28 absorption of topically applied nicotine.

50 Regional dif-
ferences in the percutaneous absorption of piroxicam,
a nonsteroidal antiinflammatory drug, depend on the
local vasculature rather than on skin barrier function.57
An additional consideration is that the rate of
resorption may indirectly influence the diffusion of
compounds to the underlying musculature, tissues,
and joints.58 The principle of locally enhanced deliv-
ery to underlying musculature has been demon-
strated for piroxicam as well as several local anesthetic
preparations.59
INFLUENCE OF
Part 28
For example, whereas the skin of aged people exhib-
its normal barrier function, the recovery of barrier
activity after perturbation is markedly reduced.63 This
kinetic basis for reduced barrier function may also
account for interindividual variation in barrier func-
tion or the apparently increased susceptibility of cer-
tain individuals to contact dermatitis.64
OTHER FACTORS THAT
AFFECT ABSORPTION
STRATUM CORNEUM

PATHOLOGIC PROCESSES Stratum corneum, the rate-limiting barrier to percuta-

ON SKIN BARRIER neous drug delivery, is composed of ceramides, free
fatty acids, and cholesterol in a 1:1:1 molar ratio. By
::

FUNCTION weight, the stratum corneum consists of 50% cerami-

Topical and Systemic Treatments

des (acylceramides being the most abundant), 35%

Reduced skin barrier function has been observed in
pathologic conditions, including the ichthyoses,60
psoriasis,27 atopic dermatitis,61 and contact dermatitis.61
It is generally accepted that this is attributable to struc-
tural alterations in the stratum corneum. These struc-
tural 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 resulting from an increase in
keratinocyte proliferation. Thus, in individuals pre-
disposed to a defective barrier, a minor perturbation
may become amplified as the skin “attempts to com-
pensate” by increasing keratinocyte proliferation.62 A
further consideration is that the homeostatic mecha-
nisms responsible for recovery of barrier activity after
perturbation may be altered in some diseases or physi-
ologic states.
cholesterol, and 15% free fatty acids. Stratum corneum
thickness and thus drug penetration vary depending
on body site (Fig. 183-2).65
There are two main routes for permeation through
the stratum corneum: the (1) transepidermal and (2)
transappendageal pathways (Fig. 183-3). The transap-
pendageal, or shunt, route involves the flow of mol-
ecules through eccrine glands and hair follicles via the
associated sebaceous glands.66 In the transepidermal
route, molecules pass between the corneocytes via the
intercellular micropathway or through the cytoplasm
of dead keratinocytes and intercellular lipids, defined
as the transcellular micropathway.66,67 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,

Relative percutaneous absorption of hydrocortisone

Foot arch
Ankle
Palm
Ventral forearm
Dorsal forearm
Back
Scalp
Axilla
Forehead
Jaw angle
Scrotum
0 5 10 15 20 25 30 35 40 45

Figure 183-2 Relative percutaneous absorption of hydrocortisone. Regional variation was measured in males using
carbon14-labeled hydrocortisone dissolved in acetone solvent. Values depicted are relative to the percutaneous absorp-
3370 tion of topical applied to the ventral forearm. (Adapted from Feldman RJ, Maibach HI. Regional variation in percutaneous
penetration of 14C cortisol in man. J Invest Dermatol. 1967;48(2):181-83.)

Kang_CH183_p3363-3381.indd 3370 08/12/18 1:46 pm

 Penetration pathways
Intracellular
Transappendegeal
absorption absorption
Stratum
corneum
Hair Sweat/
follicle eccrine
gland
Figure 183-3 Penetration pathways.
decreased, or absent) stratum corneum, thus changing
the body site’s barrier function.68 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 medications
with these components may enhance absorption.69
Importantly, simple hydration of the stratum corneum
enhances the absorption of topically applied steroids
by four to five times.10 Abnormal epidermal prolifera-
tion disrupts the skin barrier architecture, enhancing
percutaneous absorption.
OCCLUSION
Occlusion via closed, airtight dressings or greasy oint-
ment bases increases stratum corneum hydration;
limits rub-off and wash-off of the drug; and, conse-
quently, enhances penetration. Occlusion techniques
range from application under an airtight dressing such
as vinyl gloves, plastic wrap, and hydrocolloid dress-
ings to occlusion at night for treatment of hands and
feet, to application of a medication already impreg-
nated into an airtight dressing, as seen in flurandre-
nolide tape. With many drugs, occlusion increases
drug delivery by 10 times the amount of drug deliv-
ered when not occluded.70 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 drug’s adverse effects, such as the ability of
topical corticosteroids to induce local skin atrophy or
suppression of the hypothalamus–pituitary–adrenal
axis. Occlusion may promote infection, folliculitis,
or miliaria. In the case of topical anesthetics such as
Kang_CH183_p3363-3381.indd 3371
lidocaine and prilocaine, occlusion hastens absorp-
tion into both the skin and the bloodstream, which has
28
led in rare cases to cardiac complications from lido-
caine toxicity or methemoglobinemia from prilocaine
toxicity.
APPLICATION FREQUENCY
The frequency of topical application for some drugs,
such as corticosteroids, appear to saturate the stratum
corneum so that multiple daily application yields min-
imum penetration increases compared with once-daily
Chapter 183 :: Principles of Topical Therapy
application.71,72 Clinical studies support the same con-
clusion, so many topical package inserts are labeled for
once-daily use.
QUANTITY OF APPLICATION
The quantity of the drug applied likely has a negligible
effect on drug absorption. Obviously, enough drug
must be dispensed and spread to cover the affected
areas. Furthermore, the quantity of drug applied might
affect patient adherence to the prescribed regimen. For
example, too much applied drug might negatively
alter the subjective experience of having a medication
on the skin, that is, the drug may feel “wrong” (greasy,
caked, chalky, and so on) or is cosmetically unattractive
(shiny, white color). Regardless, the amount prescribed
must be adequate to treat the affected body surface
area (BSA) for the necessary length of time. In this
regard, patient education is critical to prevent wasteful
overuse or ineffective underuse of the medication. The
amounts of topical medications to dispense is based
on the estimated BSA, frequency of application, and
duration of therapy. For topical medications such as
sunscreens that are used over large areas, underap-
plication is a problem for most patients. However, for
smaller areas, patients may apply a large amount of an
ointment, for example, leading to complaints of greasi-
ness or rubbing off on clothing, which can be mini-
mized by using an appropriate amount. The finger-tip
unit (FTU) is a measurement that allows health care
providers and patients to easily communicate about
treatment application. An FTU is the amount of topical
dispensed from a 5-mm-diameter nozzle onto the tip of
the palmar aspect of the index finger to the distal inter-
phalangeal joint skin crease. One FTU is equivalent to
approximately 500 mg of the topical agent, which can
cover about 2% of the BSA.
MISCELLANEOUS FACTORS
Vigorous rubbing or massaging of the drug into the
skin not only increases the surface area of skin cov-
ered but also increases blood supply to the area locally, 3371
augmenting systemic absorption. It may cause a local
08/12/18 1:46 pm
28 exfoliative effect that also enhances penetration. The
presence of hair follicles on a particular body site also TABLE 183-3
enhances drug delivery, with the scalp and beard areas Vehicle Ingredients Commonly Used In Topical
presenting less of a barrier compared with the rela- Preparations
tively hairless body sites.
Emulsifying Agents
Reducing the particle size of the active ingredi-
■ Cholesterol
ent increases its surface area–volume ratio, allowing
■ Disodium mono-oleamidosulfosuccinate
for a greater solubility of the drug in its vehicle. This
■ Emulsifying wax
forms the basis for the increased absorption of certain ■ Polyoxyl 40 stearate
micronized drugs.73 ■ Polysorbates
■ Sodium laureth sulfate
■ Sodium lauryl sulfate

CLASSIFICATION AND Auxiliary Emulsifying Agents or Emulsion Stabilizers

■ Carbomer
CLINICAL APPLICATION OF ■ Catearyl alcohol
Part 28

■ Cetyl alcohol
TOPICAL FORMULATIONS ■ Glyceryl monostearate
■ Lanolin and lanolin derivatives
■ Polyethylene glycol
::

The vehicle is the inactive part of a topical preparation

that brings a drug into contact with the skin. Before ■ Stearyl alcohol
Topical and Systemic Treatments

the mid-1970s, pharmaceutical companies performed Stabilizers

limited testing of the impact of vehicle on the potency ■ Benzyl alcohol
of a given formulation. Lack of a scientific analysis ■ Butylated hydroxyanisole
of the vehicle led to the marketing of topical drugs ■ Butylated hydroxytoluene

that, although having different concentrations of the ■ Chlorocresol

■ Citric acid
same active ingredient, nevertheless exhibited simi-
■ Edetate disodium
lar bioavailability and potency. For example, older
■ Glycerin
preparations of triamcinolone acetonide showed no ■ Parabens
real differences in potency among the 0.025%, 0.1%, ■ Propyl gallate
and 0.5% concentrations. By contrast, modern drug ■ Propylene glycol
development attempts to maximize drug bioavail- ■ Sodium bisulfite
ability by optimizing vehicle formulation. Addition- ■ Sorbic acid or potassium sorbate
ally, during the current drug development process, Solvents
dose–response studies determine the maximal effec- ■ Alcohol
tive concentration within a given vehicle, above ■ Diisopropyl adipate
which any further increase in concentration serves no ■ Glycerin
therapeutic benefit. ■ 1,2,6-Hexanetriol
Vehicle of a topical formulation often has beneficial ■ Isopropyl myristate
■ Propylene carbonate
nonspecific effects by possessing cooling, protective,
■ Propylene glycol
emollient, occlusive, or astringent properties. Ratio-
■ Water
nal topical therapy matches an appropriate vehicle
that contains an effective concentration of the drug. Thickening Agents
■ Beeswax
The vehicle functions optimally when it is stable both
■ Carbomer
chemically and physically and does not inactivate the
■ Petrolatum
drug. The vehicle also should be nonirritating, non- ■ Polyethylene
allergenic, cosmetically acceptable, and easy to use. ■ Xanthan gum
Additionally, the vehicle must release the drug into
Emollients
the pharmacologically important compartment of the
■ Caprylic or capric triglycerides
skin. Finally, the patient must accept using the vehicle ■ Cetyl alcohol
or else compliance will be poor. For example, although ■ Glycerin
ointments are often pharmacodynamically more effec- ■ Isopropyl myristate
tive than creams, patients generally prefer creams to ■ Isopropyl palmitate
ointments, and thus, more prescriptions are written for ■ Lanolin and lanolin derivatives
cream-based formulations. Table 183-3 lists many com- ■ Mineral oil
monly used ingredients in topical preparations. Many ■ Petrolatum
of these compounds serve more than one function in a ■ Squalene
■ Stearic acid
particular formulation.
■ Stearyl alcohol
Humectants
■ Glycerin
TOPICAL FORMULATIONS ■ Propylene glycol
3372 ■ Sorbitol solution
See Table 183-4.

Kang_CH183_p3363-3381.indd 3372 08/12/18 1:46 pm

 TABLE 183-4
28
Summary of Topical Formulations
FORMULATION COMMON COMPONENTS DESCRIPTION

Powders Zinc oxide, talc (magnesium silicate) Cosmetic, hygienic purposes; ideal for intertriginous areas
and feet
Poultice Dextranomer beads Wound cleansers, absorptive agents; applied on decubiti
or leg ulcers
Ointments  
Hydrocarbon base Petrolatum most commonly used Prevent evaporation of moisture from the skin; contain no
(ointments; Silicon ointments preservatives; not for water-soluble drug use; ideal for
oleaginous bases; diaper rash, incontinence, bedsores, colostomy sites
emollients)

Chapter 183 :: Principles of Topical Therapy

Absorption base Lanolin and lanolin derivatives Lubricating and hydrophilic substances; can form
Cholesterol and cholesterol derivatives emulsions; emollients and protectants; easier to
Sorbitan monostearate remove than hydrocarbon bases
Emulsions (water in oil; Sodium lauryl sulfate, quaternary ammonium compounds, Less greasy; easy to spread on film; provide a protective
<25% water) (creams) spans, tweens film of oil as an emollient with a cooling effect
Emulsions (oil in water; Glycerin, propylene glycol, PEG, paraffin alcohols Most commonly used to deliver a drug; easily spread,
>31% water) (creams) water washable and less greasy; easily removed from
the skin; preservative containing (parabens)
Water-soluble bases PEGs (liquid or solid) No preservatives or additives; less occlusive, nonstaining,
greaseless, easily washed off from the skin; poor
absorption into the skin but maintains a high surface
concentration; ideal for topical antifungals and topical
antibiotics
Gels Water, propylene glycol, PEGS with a cellulose derivative or Organic molecules uniformly distributed in a lattice
Carbopol throughout the liquid; deposits drug in concentrated
form; ideal for use in facial or hair bearing areas; lack
protective or emollient effects; may cause drying or
stinging
Pastes (up to 50% Zinc oxide, starch, calcium carbonate, talc Less greasy than ointments; more drying and less
powder in ointment occlusive; used as protectants, sunblocks, or for
base) localizing a drug that may be staining or irritating
Liquids  
Solutions Liquid vehicle may be aqueous, hydroalcoholic, or nonaqueous Function as astringents, counterirritants, antipruritics,
■ Tincture: hydroalcoholic solution with 50% alcohol; collodion: emollients
nonaqueous solution of pyroxylin with ether and ethanol
■ Liniments: nonaqueous solutions or drugs in oil or alco-
holic soap solutions
Suspensions Biphasic solution: insoluble drug in up to 20% concentration Cooling effect; easier to apply and allows for uniform
dispersed in liquid coating of larger affected areas; more drying than
ointments
Shake lotions Solutions with added powder; zinc oxide, talc, calamine, Used to dry and cool wet and weeping skin
glycerol, alcohol, and water
Foams Triphasic solution with oil, organic solvents, and water, Deliver a greater amount of drug at an increased rate;
formulated with a hydrocarbon propellant especially useful for scalp application
Aerosols Drug in a solution mixed with a pure propellant Deliver drugs formulated as solutions, suspensions,
(nonpolar hydrocarbons) emulsions, powders, and semisolids; ease of application
to hair-bearing areas

PEG, polyethylene glycol.

the feet. Adverse effects of powders include caking

POWDERS
Powders absorb moisture and decrease friction.
Because they adhere poorly to skin, their use is mainly
limited to cosmetic and hygienic purposes. Generally,
powders are used in the intertriginous areas and on
(especially if used on weeping skin), crusting, irrita-
tion, and granuloma formation. Furthermore, powders
may be inhaled by the user. Most powders contain zinc
oxide for antiseptic and covering properties, talc (pri-
marily composed of magnesium silicate) for lubricat- 3373
ing and drying properties, and a stearate for improved

Kang_CH183_p3363-3381.indd 3373 08/12/18 1:46 pm

28 adherence to the skin. Calamine is a popular 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.73
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
Part 28
used as wound cleansers and absorptive agents in exu-
dative lesions such as decubiti and leg ulcers.73
::
Topical and Systemic Treatments
OINTMENTS
Ointments, semisolid preparations that spread easily,
are petrolatum-based vehicles capable of providing
occlusion, hydration, and lubrication. Drug potency
often is increased by an ointment vehicle because of its
ability to enhance permeability.5 Ointment bases used
in dermatology can be classified into five categories:
(1) hydrocarbon bases, (2) absorption bases, (3) emul-
sions of water-in-oil, (4) emulsions of oil-in-water, and
(5) water-soluble bases. Dermatologists commonly
refer to the hydrocarbon bases and absorption bases as
ointments and the water-in-oil and oil-in-water emul-
sion bases as creams. In pharmaceutical terms, all of
these preparations are ointments and are specifically
indicated for conditions affecting the glabrous skin
(palms and soles) and lichenified areas.10
HYDROCARBON BASES
Also called oleaginous bases, hydrocarbon bases are
often referred to as emollients because they prevent
the evaporation of moisture from skin, are composed
of a mixture of hydrocarbons of varying molecular
weights, with petrolatum being the most commonly
used (white petrolatum, except for being bleached, is
identical to yellow petrolatum). They are greasy and
can stain clothing. Silicon ointments are composed of
alternating oxygen 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, bedsores, and colostomy sites. Hydro-
carbon bases are generally stable and do not contain
preservatives. They cannot absorb aqueous solutions
and thus are not used for water-soluble drugs.73
ABSORPTION BASES
Absorption bases contain hydrophilic substances that
3374 allow for the absorption of water-soluble drugs. The
hydrophilic (polar) compounds may include lanolin
Kang_CH183_p3363-3381.indd 3374
and its derivatives, cholesterol and its derivatives, and
partial esters of polyhydric alcohols such as sorbitan
monostearate. These ointments are lubricating and
hydrophilic, and they can form emulsions. They func-
tion well as emollients and protectants. They are greasy
to apply but are easier to remove than hydrocarbon
bases. They do not contain water. Examples include
anhydrous lanolin and hydrophilic petrolatum.73
WATER-IN-OIL EMULSIONS (CREAMS)
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. Examples
of surfactants used include sodium lauryl sulfate, qua-
ternary ammonium compounds, Spans (sorbitan fatty
acid esters), and Tweens (polyoxyethylene sorbitan
fatty acid esters). Preservatives are frequently added
to increase emulsion’s shelf life. Water-in-oil emulsions
are less greasy, spread easily on the skin, and provide
a protective film of oil that remains on the skin as an
emollient, and the slow evaporation of the water phase
provides a cooling effect.5
OIL-IN-WATER EMULSIONS
An oil-in-water emulsion contains greater than 31%
water. In fact, the aqueous phase may constitute up
to 80% of the formulation. This type of formulation is
most commonly chosen to deliver a dermatologic drug.
Clinically, oil-in-water emulsions spread easily, 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 mold
growth. Additionally, oil-in-water emulsions contain a
humectant (an agent that draws moisture into the skin),
such as glycerin, propylene glycol, or polyethylene gly-
col (PEG), to prevent the cream from drying out. The oil
phase may contain either cetyl or stearyl alcohol (paraf-
fin alcohols) to impart a stability and velvety smooth
feel upon application to the skin. After application,
the aqueous phase evaporates, leaving behind a small
hydrating oil layer and a concentrated drug deposit.73
WATER-SOLUBLE BASES
Water-soluble bases consist either primarily or com-
pletely of various PEGs. Depending on their molecu-
lar weight, PEGs are either liquid (PEG 400) or solid
(PEG 4000). These formulations are water soluble, do
not decompose, and do not support mold growth and
therefore require no preservative additives. They are
much less occlusive than water-in-oil emulsions and
are nonstaining, greaseless, and easily washed off of
the skin. Without water, the ointment poorly delivers
08/12/18 1:46 pm
 its coformulated drug. Therefore, it is useful in scenar-
ios when the practitioner desires a high surface con-
centration and low percutaneous absorption of drug.
For example, topical antifungal drugs and topical anti-
biotics (eg, mupirocin) are formulated in this 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.
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
remains.10 Nevertheless, they lack 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.74
Microspheres, or microsponges, are formulated in
an aqueous gel. Medication, in this case tretinoin, is
combined into porous beads 10 to 25 µm in diameter.
The beads are made up of methyl methacrylate and
glycol dimethacrylate.
PASTES
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
powder must be insoluble in the ointment. Invariably,
they are “stiffer” than the original ointment. 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 (ie, anthralin).
They also function as impermeable barriers that serve
as protectants or sunblocks. Pastes are less greasy than
ointments, more drying, and less occlusive.73
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 vehi-
cle may be aqueous, hydroalcoholic, or nonaqueous
Kang_CH183_p3363-3381.indd 3375
(alcohol, oils, or propylene glycol). An example of an
aqueous solution is aluminum acetate or Burow solu-
28
tion. A hydroalcoholic solution with a concentration
of alcohol of approximately 50% is called a tincture. A
collodion is a nonaqueous solution of pyroxylin 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 example, to
deliver 10% salicylic acid as a keratolytic agent. Lini-
ments 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.73
Chapter 183 :: Principles of Topical Therapy
SUSPENSIONS (LOTIONS)
A suspension, or lotion, is a two-phase system consist-
ing of a finely divided, insoluble drug dispersed into
a liquid in a concentration of up to 20%. Nonuniform
dosing can result if the suspended particles coalesce and
separate out of a homogeneous mixture, therefore shak-
ing 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 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 prepara-
tions with alcohol tend to sting eczematized or abraded
skin. Lotions are suitable for application to large surface
areas because of their ability to spread easily.73
SHAKE LOTIONS
Shake lotions are lotions to which a powder is added
to increase the surface area of evaporation. As a result
of increased evaporation, 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 spe-
cific 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 suspension. 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.73
FOAMS
Foams are triphasic liquids composed of oil, organic
solvents, and water, kept under pressure in aluminum
cans. Foams are formulated with a hydrocarbon pro-
pellant, either butane or propane.75 The foam lattice is
formed when the valve is activated. When in contact
with skin, the lattice breaks down, the alcohol evapo- 3375
rates within 30 seconds and leaves minimal residue
08/12/18 1:46 pm
28 in the skin. The alcohol component of the foam is
thought to act as a penetration enhancer, momentarily
altering the barrier properties of the stratum corneum
and increasing drug delivery through the intercellular
route.75 Foam vehicles are highly effective in delivering
greater amount of active drug at an increased rate com-
pared with other vehicles that traditionally depend on
hydration of the intercellular spaces within the stra-
tum corneum. Foams have not been associated with an
increase in the adverse events, and compliance seems
to be better with this formulation, especially for local-
ized conditions affecting the scalp.75
Part 28
AEROSOLS
Topical aerosols may be used to deliver drugs formu-
::
lated as solutions, suspensions, emulsions, powders, and
Topical and Systemic Treatments
semisolids. Aerosols involve formulating the drug in a
solution within a pure propellant. Usually, the propel-
lant is a blend of nonpolar hydrocarbons. When applied
to abraded or eczematized skin, aerosols lack the irrita-
tion 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 cortico-
steroids such as betamethasone valerate and clobetasol
propionate. The foam contains the drug within an emul-
sion formulated with a foaming agent (a surfactant), a
solvent system (eg, water and ethanol), 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 skin. Foams that are alcohol
based leave little residue within seconds of application.
Furthermore, a given corticosteroid formulated in a
foam vehicle demonstrates comparable potency com-
pared with the same corticosteroid in other vehicles.11,76
Although aerosols allow for the ease of application (espe-
cially to hair-bearing areas) and high patient satisfaction,
they suffer from the disadvantages of being expensive
and potentially ecologically damaging.73
LIPOSOMES AS
TRANSDERMAL DELIVERY
SYSTEMS
Liposomes are microscopic spheres consisting of a
bilayer that encloses an inner aqueous core. A wide
variety of cosmetics contain liposomes. Liposome-
based formulations are safe, cosmetically attractive,
and well accepted. There is considerable evidence that,
at least for some preparations, application of liposomes
is mildly occlusive and improves stratum corneum
3376 hydration. Interest in the use of liposomes to enhance
the delivery of drugs across the skin has been spurred
Kang_CH183_p3363-3381.indd 3376
by observations in animal models: liposome formu-
lations were believed to enhance the penetration of
compounds across the skin or to optimize the reten-
tion of bioactive compounds in target tissues.32 How-
ever, these early studies, which relied largely on animal
models, were followed by relatively few in vivo studies
for humans conducted under standard conditions.69
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 liposomes
get damaged and release their drug, which has to pass
through the last cell layers of the stratum corneum by
itself to reach the living cells.
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
compounds into sebaceous glands or hair follicles.16,66
Rigid liposomes penetrate better into the hair follicles
than flexible liposomes, which supports the assump-
tion that the moving hairs act as a geared pump.52,66
PENETRATION ENHANCERS
CHEMICAL ENHANCERS
A penetration enhancer is a compound that is able to pro-
mote drug transport through skin. Skin hydration and
interaction with the polar head group of the lipids are
mechanisms for increasing penetration. Water, alcohols
(mainly ethanol), sulphoxides (dimethylsulphoxide),
decylmethylsulphoxide, azones (laurocapram), and
urea are some commonly used compounds.67 Urea is
thought to act as a penetration enhancer because of
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.69
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.77
PHYSICAL ENHANCERS
Physical methods such as the application of a small
electric current (iontophoresis), ultrasound energy
(phono- or sonophoresis), and the use of microneedles
increase cutaneous drug penetration.67 Microder-
moabrasion 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 permeation and facilitates
drug absorption by altering the architecture of the stra-
tum corneum.78
08/12/18 1:47 pm
 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
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-releasing agents, and
previously, thimerosal. Most commonly used preser-
vatives may act as contact sensitizers.
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
in water-soluble phases. Chelating agents, such as
sodium EDTA (ethylenediaminetetraacetic acid) and
citric acid, work synergistically with antioxidants by
complexing heavy metals in aqueous phases.
THICKENING AGENTS
Thickening agents increase the viscosity of products
or suspend ingredients in a formulation. Examples
include beeswax 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.
SIDE EFFECTS AND
PRECAUTIONS
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, come-
dogenicity, formation of telangiectases, pruritus, sting-
ing, and pain. The mechanism of toxicity may be as
simple as the desiccation of the stratum corneum (eg,
the removal of sebum and oils by the preparation’s
emulsifiers) or involve a more complex effect on either
the cells of the epidermis or dermis and the struc-
tures these cells comprise (ie, epidermis, adnexae).
Local damage may occur either directly at or within
close proximity to the treated site. Furthermore, irri-
tation and damage may appear even after a drug has
been discontinued. Often the therapeutic effects of the
Kang_CH183_p3363-3381.indd 3377
active ingredient mask or immediately treat the toxic
effects of the formulation so that acutely toxic effects
28
are transient.79 For example, allergic contact dermatitis
to a preservative in a topical steroid may be masked by
the effects of the glucocorticoid itself.
IRRITANT CONTACT DERMATITIS
Irritation is driven less by drug penetration and more
by drug concentration. Thus, lowering the concen-
tration of an irritating drug may lower the risk of
side effects. However, a change in formulation may
reduce the preparation’s efficacy. Nevertheless, often
using a less concentrated preparation over a greater
Chapter 183 :: Principles of Topical Therapy
period of time is as therapeutically efficacious while
minimizing adverse effects (eg, the use of benzoyl
peroxide 2% to 5% preparations in contrast to 10%
preparations).79 In some instances, though, skin irri-
tancy might be central to drug efficacy. For exam-
ple, 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
CONTACT DERMATITIS
Patients may detect burning or stinging sensations
without any signs of cutaneous irritation after apply-
ing a topical medication. Several compounds, such
as tacrolimus, sorbic acid, propylene glycol, benzoyl
peroxide hydroxy acids, mequinol, ethanol, lactic acid,
azelaic acid, benzoic acid, and tretinoin, may induce
sensory irritant contact dermatitis in predisposed
individuals.80,81
ALLERGIC CONTACT DERMATITIS
Contact allergy development depends on local pen-
etration. Allergy is driven by antigen recognition and
presentation, so percutaneous 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 significantly to
percutaneous absorption. In some instances, cutane-
ous allergy may be therapeutic, for example, the treat-
ment 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.82
MALIGNANCIES
Rarely, topical therapy may result in neoplasia. For
example, the risk of secondary malignancies, such as
keratoacanthomas, basal and squamous cell carcino-
mas, lentigo maligna, and primary melanoma, have
been reported with the long-term use of nitrogen 3377
mustard.82
08/12/18 1:47 pm
28 OTHERS
The application of topical corticosteroids to the perior-
bital skin has been suggested to induce cataracts and
increase intraocular pressure.10
SYSTEMIC EFFECTS
One should be aware of the potential systemic toxici-
ties of topical drugs. Although generally safer than the
other administration routes, topical application can
result in systemic toxicities ranging from end-organ tox-
Part 28
icity (central nervous system, cardiac, renal, and so on),
teratogenicity, and carcinogenicity to drug interactions.
These outcomes may relate to the drug itself, its metabo-
lites, or even a component of the vehicle.
::
The kinetics of topically applied drugs differ sig-
Topical and Systemic Treatments
nificantly from those administered by other routes. An
important consideration is the lack of hepatic first-pass
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 cen-
tral nervous system toxicity when applied topically.
Additionally, acting as a reservoir, the stratum cor-
neum 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 sys-
temic circulation.
Percutaneous toxicity directly relates to percutaneous
absorption. Therefore, factors that modulate absorp-
tion also influence toxicity: concentration of drug, its
vehicle, use of occlusion, body site and area treated,
frequency of use, duration of therapy, and nature of
the diseased skin. For example, 6% salicylic acid in
Eucerin used for 11 days in the treatment of psoriasis
has been associated with epistaxis and deafness, and
the same concentration of salicylic acid in hydrophilic
cream under occlusion for 4 days for the treatment of
dermatitis (involving the same amount of BSA) may
result in hallucination.79 Similar to their effect on sys-
temically administered drugs, renal and hepatic dis-
eases, by influencing drug clearance, also contribute to
an increased potential for drug toxicity.
Infants and young children have a greater surface
area–volume ratio and thus are at greater risk of percu-
taneous toxicity than adults. This phenomenon neces-
sitates alternative drugs, formulations, and dosing
schedules for children with widespread cutaneous dis-
ease. Patients with acute flares of cutaneous illness (eg,
psoriasis or atopic dermatitis) may require treatment of
a larger BSA in a relatively abbreviated period. 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.73 To reduce the risk of toxicity
from topical drugs and to increase treatment efficacy,
3378 many practitioners will rationally advocate systemic
approaches (ie, methotrexate, cyclosporine, injectable
Kang_CH183_p3363-3381.indd 3378
or infusable biologics, or ultraviolet radiotherapy) to
patients whose disease involves an extensive BSA.
Nonimmunologic acute toxicity results from substances
such as pesticides and chemical warfare agents that rap-
idly diffuse through the skin and reach target organs.
IMMUNOLOGIC CONTACT
URTICARIA
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.73
MALIGNANCIES
Systemic calcineurin inhibitors have been associated
with increased risk of lymphoma and nonmelanoma
skin cancer. But the topical use of such drugs does not
yet appear to induce cancer.83 In fact, the risk for lym-
phoma 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.83 More than 50 cases of lymphoma
have been reported, although the topical calcineurin
inhibitor use may be coincidental. Nevertheless, there
is a need for additional follow-up information to estab-
lish the long-term safety profile of these drugs.83
ENDOCRINE SYSTEM
Topical corticosteroids can rarely cause hypothalamic–
pituitary–adrenal axis suppression, growth retarda-
tion, hyperglycemia, iatrogenic Cushing syndrome,
and femoral head osteonecrosis.10 Factors that enhance
drug absorption are directly related to an increase in
these side effects; therefore, careful 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 (because of their increased
surface–body mass ratio).
TRANSDERMAL DRUGS
Transdermal drug delivery, in contrast to topical drug
delivery, uses topical application of therapeutic drug
as a delivery system for systemic therapy. Transdermal
patches have been approved by the FDA since 1981 (sco-
polamine being the first) for the delivery of numerous
medications, with more seeking approval. Advantages
of this approach include controlled 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
08/12/18 1:47 pm
 12 hours to 1 week. A patch consists of a plastic backing,
a reservoir of medication, and either a rate-controlling
membrane or a polymer matrix system for controlled
diffusion followed by an adhesive facing the skin. The
most common adhesives used are acrylates, silicones,
and polyisobutylenes. These patches have been tested
and 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.
CONCLUSIONS
Topical therapies are a mainstay of treatment for the
dermatologist. An understanding of the interactions
between a drug’s concentration, penetration, availabil-
ity, and treatment of diseased skin allows physicians
to maximize both efficacy and tolerability of topical
therapy. An understanding of local and systemic tox-
icities allows selection of appropriate, safe therapy for
patients and minimizes unwanted effects. Appropriate
selection of topical agents and patient education on
proper use can optimize therapeutic outcomes.
ACKNOWLEDGMENTS
Previous authors were Aieska De Souza, Bruce E.
Strober, Hans Schaefer, Thomas E. Redelmeier, Gerhard J.
Nohynek, and Jürgen Lademann.
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