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How Vehicles Affect Patient
Adherence in Acne Therapy
Advancements in vehicle formulation can improve patient comfort.
By Coyle S. Connolly, DO
Concentration and dose-dependent irritation associated with benzoyl peroxide
(BPO) and tretinoin are well known to clinicians and to many patients. Yet
benzoyl peroxide—often used as a component of a fixed combination formulations
that also contain clindamycin—and tretinoin are among the most
commonly prescribed topical treatments for acne.1-4 Patients who experience
irritation and dryness associated with these agents are not likely to adhere to the treatment
regimen as prescribed.5-9 Patients may discontinue therapy altogether, reduce the frequency of application, or attempt to spot-treat lesions
rather than apply to the full face or full affected
anatomic site.11-13 Given that acne is a
chronic disease mediated by faulty keratinization,
P. acnes colonization, inflammation, and
excess sebum production, long-term treatment
is aimed not only at treating currently
visible lesions but preventing formation of
new lesions. As such, spot treatment undermines
this therapeutic goal. Infrequent or
inconsistent application of topical treatments
will not achieve regulation of keratinization
or sustained reduction of P. acnes.
Dermatologists have developed numerous
strategies for the introduction of topical therapy
to enhance patient comfort and encourage
adherence to the regimen (Table 1). Recent
advancements in drug development and vehicle
formulation have improved retinoid tolerability,
however, these strategies to optimize
patient comfort remain important. By recommending
these strategies in conjunction with
optimized vehicles, clinicians can promote
adherence.
Concentration Considerations
Certain drugs are inherently irritating,
although irritation is often dose- or concentration-
dependent. For example, when used at
concentrations above 5%, BPO is well known
to result in skin irritation, and it is a clinical
reality and documented phenomenon that irritation
interferes with patient adherence.14 A
21-day cumulative irritation study showed that
reducing the BPO concentration from 5% to
2.5% in clindamycin-BPO fixed-combinations
with common vehicle reduced irritation by 33
percent.15 Compared to two commonly-used
fixed-combination products containing 5%
BPO with clindamycin, the lower 2.5% concentration
BPO/clindamycin-phosphate 1.2%
(Acanya, Coria Laboratories) formulation has
been shown to provide a meaningful reduction
in irritation scores.15,16
Data confirm that there is no need to use
BPO concentrations in the irritation-producing
range above 5%. BPO has been shown to
have equal efficacy in the treatment of inflammatory
acne lesions at 2.5%, 5%, and 10%
concentrations.17 Acanya Gel was shown in an
in vitro percutaneous absorption study to have
comparable bioavailability to other marketed
fixed-combination formulations that had a
higher concentration of BPO (5%).15
Similar to benzoyl peroxide, topical
tretinoin can cause irritation, especially in the
initial days and weeks of treatment.18,19 This
irritation may interfere with patient adherence18,20
and has been blamed for abandonment
of therapy. Irritation appears to be related to
characteristics of the vehicle formulation and
to concentration, thus tretinoin has been made
available in a range of concentrations and has
been formulated into numerous vehicles since
it first came to market in the 1970s.19 A
microsponge release formulation of tretinoin 0.04% (Retin-A Micro, Ortho Dermatologics)
appears to provide better tolerability than the
original 0.1% cream. A newer low-concentration
formulation of tretinoin 0.05% (Atralin
Gel 0.05%, Coria Laboratories) in a hydrogel
vehicle (See sidebar) features a microsuspension
that permits slow release of tretinoin and
appears to provide better tolerability than other
topical tretinoin formulations.
Formulation Considerations
While drugs may themselves be irritating,
components of the vehicle can also contribute
to therapy-induced irritation. In fact, in some
sub-optimal formulations, high concentrations
of chemical penetration enhancers, which can
actually disrupt the epidermal barrier, are used.
Certain excipients (preservatives, surfactants,
alcohol) are known to cause cutaneous irritation
and dryness.21 However, recently, formulators
have emphasized the importance of vehicle
formulations that efficiently deliver active drug
while also minimizing or even reversing possible
damaging effects of some drugs by helping
to preserve transepidermal water loss (TEWL)
and skin hydration.
Characteristics of the formulation can significantly
affect irritation and dryness, as well
as efficacy, of benzoyl peroxide and tretinoin.18
Novel hydrogel formulations of acne therapies—
Acanya Gel and Atralin—have been
shown to provide better patient comfort and
tolerability compared to older formulations.
The aqueous gel formulation used in
Acanya Gel ensures the stability of otherwise
incompatible active ingredients: solubilized
clindamycin phosphate and a microsuspension
of BPO. The formulation contains low
amounts of propylene glycol (PG) that act as a
delivery solvent for the BPO microcrystals after
application to the skin. However PG is also a
humectant-type moisturizer, providing cosmetic
elegance to the formulation. A benefit of
micronized particles of BPO in suspension is
that they can be uniformly distributed within
the formulation, and thus evenly applied to the
skin, compared to solubilized BPO. This even
distribution appears to be associated with
decreased drug-induced irritation.
One study compared the effects on TEWL
and stratum corneum hydration of fixed-combination combination
of clindamycin phosphate 1.2% and
BPO 5% (BenzaClin, Dermik/Sanofi-Aventis)
to Acanya Gel. The investigators found that
once-daily use of Acanya gel produced no relevant
irritant effect or negative influence on
stratum corneum hydration. However, clindamycin
phosphate 1.2%/BPO 5% produced
a significant decrease in skin hydration and had
a clinically apparent drying effect.22
First generation tretinoin formulations (and
their generic equivalents) contained solubilized
tretinoin and high levels of potentially irritating
penetration enhancing excipients, such as
isopropyl myristate or alcohol. When these formulations
are applied to the skin, the penetration
ehancers drive the active drug quickly into
the epidermis, creating a “burst” of drug delivery.
The burst delivery is associated with significant
drying and peeling and in some cases
scaling and redness.
By suspending micronized tretinoin in a
moisturizing vehicle, Atralin Gel 0.05% minimizes
the burst effect. The tretinoin micro-particles
(85 percent of which are less than 10
microns in size) can easily enter the pilosebaceous
unit and concentrate in the infundibulum,
and slowly dissolve directly in the sebum.
In addition to this controlled release,
Atralin Gel further minimizes irritation
through the incorporation of excipients commonly
found in skin hydration and moisturizer
products: soluble collagen, sodium
hyaluronate, and glycerin.
Optimized Formulations,
Enhanced Adherence
Long-term patient adherence with topical therapeutic
regimens for chronic skin diseases can
be a clinical challenge. This is especially true in
the case of acne, when adolescents may desire
rapid response to therapy and have little tolerance
for therapy-induced irritation or discomfort.
Fortunately, modern formulation technologies
continue to produce new, optimized
topical formulations for a range of skin diseases,
including acne.
Acanya Gel and Atralin Gel—each in moisturizing
hydrogel vehicles—are both shown to
reduce irritation and dryness in acne vulgaris.
Prescribers should consider the patient’s likely
therapeutic experience and comfort when selecting topical therapies. Optimized formulations
associated with decreased irritation and
enhanced patient comfort may be preferred to
other formulations.
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