cream-based formu-
lations. Box 214-2 lists many commonly used ingredi-
ents in topical preparations. Many of these compounds
may serve more than one function in a particular
formulation.
POWDERS
Powders absorb moisture and decrease friction.
Because they adhere poorly to the skin, their use is
mainly limited to cosmetic and hygienic purposes.
Generally, powders are used in the intertriginous areas
and on the feet. Adverse effects of powders include
caking (especially if used on weeping skin), crusting,
irritation, and granuloma formation. Further, powders
may be inhaled by the user. Most powders contain
zinc oxide for its antiseptic and covering properties,
talc (primarily composed of magnesium silicate) for
its lubricating and drying properties, and a stearate for
improved adherence to the skin. Calamine is a popu-
lar skin-colored powder composed of 98% zinc oxide
and 1% ferric oxide and acts as an astringent to relieve
pruritus. Other drugs formulated as powders include
some over-the-counter antifungals.12
POULTICES
A poultice, also referred to as a cataplasm, is a wet solid
mass of particles, sometimes heated, that is applied to
diseased skin. Historically, poultices contained meal,
herbs, plants, and seeds. The modern poultice often
consists of porous beads of dextranomer. Poultices are
used as wound cleansers and absorptive agents in exu-
dative lesions such as decubiti and leg ulcers.12
OINTMENTS
Ointments are semisolid preparations that spread eas-
ily. They are petrolatum-based vehicles, capable of
providing occlusion, hydration, and lubrication. Drug
potency often is increased by an ointment vehicle due
to its ability to enhance permeability.5 Ointment bases
used in dermatology can be classified into five cat-
egories: (1) hydrocarbon bases, (2) absorption bases,
(3) emulsions of water-in-oil, (4) emulsions of oil-in-
water, and (5) water-soluble bases. Dermatologists
commonly refer to the hydrocarbon bases and absorp-
tion bases as ointments and the water-in-oil/oil-in-
water emulsion bases as creams. In pharmaceutical
terms, all of these preparations are ointments and are
specifically indicated for conditions affecting the gla-
brous skin (palms and soles) and lichenified areas.5
HYDROCARBON BASES. Also called oleaginous
bases, hydrocarbon bases are often referred to as emol-
lients because they prevent the evaporation of mois-
ture from the skin and are composed of a mixture of
hydrocarbons of varying molecular weights, with pet-
rolatum being the most commonly used (white petro-
latum, except for being bleached, is identical to yellow
petrolatum). They are greasy and can stain clothing.
The silicon ointments are composed of alternating oxy-
gen and silicon atoms bonded to organic groups, such
as phenyl or methyl, and are excellent skin protectants.
They can be used for diaper rash, incontinence, bed-
sores, and colostomy sites. Hydrocarbon bases are gen-
erally stable and do not contain preservatives. They
cannot absorb aqueous solutions, and thus are not
used for water-soluble drugs.12
ABSORPTION BASES. Absorption bases contain
hydrophilic substances that allow for the absorption
of water-soluble drugs. The hydrophilic (polar) com-
pounds may include lanolin and its derivatives, cho-
lesterol and its derivatives, and the partial esters of
polyhydric alcohols such as sorbitan monostearate.
These ointments are lubricating and hydrophilic, and
they can form emulsions. They function well as emol-
lients and protectants. They are greasy to apply but are
easier to remove than the hydrocarbon bases. They do
not contain water. Examples include anhydrous lano-
lin and hydrophilic petrolatum.12
WATER-IN-OIL EMULSIONS (CREAMS).
36
Emulsions are two-phase systems involving one or
more immiscible liquids dispersed in another, with the
assistance of one or more emulsifying agents. A water-
in-oil emulsion, by definition, contains less than 25%
water, with oil being the dispersion medium. The two
phases may separate unless shaken. The emulsifier (or
surfactant) is soluble in both phases and surrounds the
dispersed drops to prevent their coalescence. Exam-
ples of surfactants used include sodium lauryl sulfate,
the quaternary ammonium compounds, Spans (sor-
bitan fatty acid esters), and Tweens (polyoxyethylene
sorbitan fatty acid esters). Preservatives are frequently
added to increase the emulsions shelf life. Water-in-
oil emulsions are less greasy, spread easily on the skin,
Chapter 214
and provide a protective film of oil that remains on the
skin as an emollient, while the slow evaporation of the
water phase provides a cooling effect.8
OIL-IN-WATER EMULSIONS. An oil-in-water
::
emulsion contains greater than 31% water. In fact, the
Principles of Topical Therapy
aqueous phase may comprise up to 80% of the for-
mulation. This type of formulation is the one most
commonly chosen to deliver a dermatologic drug.
Clinically, oil-in-water emulsions spread very eas-
ily, are water washable and less greasy, and are easily
removed from the skin and clothing. Invariably, they
contain preservatives, such as the parabens, to inhibit
the growth of molds. Additionally, oil-in-water emul-
sions contain a humectant (an agent that draws mois-
ture into the skin), such as glycerin, propylene glycol,
or polyethylene glycol (PEG), to prevent the cream
from drying out. The oil phase may contain either cetyl
or stearyl alcohol (paraffin alcohols) to impart a sta-
bility and velvety smooth feel upon application to the
skin. After application, the aqueous phase evaporates,
leaving behind both a small hydrating layer of oil and
a concentrated deposit of the drug.12
WATER-SOLUBLE BASES. Water-soluble bases
consist either primarily or completely of various PEGs.
Depending on their molecular weight, PEGs are either
liquid (PEG 400) or solid (PEG 4,000). These formula-
tions are water soluble, will not decompose, and will
not support the growth of mold, and therefore require
no preservative additives. They are much less occlu-
sive than water-in-oil emulsions, nonstaining, grease-
less, and easily washed off of the skin. Without water,
this ointment poorly delivers its coformulated drug.
Therefore, it will be useful in scenarios where the prac-
titioner desires a high surface concentration and low
percutaneous absorption of the drug. For example,
topical antifungal drugs and topical antibiotics (e.g.,
mupirocin) are formulated in this type of base.
Gels are made from water-soluble bases by formulat-
ing water, propylene glycol, and/or PEGs with a cel-
lulose derivative or carbopol. A gel consists of organic
macromolecules uniformly distributed in a lattice
throughout the liquid. After application, the aqueous
or alcoholic component evaporates, and the drug is
deposited in a concentrated form. This provides a faster
release of the drug independent of its water solubility. 2647
36 Gels are popular because of their clarity and ease of both
application and removal. They are suitable for facial or
hairy areas because after application little residue is left
behind.5 Nevertheless, they lack any protective or emol-
lient properties. If they contain high concentrations of
alcohol or propylene glycol, they tend to be drying or
cause stinging. Gels require preservatives.12 Newer gel
formulations may contain the humectant glycerin, the
emollient dimethicone, or the viscoelastic polysaccha-
ride hyaluronic acid, which can mitigate some of the
associated irritation. Nonaqueous gels, with bases such
as glycerol, may be used for poorly solubilized thera-
peutics such as 5-aminolevulonic acid.13
Microspheres, or microsponges, are formulated in
an aqueous gel. Medication, in this case tretinoin, is
Section 36
combined into porous beads 1025 m in diameter.
The beads are made up of methyl methacrylate and
glycol dimethacrylate.
::
PASTES
Topical Therapy
Pastes are simply the incorporation of high concentra-
tions of powders (up to 50%) into an ointment such as a
hydrocarbon base or a water-in-oil emulsion. The pow-
der must be insoluble in the ointment. Invariably, they
are stiffer than the original ointment. The powders
commonly used are zinc oxide, starch, calcium carbon-
ate, and talc. Pastes function to localize the effect of a
drug that may be staining or irritating (i.e., anthralin).
They also function as impermeable barriers that serve
as protectants or sunblocks. Pastes are less greasy than
ointments, more drying, and less occlusive.12
LIQUIDS
Liquids can be subdivided into solutions, suspensions,
emulsions (discussed in Section Ointments), and foams.
SOLUTIONS. A solution involves the dissolution
of two or more substances into homogenous clarity.
The liquid vehicle may be aqueous, hydroalcoholic,
or nonaqueous (alcohol, oils, or propylene glycol). An
example of an aqueous solution is aluminum acetate or
Burow solution. A hydroalcoholic solution with a con-
centration of alcohol of approximately 50% is called a
tincture. A collodion is a nonaqueous solution of pyrox-
ylin in a mixture with ether and ethanol, and is applied
to the skin with a soft brush. Flexible collodions have
added castor oil and camphor and are used, for exam-
ple, to deliver 10% salicylic acid as a keratolytic agent.
Liniments are nonaqueous solutions of drugs in oil
or alcoholic solutions of soap. The base of oil or soap
facilitates application to the skin with rubbing or mas-
sage. Liniments can be used as counterirritants, astrin-
gents, antipruritics, emollients, and analgesics.12
SUSPENSIONS (LOTIONS). A suspension, or
lotion, is a two-phase system consisting of a finely
divided, insoluble drug dispersed into a liquid in a
concentration of up to 20%. Nonuniform dosing can
2648 result if the suspended particles coalesce and separate
out of a homogeneous mixture, therefore shaking of the
lotion before application may be required. Examples
include calamine lotion, steroid lotions, and emollients
containing urea or lactic acid. The applied lotion leaves
the skin feeling cooler via evaporation of the aqueous
component. Lotions are easier to apply and allow for
uniform coating of the affected area, and are often the
favorite preparation in treating children. Lotions are
more drying than ointments, and preparations with
alcohol tend to sting eczematized or abraded skin.12
Lotions are suitable for application to large surface
areas due to their ability to spread easily.5
SHAKE LOTIONS. Shake lotions are lotions to
which a powder is added to increase the surface area of
evaporation. As a result of the increased evaporation,
the application of shake lotions effectively dries and
cools wet and weeping skin. Generally, shake lotions
consist of zinc oxide, talc, calamine, glycerol, alcohol,
and water, to which specific drugs and stabilizers may
be added. Shake lotions tend to sediment, and derive
their name from the need to shake the preparation
before each use to obtain a homogeneous suspen-
sion. In addition, after water has evaporated from the
lotion, the powder component may clump together
and become abrasive. Therefore, patients should be
instructed to remove the residual particles before the
reapplication of shake lotions.12
FOAMS. Foams are triphasic liquids composed of oil,
organic solvents and water, which are kept under pres-
sure in aluminum cans. Foams are formulated with a
hydrocarbon propellant, either butane or propane.14
The foam lattice is formed when the valve is activated.
Once in contact with the skin, the lattice breaks down,
the alcohol evaporates within 30 seconds, and leaves
minimal residue in the skin. The alcohol component
of the foam is thought to act as a penetration enhancer,
momentarily altering the barrier properties of the stra-
tum corneum and increasing drug delivery through
the intercellular route.14 Previous studies have demon-
strated that foam vehicles are highly effective in deliv-
ering greater amount of active drug at an increased
rate when compared to other vehicles that tradition-
ally depend upon hydration of the intercellular spaces
within the stratum corneum.14 Foams have not been
associated with an increase in the adverse events and
compliance seams to be better with this formulation,
especially for localized conditions affecting the scalp.14
AEROSOLS
Topical aerosols may be used to deliver drugs formu-
lated as solutions, suspensions, emulsions, powders,
and semisolids. Aerosols involve formulating the drug
in a solution within a pure propellant. Usually, the
propellant is a blend of nonpolar hydrocarbons. When
applied to abraded or eczematized skin, aerosols lack
the irritation of other formulations, especially when
the quality of the skin makes direct application painful
or difficult. Furthermore, aerosols dispense a drug as a
thin layer with minimal waste, and the unused portion
cannot be contaminated. Aerosol foams, a relatively
new vehicle for drug delivery, are commonly used to
deliver corticosteroids such as betamethasone valerate
and clobetasol propionate. The foam contains the drug
within an emulsion formulated with a foaming agent
(a surfactant), a solvent system (such as water and eth-
anol), and a propellant. On application, a foam lattice
forms transiently until it is broken by both the heat of
the skin and the heat of rubbing the foam onto the skin.
Foams that are alcohol based leave very little residue
within seconds of their application. Furthermore, a
given corticosteroid formulated in a foam vehicle dem-
onstrates comparable potency when compared with
the same corticosteroid in other vehicles.1,15 Although
aerosols allow for the ease of application (especially to
hair-bearing areas) and high patient satisfaction, they
suffer from the disadvantages of being expensive and
potentially ecologically damaging.12
PENETRATION ENHANCERS
CHEMICAL ENHANCERS. A penetration enhancer
is a compound that is able to promote drug transport
through the skin barrier. Skin hydration and interaction
with the polar head group of the lipids are mechanisms
for increasing penetration. Water, alcohols (mainly etha-
nol), sulphoxides (dimethylsulphoxide/DMSO), decy-
lmethylsulphoxide/DCMS, azones (laurocapram), and
urea are some of the most commonly used compounds.4
Urea is thought to act as a penetration enhancer due to
its keratolytic properties and by increasing the water
content in the stratum corneum. Other substances that
may also act as enhancers include propylene glycol,
surfactants, fatty acids, and esters.
Vesicular systems are widely used in dermatologic
and cosmetic fields to enhance drug transport into the
skin through the transcellular and follicular pathways.
Examples of vesicular systems include liposomes
(phospholipid-based vesicles), niosomes (nonionic
surfactant vesicles), proliposomes and proniosomes,
which, respectively, are converted to liposomes and
niosomes upon hydration.16
PHYSICAL ENHANCERS. Physical methods such
as the application of a small electric current (iontopho-
resis), ultrasound energy (phono- or sonophoresis)
and the use of microneedles increase cutaneous drug
penetration.4 Microdermoabrasion is the application of
crystals (generally aluminum oxide) on the skin and
the collection of such crystals and skin debris under
vacuum suction. This technique enhances drug per-
meation and facilitates drug absorption by altering the
architecture of the stratum corneum.17
STABILIZERS
Stabilizers are nontherapeutic ingredients and include
the preservatives, antioxidants, and chelating agents.
Preservatives protect the formulation from microbial
growth. The ideal preservative is effective at a low
concentration against a broad spectrum of organisms,
nonsensitizing, odor free, color free, stable, and inex-
pensive. Unfortunately, the ideal preservative does
36
not exist. The parabens are the most frequently added
preservatives, and are active against molds, fungi, and
yeasts, but less effective against bacteria. Alternative
agents include the halogenated phenols, benzoic acid,
sodium benzoate, formaldehyde, the formaldehyde-
releasing agents, and previously, thimerosal. Most
commonly used preservatives may act as contact sen-
sitizers.
Antioxidants or preservatives prevent the drug
or vehicle from degrading via oxidation. Examples
include butylated hydroxyanisole and butylated
hydroxytoluene, used in oils and fats. Ascorbic acid,
sulfites, and sulfur-containing amino acids are used
Chapter 214
in water-soluble phases. Chelating agents, such as
sodium EDTA and citric acid, work synergistically
with antioxidants by complexing heavy metals in
aqueous phases.
::
THICKENING AGENTS
Principles of Topical Therapy
Thickening agents increase the viscosity of products
or suspend ingredients in a formulation. Examples
include bees-wax and carbomers. In addition to func-
tioning as an ointment vehicle, petrolatum may be
added to an emulsion to increase its viscosity. As in
this example, an ingredient may have a therapeutic
effect as well as acting as part of a vehicle.
TOXICITY OF TOPICAL DRUGS
LOCAL EFFECTS
Either the vehicle or its active ingredients may cause
local toxicity to the applied site. Local adverse effects
are usually minor and reversible. Major cutaneous
side effects include irritation, allergenicity, atrophy,
comedogenicity, formation of telangiectases, pruri-
tus, stinging, and pain. The mechanism of toxicity
may be as simple as the desiccation of the stratum
corneum (the removal of sebum and oils by the prep-
arations emulsifiers, for example), or involve a more
complex effect on either the cells of the epidermis or
dermis and the structures these cells comprise (i.e.,
epidermis, adnexae). Local damage may occur either
directly at, or within close proximity to, the treated
site. Further, irritation and damage may appear even
after a drug has been discontinued. Often the thera-
peutic effects of the active ingredient mask or imme-
diately treat the toxic effects of the formulation so that
acutely toxic effects are transient.18 For example, an
allergic contact dermatitis to a preservative in a topi-
cal steroid may be masked by the effects of the steroid
itself.
IRRITANT CONTACT DERMATITIS. Irritation
is driven less by drug penetration and more by drug
concentration. Thus, lowering the concentration of
an irritating drug may lower the risk of side effects.
However, a change in formulation may reduce the 2649
36 preparations efficacy. Nevertheless, often using a
less concentrated preparation over a greater period of
time is as therapeutically efficacious while minimizing
adverse effects; for example, the use of benzoyl perox-
ide 2% to 5% preparations in contrast to 10% prepara-
tions.18 In some instances, though, skin irritancy might
be central to drug efficacy. For example, although not
conclusively shown, the power of immunomodulating
agents such as imiquimod might rely on an increased
innate (inflammatory or irritant) immune response.
SUBJECTIVE OR SENSORY IRRITANT CON-
TACT DERMATITIS. Patients may detect burning
or stinging sensations without any signs of cutaneous
irritation after applying a topical medication.19,20 Sev-
Section 36
eral compounds may induce sensory irritant contact
dermatitis in predisposed individuals, such as tacroli-
mus,21 sorbic acid, propylene glycol, benzoyl peroxide
hydroxy acids, mequinol, ethanol, lactic acid, azelaic
acid, benzoic acid, and tretinoin.19,20
::
Topical Therapy
ALLERGIC CONTACT DERMATITIS. In contrast
to local irritation, contact allergy development depends
on local penetration. Allergy, of course, is driven by
antigen recognition and presentation, and thus, per-
cutaneous absorption of the drug must be at a level
that guarantees interaction with the immune effector
cells of the skin. Therefore, the contact allergenicity
of a drug relates most significantly to percutaneous
absorption. In some instances, cutaneous allergy may
be therapeutic, for example, the treatment of patients
with cutaneous T-cell lymphoma with topical nitrogen
mustard. The shift in malignant T cells from T helper
(Th) 2 to Th1-type cytokine expression is believed to
lead to apoptosis of the malignant T cells and tumor
regression.22
MALIGNANCIES. Rarely, topical therapy may
result in neoplasia. For example, the risk of second-
ary malignancies, such as keratoacanthomas, basal
and squamous cell carcinomas, lentigo maligna and
primary melanoma have been reported with the long-
term use of nitrogen mustard.22
OTHERS. The application of topical corticosteroids to
the periorbital skin has been reported both to induce
cataracts and increase in intraocular pressure.5
SYSTEMIC EFFECTS
One should be aware of the potential systemic toxici-
ties of topical drugs. Although generally safer than the
other routes of administration, topical application can
result in systemic toxicities ranging from end-organ
toxicity (central nervous system, cardiac, renal, etc.),
teratogenicity, and carcinogenicity to drug interac-
tions. These outcomes may relate to the drug itself, its
metabolites, or even a component of the vehicle.
The kinetics of topically applied drugs differ signifi-
cantly from those administered by other routes. One
important consideration is the lack of hepatic first-pass
2650 metabolism of a topical drug. This is especially rele-
vant to drugs such as salicylic acid that are relatively
innocuous when given enterally, but may manifest
central nervous system toxicity when applied topi-
cally. Additionally, acting as a reservoir, the stratum
corneum may store large amounts of a topical drug,
and a subsequently long diffusion period of many
days may ensue, delivering a steady supply of drug to
the systemic circulation.
Percutaneous toxicity directly relates to percutaneous
absorption. Therefore, factors that modulate absorption
also influence toxicity: the concentration of the drug,
its vehicle, the use of occlusion, the body site and area
treated, frequency of use, the duration of therapy, and
the nature of the diseased skin. For example, 6% sali-
cylic acid in Eucerin used for 11 days in the treatment
of psoriasis has been associated with epistaxis and deaf-
ness, while the same concentration of salicylic acid in
hydrophilic cream under occlusion for 4 days for the
treatment of dermatitis (involving the same amount of
body surface area) may result in hallucination.18 Simi-
lar to their effect on systemically administered drugs,
renal and hepatic diseases, by influencing drug clear-
ance, also contribute to an increased potential for drug
toxicity.
Young children have a greater surface areavolume
ratio, and thus are at greater risk of percutaneous
toxicity than adults. This phenomenon necessitates
alternative drugs, formulations, and dosing sched-
ules for children with widespread cutaneous disease.
Patients with acute flares of cutaneous illness (for
example, psoriasis or atopic dermatitis) may require
the treatment of a larger body surface area in a rela-
tively abbreviated period of time. These patients may
also increase their dose and frequency of application
during such flares. Coupled with the likely increased
percutaneous absorption of the diseased skin, these
scenarios exponentially increase the possibility of
systemic toxicity, and patient education is vital to pre-
vent adverse outcomes.12 To reduce the risk of toxicity
from topical drugs and to increase treatment efficacy,
many practitioners will rationally advocate systemic
approaches (i.e., methotrexate, cyclosporine, inject-
able or infusable biologics, or ultraviolet radiother-
apy) to patients whose disease involves an extensive
body surface area.
TYPE I HYPERSENSITIVITY REACTIONS.
In rare instances, anaphylactic shock can be precipi-
tated by topical drug application. For example, when
applied to diseased or abraded skin, bacitracin oint-
ment can induce an immediate-type (type I) hyper-
sensitivity reaction in susceptible individuals. Such
reactions might be represented by a local and then
subsequently generalized pruritus leading to cardio-
pulmonary arrest.12 Nonimmunologic acute toxicity
results from substances such as pesticides and chemi-
cal warfare agents that rapidly diffuse through the skin
and reach target organs.
MALIGNANCIES. Systemic calcineurin inhibitors
have been associated with increased risk of lym-
phoma and nonmelanoma skin cancer. But the topi-
cal use of such drugs does not appear to be related
to cancer.23,24 In fact, the risk for lymphoma with the
use of topical calcineurin inhibitors was assessed in
animal studies that demonstrated an increased risk
only when blood levels were 30 times higher than
those measured after topical application in human
subjects.24 Numerous studies have demonstrated the
efficacy and safety of topical calcineurin inhibitors.
More than 50 cases of lymphoma have been reported,
although the topical calcineurin inhibitor use may be
coincidental. Nevertheless, there is a clear need for
additional follow-up information to establish the
long-term safety profile of this class of drugs. Two
long-term trials currently being conducted might
help address these concerns.24
ENDOCRINE SYSTEM. Topical corticosteroids can
rarely cause hypothalamicpituitaryadrenal axis sup-
pression, growth retardation, hyperglycemia, iatrogenic
Cushing syndrome and femoral head osteonecro-
sis.5 Factors that enhance drug absorption are directly
related to an increase in these side effects; therefore,
carefully monitoring must be ensured when prescribing
usage in large surfaces areas, prolonged use of potent
corticosteroids, usage under occlusion, high potency
corticosteroids, or use for the pediatric age group (due
to their increased surface to body mass ratio).
Transdermal drug delivery, in contrast to topical
drug delivery, uses topical application of therapeu-
tic drug as a delivery system for systemic therapy.
Transdermal patches have been approved by the US
Food and Drug Administration since 1981 (scopol-
amine being the first) for the delivery of 13 different
medications, with more seeking approval. The most
commonly used patches are for nitroglycerin and
fentanyl. Advantages of this approach include con-
trolled release, a steady blood-level profile with zero-
order kinetics, lack of a plasma peak, and, in some
cases, improved patient compliance. These patches
remain on the skin for 12 hours to 1 week. A patch
consists of a plastic backing, a reservoir of medica-
tion, either a rate-controlling membrane or a poly-
mer matrix system for controlled diffusion, followed
by an adhesive facing the skin. The most common
adhesives used are acrylates, silicones, and poly-
isobutylenes. These patches have been tested and
36
are approved for use on the thighs, buttocks, lower
abdomen, upper arms, and chest; application to
other sites can lead to either sub- or supratherapeutic
blood levels. Adverse effects of patches include local
irritation and allergic contact dermatitis to either an
adhesive or to the drug itself and may necessitate
discontinuation. Topical therapies are a mainstay of
treatment for the dermatologist. An understanding
of the interactions between a drugs concentration,
penetration, availability, and treatment of diseased
skin allows physicians to maximize both efficacy
and tolerability of topical therapy. An understand-
ing of local and systemic toxicities allows selection of
Chapter 214
appropriate, safe therapy for patients and minimizes
unwanted effects. Appropriate selection of topical
agents and patient education on proper use can opti-
mize therapeutic outcomes.
::
KEY REFERENCES
Principles of Topical Therapy
Full reference list available at www.DIGM8.com
DVD contains references and additional content
2. Feldman RJ, Maibach HI: Regional variation in percutane-
ous penetration of 14C cortisol in man. J Invest Dermatol
48:181, 1967
4. Trommer H, Neubert RH: Overcoming the stratum cor-
neum: The modulation of skin penetration. Skin Pharmacol
Physiol 19:106-121, 2006
7. Eaglstein WH, Farzad A, Capland L: Topical corticoste-
roid therapy: Efficacy of frequent application. Arch Der-
matol 110:955, 1974
8. Zaghloul SS, Goodfield MJ: Objective assessment of com-
pliance with psoriasis treatment. Arch Dermatol 140:408,
2004
12. Ricciatti-Sibbald D, Sibbald RG: Dermatologic vehicles.
Clin Dermatol 7:11, 1989
14. Huang X et al: A novel foam vehicle for delivery of topical
corticosteroids. J Am Acad Dermatol 53:S26-S38, 2005
23. Bashir SJ, Maibach HI: Topical drug testing. In: Com-
prehensive Dermatologic Drug Therapy, edited by Wol-
verton SE. Philadelphia, W.B. Saunders Company,
2001, p. 911
2651
36 Chapter 215 :: Pharmacokinetics and Topical
Applications of Drugs
:: Hans Schaefer, Thomas E. Redelmeier,
Gerhard J. Nohynek, & Jrgen Lademann
PHARMACOKINETICS AT A GLANCE
Compounds applied topically to the
skin surface migrate along concentration
gradients.
Section 36
The drug or its formulation may affect the
skin barrier, resulting in time-dependent
changes of the barrier function.
::
There are significant regional variations in
Topical Therapy
the barrier properties of the skin.
Formulations differ in their physicochemical
propertiesthis influences the kinetics of
release and/or absorption and the onset,
duration, and extent of a biologic response.
The primary compartment that limits the
percutaneous absorption of compounds is
the stratum corneum.
Diffusion within the viable tissue, as well as
metabolism and resorption, also influence
the bioavailability of compounds in specific
skin compartments.
Metabolic activity is a primary consideration
in the design of prodrugs and may influence
the bioavailability of drugs delivered via
dermatologic or transdermal formulations.
Pharmacokinetics related to topical applications of
drugs describes the time-dependent drug concentra-
tion following the application of the drug to the skin
surface, its subsequent passage through the skin bar-
rier into the underlying skin layers, and its distribution
into the systemic circulation. The subject continues to
hold the attention of research scientists and clinicians
alike because of its relevance to dermatologic ther-
apy and the possibility of topical application of cur-
rent systemic medication that cannot be administered
orally, such as peptides or proteins. However, this is an
inherently complex subject, despite the advent of new
insights into the principal factors that govern diffusion
of a drug into and across the skin.
The major difficulty in developing an accurate
description of the percutaneous absorption of a drug
is related to the size of the compartments. A topical
application of a cream or ointment is generally spread
2652 to a thickness of not greater than 10 m. The thick-
ness of the stratum corneum is also approximately
10 m, whereas the viable epidermis, dermis, and, to a
greater extent, the systemic compartment, represent a
large sink in which absorbed drugs undergo dilution
to levels that often remain undetectable to all but the
most sensitive techniques. The determination of the
time-dependent changes in the concentration of a drug
in individual compartments is technically challenging.
After topical application of a drug formulation, several
parameters can affect this process (Box 215-1).
DIFFUSION
LAWS OF DIFFUSION
Compounds applied topically to the skin surface
migrate along concentration gradients according to
well-described laws governing diffusion of solutes in
solutions and/or their diffusion across membranes.
For a detailed discussion of relevant equations, read-
ers are referred to several comprehensive reviews.14
FICKS LAWS
Diffusion of uncharged compounds across a mem-
brane or any homogeneous barrier is described by
Ficks first and second laws. The first law
J = D (C/)
BOX 215-1 PARAMETERS THAT
AFFECT DRUG AMOUNTS IN SKIN
COMPARTMENTS
Formulations may undergo drastic changes in com-
position and structure.
Drug or formulation may affect the skin barrier,
resulting in time-dependent changes of the barrier
function.
Skin barrier may be affected by the type and pro-
gression of a disease.
Regional variations in the barrier properties of the
skin.
Skin may respond to topical drug, enhancing or
retarding percutaneous absorption.
Metabolic capacity of skin may lead to exposure of
skin or systemically to both parent drug and phar-
macologically active metabolite(s).
states that the steady-state flux of a compound (J =
moles/cm/s) per unit path length (, cm) is propor-
tional to the concentration gradient (C) and the diffu-
sion coefficient (D, cm2/s). The negative sign indicates
that the net flux is in the direction of the lower concen-
tration. This equation applies to diffusion-mediated
processes in isotropic solutions under steady-state
conditions. Ficks second law predicts the flux of com-
pounds under nonsteady-state conditions. Diffusion
is an effective transport mechanism over very short
distances, but not over long ones. The relationship
between the time (t) it takes for a molecule to migrate
along a path length (x) and its diffusion coefficient is
governed by the equation:
a water molecule would migrate over a 10-m path
(the equivalent of the width of the stratum corneum)
36
in 0.4 ms. However, because diffusion depends upon
the square of the distance, longer distances are not effi-
ciently covered; a 100-m path would take 40 ms.
THREE-COMPARTMENT MODEL
Although pharmacokinetic analysis of topical prepara-
tions may require the description of a relatively large
number of compartments, this discussion is confined to
the three outlined in Figure 215-1: (1) the skin surface,
(2) the stratum corneum, and (3) the viable tissue. The
formulation itself forms a reservoir, from which the

t = x2/2D.
For example, the diffusion coefficient for water in an
aqueous solution is: 2.5 105 cm2/s, suggesting that
Chapter 215
compound must be released; in order to undergo per-
cutaneous absorption, the compound then must pen-
etrate the stratum corneum, diffuse into and through

::
The three compartments of the skin

Pharmacokinetics and Topical Applications of Drugs

ne ion n
Pe eat sio

n
rm iffu

tio
tra
Pe t d
un
Sh

Vehicle
reservoir Reservoir function Barrier function
Str. corneum Binding
~20 m
Binding
Viable
epidermis
~
100 m

Resorption Resorption

Cutaneous
Lymph vasculature
vessels

Binding
~
1200 m
Permeation

Hypodermis

Figure 215-1 Diagrammatic representation of three compartments of the skin: surface, stratum (Str.) corneum, and viable
tissues. After surface applications, evaporation and structural/compositional alterations in the applied formulation may
play an important role in determining the bioavailability of drugs. The stratum corneum, the outermost layer, plays the
most significant role in determining the diffusion of compounds into the body. After absorption, compounds may bind or
diffuse within the viable tissues, or become resorbed by the cutaneous vasculature. 2653
36 TABLE 215-1
Compartments Encountered by Substances Undergoing Percutaneous Absorption: General Relevance
of Processes to Bioavailability

General Relevance to
Compartment Processes Bioavailability
Vehicle Diffusion ++
Thermodynamic activity ++
Evaporation +
Precipitation
Stratum corneum Reservoir function +++
Diffusion +++
Binding +
Section 36

Metabolism
Epidermis Diffusion

Cutaneous vasculature Metabolism

::

Binding ++
Resorption +
Topical Therapy

Underlying tissues including dermis Diffusion

Metabolism
Binding

= although theoretically possible, this process is probably not of general relevance; = this process is of direct relevance, but only in a
restricted number of cases; + = the process is in general relevant, but not as important as ++ or +++.

the viable epidermis into the dermis, and, finally, gain
access to the systemic compartment through the vas-
cular system. In addition, the substance may diffuse
through the dermal and hypodermal layers to reach
underlying tissues. As summarized in Table 215-1,
within each compartment, the compound may diffuse
down along its concentration gradient, bind to specific
components, or be metabolized. The size or character-
istics of each compartment may alter with time, and
the factors determining diffusion within each compart-
ment may be affected by disease state as well as the
nature or the pharmacologic/biologic activity of the
drug or its excipients.
THE SKIN SURFACE
SURFACE APPLICATIONS OF FORMULA-
TIONS. Formulations differ in their physicochemical
properties, and, as discussed in Section Formula-
tions, this influences the kinetics of release and/or
absorption. However, the principal consideration is
that topically applied drug products represent a physi-
cally small compartment, which limits the amount
of compound that can be applied to the skin surface.
When a patient applies a dermatologic preparation,
the layer of a formulation covering the skin is very thin
(approximately 0.52.0 mg/cm2). Thicker layers are felt
as unpleasant and are consciously or subconsciously
rubbed off or spread to larger surfaces. This restricts
the amount of an active compound that can effectively
come in contact with the skin surface to approximately
2654 520 g/cm2 for a 1% (wt/wt) topical formulation.
However, even after being rubbed in, formulations
do not remain homogeneous over the time course of
penetration. For example, topical applications contain-
ing water, alcohol, or similar solvents undergo rapid
evaporation.5 This phenomenon is readily recognized
by patients as a cooling sensation. The evaporation
results in rapidly increasing concentrations of non-
volatile substances on the skin surface, which may
result in the formation of supersaturated solutions
or, alternatively, precipitation of active ingredients.
Formulations may also mix with skin-surface lipids
or undergo time-dependent changes in their compo-
sition as excipients and drugs undergo absorption.
Altogether, these considerations suggest that dramatic
changes in the composition and structure of formula-
tions may occur following surface application, all of
which may determine the subsequent bioavailability
of active ingredients.
RESERVOIR. The reservoir function was first
described by Vickers,6 who observed that simple occlu-
sion leads to the renewed onset of a glucocorticoid-
mediated vasoconstriction several hours after it had
declined. He interpreted this effect as renewed libera-
tion of the glucocorticoid from a reservoir stored in
the upper skin layers.
We define as reservoir the amount of an active ingre-
dient that is still in contact with the nonvolatile con-
stituents of its formulation after the latter had been
massaged into the skin surface. The compound has
not yet penetrated, but it cannot be removed by sim-
ple rubbing or contact with clothing or other tissues.
The reservoir thus adheres to the skin surface and
resides in the wrinkles and the upper layers of the
stratum corneum. Reservoirs on eczematous skin
may become even more prominent because of the
scaliness of the skin. Recently, we discovered that the
upper volume of the follicular channels serves also as
a reservoir, which may result in a relative increase in
absorption through appendages. In-vivo laser scan-
ning microscopy measurements found that the hair
follicles represent an efficient reservoir for topically
applied formulations, which can be compared with
the reservoir of the stratum corneum on several body
sites.7,8 This phenomenon may be increased in formu-
lations that contain particles or precipitates, given the
evidence that appropriately sized particles can rapidly
penetrate along the shafts of hair follicles to a depth of
up to 100500 m.912
The optimum size of the particles for penetration
into hair follicles is between 300 and 600 nm, which
corresponds to the cuticular structure of the hairs.13,14 It
was assumed that the rigid hair shaft acts as a geared
pump, because this effect could only be observed in
the case of moving hairs.14 The follicular reservoir may
result in a relative increase in the absorption of topi-
cally applied substances. No evidence has been found
that topically applied substances penetrate efficiently
into the sweat glands. This may be due to sweat out-
flow or other, unknown reasons.
FORMULATIONS. Formulations can be differen-
tiated on the basis of whether they are designed to
remain on the skin surface (sunscreen products and
cosmetics), to be delivered to compartments in the
skin (topical formulations), or to migrate across the
skin into the central compartment (transdermal
formulations).
Formulations may affect the kinetics and the degree
of percutaneous absorption and, subsequently, the
onset, duration, and extent of a biologic response. In
the context of percutaneous absorption, there are sev-
eral different parameters that should be considered
when selecting a formulation1,15: the thermodynamic
activity of the active ingredient16; the amount of com-
pound that can be incorporated into the formulation17;
the stability of the formulation on the skin surface (e.g.,
emulsions may break easily)18; the partition coefficient
of the active ingredient between the vehicle and the
stratum corneum19; and the enhancer activity.
In general, percutaneous absorption is proportional
to the thermodynamic activity of the compound. Thus,
the greatest flux is observed at the active ingredients
maximum solubility in a vehicle. Vehicles that are very
good solvents should be avoided because they may
retain the active ingredient on the skin surface.
LIPOSOMES AS TRANSDERMAL DELIVERY
SYSTEMS. Liposomes are microscopic spheres
comprising a bilayer that encloses an inner aqueous
core. A wide variety of cosmetics contain liposomes.
Liposome-based formulations have proved to be safe,
cosmetically attractive, and well accepted. There is
considerable evidence that, at least for some prepa-
rations, application of liposomes is mildly occlusive
and improves the hydration level of the stratum cor-
neum. Interest in the use of liposomes to enhance the
36
delivery of drugs across the skin has been spurred by
several observations in animal models: liposome for-
mulations were believed to enhance the penetration of
compounds across the skin or to optimize the retention
of bioactive compounds in target tissues.20 However,
these early studies, which relied largely on animal
models, were followed by relatively few in-vivo stud-
ies for humans17 conducted under standard conditions.
The action mechanism of liposomes is based on a
partly damaged liquid layer of the stratum corneum,
so that the liposomes can penetrate efficiently into the
skin barrier. Deep in the stratum corneum, the lipo-
somes get damaged and release their drug, which has
Chapter 215
to pass through the last cell layers of the stratum cor-
neum by itself to reach the living cells.21
There is no clear evidence that liposomes can pass
the skin barrier as intact structures, but intact lipo-
somes can penetrate along the hair shaft and this route
may be appropriate for delivery of bioactive com-
::
pounds into sebaceous glands or hair follicles.7,8 Rigid
Pharmacokinetics and Topical Applications of Drugs
liposomes penetrate better into the hair follicles than
flexible liposomes, which supports the assumption
that the moving hairs act as a geared pump.21
THE SKIN BARRIER
(See Chapter 47.)
The primary compartment that limits the percutane-
ous absorption of compounds is the stratum corneum.
This thin (1020 m) layer effectively surrounds the
body and represents a highly differentiated structure
that determines the diffusion of compounds across
the skin. The physical description of the stratum cor-
neum is well documented,22 and it can be accurately
described as bricks of bundled, water-insoluble pro-
teins, embedded in a mortar of intercellular lipid.
The stratum corneum is a highly organized, differ-
entiated structure. To participate fully in forming an
effective barrier to diffusion, the biogenesis of the cor-
neocytes as well as the synthesis and processing of the
intercellular lipid must proceed in an orderly manner.
Disruption in the kinetics of skin barrier formation by
accelerating the division of the keratinocytes in the
underlying layers will lead to a disruption in the bar-
rier properties of the skin.23 Thus, the concept of dead
or dying skin forming a passive barrier to diffusion is
now replaced by a model of the stratum corneum as a
highly differentiated structure with unique properties
that are particularly suited for its role in forming the
skin barrier (see Chapter 47).24
APPENDAGES. A variety of appendages pene-
trate the stratum corneum and epidermis, facilitating
thermal control and providing a protective covering.
Appendages are potential sites of discontinuity in the
integrity of the skin barrier. The density of the hair
follicles varies on different body sites. Hair follicles
represent a reservoir that may store topically applied
substances. A detailed analysis of the reservoir of
the hair follicles showed that the highest reservoir is 2655
36 on the scalp, followed by the forehead and the calf.25
On the forehead, there are a high number of small
follicles, while the calf contains fewer but larger hair
follicles. These reservoirs are comparable to the res-
ervoir of the stratum corneum on these body sites.
The percentage of the hair follicles on the total skin
surface varies between 0.2% and 1.3%, depending on
the body site.25 Differences in the follicular penetra-
tion were observed in different ethnic groups.26 Hair
follicles appear to present an important pathway for
percutaneous absorption in nondiseased skin.11,12 This
can be explained by the fact that only the upper wall
of the follicular apparatus (the acroinfundibulum) is
protected by a coherent stratum corneum, whereas in
the lower part (infrainfundibulum), the corneocytes
Section 36
appear undifferentiated, and protection is incomplete,
if not absent. Even solid particles may enter deep into
the follicular orifice,9,10,22 a phenomenon that lends
itself to the concept of follicular targeting of drugs.22
It follows that in relationship to the integral protec-
::
tion against the passage of xenobiotics in general, and
Topical Therapy
drugs specifically, the barrier function of the inter-
follicular stratum corneum is even more potent than
previously believed, whereas more research is needed
relative to the follicular pathway. Recent investigations
hint to the presence of active follicles (open to penetra-
tion) and passive ones.11
PENETRATION PATHWAYS. In principle, three
penetration pathways are possible: (1) the intercel-
lular penetration, inside the lipid layers around the
corneocytes; (2) the follicular penetration; and (3) the
intracellular penetration. Although in the past,
the transcorneal penetration was assumed to be the
only penetration pathway, recent investigations, as
cited above in Appendages, have demonstrated that
penetration via the hair follicles should be taken into
consideration.2527
Up to the present time, no evidence is available that
topically applied substances pass the skin barriers by
means of the intracellular route.
Pathways across the Stratum Corneum.
Several studies have directly visualized penetra-
tion pathways across the stratum corneum by elec-
tron microscopy. For example, osmium vapor can be
used to precipitate n-butanol that has penetrated the
stratum corneum.28 After a brief (560 s) exposure of
murine or human stratum corneum, the alcohol was
found to be enriched in the intercellular spaces (three-
fold), although significant levels were also found in
the corneocytes. By using a different approach that
involved rapid freezing, water, ethanol, and choles-
terol were also found preferentially concentrated in the
intercellular lipid spaces.29 Similarly, the penetration of
mercury chloride through the intercellular lipid can be
detected following precipitation with ammonium sul-
fide vapor.30
However, in most of these investigations, there was
also significant localization of compounds in the cor-
neocytes, more prevalent in the upper layers (stratum
disjunctum). Thus, corneocytes undergoing desqua-
2656 mation appear to be relatively permeable, even to
rather bulky ions such as mercury. There is additional
evidence that other compounds can and do penetrate
corneocytes. It is well established, for example, that
occlusion or immersion of skin in a bath leads to swell-
ing of the corneocytes, consistent with the entry of
water. Other compounds have also been localized in
corneocytes, such as the anionic surfactants that are
bound to keratins. Low-molecular-weight moisturiz-
ers such as glycerol are likely to partition into the cor-
neocytes and alter their water-binding capacity. Thus,
the penetration of compounds into corneocytes can-
not be excluded from considerations of percutaneous
absorption pathways. The relevance of this step relates
to whether it is rate determining, i.e., whether the dif-
fusion of compounds within the intercellular lipid is
restricted by the corneocytes.
Pathways across the Hair Follicles. Using the
method of differential strippinga combination of
tape stripping with cyanoacrylate surface biopsies
the amount of formulation stored in the hair follicles
can be quantified.31 It was found that nanoparticles
were stored 10 times longer in the hair follicles than in
the stratum corneum.14 It should be noted that when
topically applied substances penetrate into the hair
follicles, they do not necessarily penetrate through the
skin barrier into the living tissue, because the hair fol-
licles also have barrier properties.
On the other hand, the particles can be used as effi-
cient carrier systems for drug delivery into the hair fol-
licles. The hair follicles represent an important target
structure because they are surrounded by a close net-
work of blood capillaries. Additionally, they are host-
ing the stem and dendritic cells which are important
for regenerative medicine and monomodulation.
For optimal action, the drug should be released from
the particles after having penetrated deep into the hair
follicles. The pharmacokinetics is determined mainly
by the process of the drug release from the particles in
this case.61
In the past, there have been several attempts to
detect follicular penetration.3234 Experiments were
performed on animal and human skin, with differ-
ent densities of the hair follicles. Unfortunately, in all
cases, the properties of the stratum corneum had also
changed.
The analysis of the follicular penetration became
possible after the development of a method that arti-
ficially closes the hair follicles in vivo.35 Using this
method, it was demonstrated that the small molecules,
such as caffeine, may penetrate through the skin bar-
rier not only by the transcorneal, but also by the fol-
licular routes.36
INTER- AND INTRAINDIVIDUAL VARIATION
IN SKIN BARRIER FUNCTION. Finally, it is worth-
while to consider the level of inter- and intraindividual
variation in skin barrier activity, including that of fol-
licles. The most accurate and reproducible measure-
ment of skin barrier activity is transepidermal water
loss.37 The extent of variation of this parameter for the
same individual is estimated to be 8% by site and 21%
according to the day of measurement. The variations
between individuals are reported to be somewhat
larger, ranging from 35%48%.38 There appear to be no
significant gender- or ethnic-dependent differences in
skin barrier activity. The skin barrier activity of pre-
mature babies39 is markedly impaired, although skin
barrier function appears normal for full-term infants.
There seems to be no significant alteration in skin bar-
rier activity as a function of age. Differences in skin bar-
rier activity among different sites have been observed;
barrier function can be ranked as arm abdomen >
postauricular > forehead.37
VIABLE TISSUE
Although the primary barrier to percutaneous absorp-
tion lies within the stratum corneum, diffusion within
the viable tissue, as well as metabolism and resorption,
also influence the bioavailability of compounds in spe-
cific skin compartments. These processes are interre-
lated, and factors that increase the rate of one of these
processes inevitably influence the others. Because the
development of dermatologic formulations is often
focused on targeted delivery to living tissues, the
manipulation of these processes offers a clear-cut ratio-
nale for increasing the therapeutic efficacy of dermato-
logic drugs.
The passage of compounds from the stratum cor-
neum into the viable epidermis results in a substantial
dilution. This is not only the relatively larger volume
of the epidermis as compared with that of the stratum
corneum, but also the lower resistance to diffusion
within viable tissues, approximately corresponding to
that of an aqueous protein gel.38 Drug concentrations of
104106 M may be attained in the epidermis and dermis to the size of the compartment. Thus, although the
for substances that permeate readily. Although the actual
concentration gradient of a compound is affected both
by the physicochemical properties of the compounds as
well as by the duration of application, a concentration
gradient is present at all times. In other words, strategies
to enhance percutaneous absorption generally result in a
relatively uniform and parallel increase in the concentra-
tion of compounds in all compartments.
SKIN METABOLISM
The skin contains a wide range of enzymatic activi-
ties, including phase I oxidative, reductive, hydrolytic,
and phase II conjugation reactions, as well as a full
complement of drug-metabolizing enzymes.40,62 Meta-
bolic activity is a primary consideration in the design
of prodrugs and may influence the bioavailability of
drugs delivered via dermatologic or transdermal for-
mulations. Alterations in skin metabolism have been
implicated in a range of diseases, including hirsutism
and acne, and they may be relevant to the risk of topi-
cal exposure to carcinogens. Metabolic processing of
antigens by Langerhans cells is involved in the presen-
tation of allergens to the immune system. Thus, metab-
olism in skin compartments plays a significant role
in determining the fate of a topically applied active
compound.
Significant cutaneous metabolism has been demon-
strated for a wide variety of compounds of differing
36
physicochemical properties, including the steroid hor-
mones estrone, estradiol, and estriol, as well as gluco-
corticoids, prostaglandins, retinoids, benzoyl peroxide,
aldrin, anthralin, 5-fluorouracil, nitroglycerin, theoph-
ylline, and propranolol.27 Recently, it has been shown
that arylamine-type hair dye ingredients are also sub-
ject to metabolism in human and animal skin, resulting
in N-acetylated metabolites.4143 The enzyme responsi-
ble is believed to be epidermal N-acetyltransferase-1.41
For example, cutaneous metabolism reduces the sys-
temic bioavailability of nitroglycerin administered in
a transdermal drug formulation in rhesus monkeys by
16%21% and hydrolyzes virtually 100% of a salicylate
Chapter 215
diester.44 It is convenient to classify metabolic reactions
in terms of their cofactor dependence.63 Processes that
require cofactors are likely to be energy dependent,
and these are located within viable tissues. Among the
best-studied examples are the interconversion of ste-
roids (e.g., estrone and estradiol), and the oxidation of
::
polycyclic aromatic hydrocarbons with mixed-func-
Pharmacokinetics and Topical Applications of Drugs
tion mono-oxygenases. In contrast, cofactor-indepen-
dent processes involve catabolism and may be located
outside of viable tissues, i.e., in the transition region
between the stratum corneum and stratum granulo-
sum. The best characterized of these involve hydro-
lytic reactions such as nonspecific ester hydrolysis.
Metabolic activity is found in (1) skin-surface micro-
organisms, (2) appendages, (3) the stratum corneum,
(4) the viable epidermis, and (5) the dermis. In con-
sidering the site of the most significant metabolism,
one has to take into account the relevant enzymes and
their specific activity, as well as their capacity relative
level of many enzymes is highest in the epidermis,
the relatively large size of the dermal compartment
may result in a significant role in the metabolism of
topically applied substances. A further consideration
is that enzymes involved in cutaneous metabolism
may be induced upon exposure to xenobiotics. This
has been well described for various mixed-function
monooxygenases.45 Finally, the qualitative and quan-
titative extrapolation of results from animal models to
humans is uncertain, owing to the significant species
differences in the metabolism of compounds.
Percutaneous absorption and metabolism of com-
pounds can be viewed as two events in kinetic com-
petition with each other.46 Generally, compounds that
remain in the skin for longer periods of time undergo
significantly more metabolism. Furthermore, the type
of metabolism of a substance may also be influenced
by the nature of its formulation, as illustrated by inves-
tigations on the metabolism of several transdermal
nitroglycerin formulations.47 The inclusion of enhanc-
ers in the formulation not only increased the bioavail-
ability of the nitroglycerin but also the ratio of one
metabolic compound (1,2-glyceryl dinitrate) in rela-
tion to another (1,3-glyceryl dinitrate). This may limit
the suitability of in-vitro experiments for estimating
the significance of cutaneous metabolism because the
vasculature is not functional in vitro. It further empha-
sizes that it is difficult to extrapolate quantitatively the 2657
36 level of metabolism obtained for different formula-
tions. This has significant implications for the estima-
tion of bioequivalence.
However, despite the variety of skin-associated
metabolic processes, the extent of metabolism is nor-
mally modest, i.e., 2%5% of the absorbed compounds,
although for N-acetylation of arylamines, metabolism
may be quantitative.43 Metabolism is limited not only
by the relatively short period of time that a compound
spends in the viable layers of the skin, but also by the
overall low level of enzyme activity. Thus, under many
circumstances, the available enzymes are saturated
by the level of compound undergoing percutaneous
absorption.40
Section 36
RESORPTION
Resorption, defined as the uptake of compounds by
the cutaneous microvasculature, is directly related to
::
the surface area of the exchanging capillaries as well
Topical Therapy
as their blood flow. Total blood flow to the skin may
vary up to 100-fold, a process primarily regulated by
vascular shunts, but also by recruitment of new capil-
lary beds. It is estimated that, under resting conditions,
only 40% of the blood flow passes via exchanging
capillaries capable of acting as a sink for absorbed
compounds. However, this value demonstrates con-
siderable variation between body sites, individuals,
and species and is influenced by disease states and
environmental conditions. In particular, changes in
temperature and humidity as well as the presence of
vasoactive compounds may directly influence skin
blood flow.48
For most compounds and situations, resorption does
not limit the delivery of compounds to the central com-
partment after topical applications. This is a result of the
relatively high resistance to diffusion within the stratum
corneum as compared with uptake by the vasculature.
However, for compounds or situations in which diffu-
sion across the stratum corneum is rapid, resorption
limits the maximum rate of absorption.48 The evidence
that resorption can limit the delivery of compounds to
the central compartment comes primarily from studies
that examined the influence of blood flow on this pro-
cess. The percutaneous absorption of methyl salicylate
is increased by elevated ambient temperature or strenu-
ous exercise, an observation consistent with increased
resorption as a result of cutaneous blood flow.49 More-
over, intravenously administered nicotine (a vaso-
constrictor) reduces the percutaneous absorption of
topically applied nicotine.50 Regional differences in the
percutaneous absorption of piroxicam, a nonsteroidal
anti-inflammatory agent, are dependent upon the local
vasculature rather than upon skin barrier function.51
Perhaps the most convincing evidence that resorption
can limit delivery to the vasculature comes from in-vitro
studies on the perfused porcine skin flap.52
2658
An additional consideration is that the rate of resorp-
tion may indirectly influence the diffusion of compounds
to the underlying musculature, tissues, and joints.53 The
principle of locally enhanced delivery to underlying
musculature has been demonstrated for piroxicam as
well as several local anesthetic preparations.54
INFLUENCE OF PATHOLOGIC
PROCESSES ON SKIN BARRIER
FUNCTION
Reduced skin barrier function has been observed
in a number of pathologic conditions, including the
ichthyoses,55,56 psoriasis,22,57 atopic dermatitis,58 and
contact dermatitis.59 It is generally accepted that this
is attributable to structural alterations in the stratum
corneum.22 These structural deficiencies may arise
from an absence of an enzyme or structural protein
in the underlying viable tissues or may be related to
the improper formation of the stratum corneum result-
ing from an increase in keratinocyte proliferation.64
Thus, in individuals predisposed to a defective barrier,
a minor perturbation may become amplified as the
skin attempts to compensate by increasing kerati-
nocyte proliferation.60 A further consideration is that
the homeostatic mechanisms responsible for recovery
of barrier activity after perturbation may be altered in
some diseases or physiologic states.
For example, whereas the skin of aged people exhib-
its normal barrier function, the recovery of barrier
activity after perturbation is markedly reduced.55,56
This kinetic basis for reduced barrier function may also
account for interindividual variation in barrier func-
tion and/or the apparently increased susceptibility of
certain individuals to contact dermatitis.59
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