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.