Introduction
Topical products containing a wide
range of corticosteroids and presented in different strengths are
available for the treatment of various skin disorders (1). However, the
efficacy of a specific topical corticosteroid (TC) is related to its
potency and ability to be absorbed into target cells within the viable
epidermis and dermis (2). The clinical choice of a particular topical
corticosteroid product (TCP) is governed by the type and severity of
inflammatory skin condition/lesions, location of the lesion, and age of
the patient, amongst others. For example, dermatologists recommend lower
potency TCPs for infants and the elderly owing to an increased
surface‐to‐weight ratio and skin fragility, respectively resulting in
the absorption of proportionally large amounts of TC. Agents belonging
to the lower potency classes are used to treat acute inflammatory
lesions of the face and other body parts with thinner skin, whereas
highly potent agents are preferred in the treatment of chronic,
keratotic, or lichenified lesions found on surfaces with thicker skin,e.g. , palms, soles. Additionally, the type of lesion to be
treated influences the choice of vehicle, e.g. , ointment bases
are recommended for lichenified lesions as they improve drug penetration
due to an occlusive effect and subsequent hydration (3). A consideration
of possible side effects is important when prescribing TCPs since
unwanted cutaneous (atrophy, striae, telangiectasia, hypo-pigmentation,
acne, rosacea, perioral dermatitis, and hypertrichosis) and also several
systemic effects including cataracts, hyperglycemia, and
hypothalamic-pituitary-adrenal suppression can occur (3).
The standard methods to evaluate the potencies of TCPs have largely been
based on results of their clinical use and/or randomised clinical
comparative studies using the vasoconstrictor assay (VCA) (4). The VCA
evaluates corticosteroid potency based on the contribution of several
factors: ability to penetrate the skin barrier after release from the
vehicle, intrinsic activity at the receptor, and rate of clearance from
the site of application (5,6). Vasoconstrictor rankings based on
validated and appropriately conducted VCA studies are generally good
predictors of the efficacy of TCs (7).
Various factors such as drug lipophilicity and solubility, drug
concentration, anatomical site, age of the patient, presence of skin
disease, and use of occlusive dressings may influence percutaneous
absorption TC. These factors, amongst others, impact the degree to which
TCs achieve their intended therapeutic outcome (8). The therapeutic
benefit of a topically applied corticosteroid is derived from a
combination of its pharmacokinetic and pharmacodynamic effects.
Furthermore, the intrinsic activity of a TC at the cellular level is
also dependent on the release and delivery of drugs from the vehicle to
the site of action. Overall, the VCA tells us a lot about corticosteroid
potency, which is a complex function of both the chemical and physical
properties of the drug and its vehicle (2). It indicates the ability of
the vehicle to deliver the TC molecule into the skin and its ability to
activate the receptor (7). Current classification systems rank the
relative potencies of specific proprietary preparations assuming potency
and side effects are directly related (9).
Potency ranking of TCPs in the USA involves seven classes from
superpotent to least potent whereas a four-category system is used in
Northern Europe, the United Kingdom (UK), France, Germany, The
Netherlands and New Zealand (3,10–15). However, in New Zealand, class I
is the most potent and class IV the least potent, whilst in Germany,
class I is considered mildly potent and class IV very highly potent
(11,13,14). Furthermore, various formulation factors such as vehicle and
excipients can affect potency including the presence or absence of
penetration enhancers, lipophilicity of the drug and additives used,
chemical modifications, and substitutions which have not been taken into
consideration (16,17).
Various discrepancies relating to the current classification systems
have been observed, which are probably due to the use of
non-standardised approaches to assess potency. Furthermore, in some
cases, clinical data have been used, whereas in other instances,
vasoconstrictor responses have been used as the basis of potency
assessment. Also, several publications do not even include information
on how the potency was assessed. The use of non-standardised VCA method
to assess potency is also a cause for concern since it can result in
erratic and erroneous data. For example, some generic formulations have
been shown to be less or more potent than their brand-name equivalent,
indicating a discrepancy between clinical assessment and VCA (18).
Creams containing 0.25 and 0.05% desoximetasone were found to be
equipotent by Stoughton et al (19). However, the USA
classification list ranks the 0.25% cream as a class II (high potency)
TCP (20), whereas the 0.05% cream is classified as a class IV/V (medium
potency) agent. A further example showing inconsistency using a single
point visual assessment lists creams containing 0.05% diflorasone
diacetate as a group II (high potency) (21) whereas the USA
classification list ranks it as a class I (ultra-high potency) (20).
However, the data generated did not comply with the requirements of the
VCA guidance (22) since a simple single-point assessment was used,
making such results questionable.
On the other hand, using a
validated VCA method in compliance with related requirements assures
consistency relating to precision, reproducibility, and associated
validation parameters. Additional discrepancies in the published
literature relate to differences in the ranking procedures used in
different classification systems. In the UK, products containing 0.1%
mometasone furoate (Elocon®), irrespective of the
formulation, are ranked as potent (method of assessment not provided)
(23) compared to the USA classification, which classifies products
containing 0.1% mometasone furoate depending on the formulation (3).
Hence, Elocon® ointment has been classified as
superpotent, and Elocon® cream is ranked under
midstrength potency (3). Furthermore, the Monthly Prescribing Reference
(MPR) lists Elocon® cream, ointment, and lotion as
being of intermediate potency (24). In the classification list published
by the British National Formulary, none of the items indicate the type
of formulation, and most do not state the percentage of the active
pharmaceutical ingredient (API) incorporated in the dosage form (23).
Similarly, in New Zealand’s classification list, apart from
betamethasone dipropionate products, no mention is made of the
formulation or corticosteroid concentration (11). The method of potency
classification is based on a comparison with hydrocortisone, creating a
further discrepancy. In some instances, classifications have been based
on skin pathology, e.g. , in a study comparing
Eumovate® (0.05% clobetasone 17-butyrate) vsLocoid® (0.1% hydrocortisone 17-butyrate) ointments,
the potency was based on the various responses between effects on eczema
and psoriasis (25). In the former condition, the products were shown to
be equipotent, whereas, in the latter, Eumovate® was
superior to Locoid®, which is classified as a potent
preparation (25). The general assumption that the higher concentrations
are more potent than the lower concentrations irrespective of the
particular corticosteroid may not always be true (19). Furthermore,
different dosage forms containing the same TC may have different
potencies. For instance, 0.1% halcinonide cream is ranked as a class II
agent that is more potent than 0.1% halcinonide ointment which is
ranked as a class III TCP (3). Stoughton and Cornell conducted a series
of experiments to compare the ability of VCA with clinical data to
establish the potencies of specific TCPs. In 20 of the 23
(~ 87%) comparisons involving 30 TCPs, VCA was in
agreement with the clinical studies, whereas data for the other 7 TCPs
were inconclusive (4) although a non-validated VCA was used. The author
stressed the need to develop a system for evaluating the potency of
these compounds without having to rely on clinical data (4).
The relatively vague bases of the potency determinations raise concerns
about the reliability of the current potency classification systems.
Some do not provide any indication of how the classification was done.
In most cases, there is no clarity on how the TCPs were ranked in terms
of their potency, and tables with the different potency classes and
classification are simply provided without explanation. Whereas the
application of VCA usually requires the use of a chromameter, most
rankings and classifications using the VCA were based solely on visual
assessment. These were usually based on a single visual reading, where
the dose or dose duration used were not standardised, and the method
used was not appropriately validated. Therefore, there is an urgent need
to revisit and reassess the existing classification systems using newer,
reliable, and innovative technology using chromametric measurements of
the skin blanching response (3,22).
Hence, the objective of this study
was to compare the potencies of two marketed TCPs using the Food and
Drug Administration’s (FDA’s) VCA as described in a previous publication
(26) used to rank TC APIs and also to illustrate the influence of
formulation and associated vehicle properties on potency.