Results
Potency assessment of Dermovate® and Elocon® creams
Ten Caucasian subjects (2 females and 8 males) were enrolled and all completed the study without any adverse drug reactions or other clinical events. The dose duration-response data of the subjects were obtained for the two TCPs, Dermovate® and Elocon® creams. Figure 1a illustrates a typical blanching response of one of the subjects after application of Dermovate® and Elocon®. Figure 1b shows a typical blanching response of one of the subjects after application of 0.0025 M (~0.1%) solutions of CP and MF from a previous study conducted by Zvidzayi et al (26). Details of the dose durations and treatments received by subjects in Figures 1a-b are provided under supplementary material in Tables S1-2.
After the different times of exposure (i.e. , at 5, 10, 20, 40, 60, 90, and 150 min dose durations), the blanching effects for both Dermovate® and Elocon® peaked at 12 h after product removal, decreasing thereafter. The mean baseline corrected and untreated site corrected a-scale values for Dermovate® and Elocon® were plotted against the time after product removal, illustrating the blanching response of the 10 subjects as shown in Figures 2a-b, respectively. The negative values of the means (i.e. , mean multiplied by -1) were plotted since the actual means were < 0. The plots show that as the dose durations increase, there is a corresponding increase in the skin blanching response.
The data sets for the products were analysed using population modelling to fit the Emax model according to Equation 1. The AUEC values (< 0 indicates blanching) were calculated to yield a fitted dose-duration versus AUEC profile of all the subjects to illustrate the response at the various dose durations for Dermovate® and Elocon® as shown in Figures 3a-b, respectively. The results obtained from data fitting analyses using P-Pharm software are summarised in Table 1.
Comparisons of TC API solutions and TCPs
The Emax values of the 10 subjects for Dermovate® and Elocon® creams along with the Emax data from Zvidzayi et al (26) (10 subjects for CP and MF) were statistically evaluated as previously described. The pairedt- test results indicated statistically significant differences amongst the TCs (t = 7.29; p < 0.0001) as well as the TCPs (t = 5.32; p = 0.0005). Furthermore, the one-way ANOVA revealed significant differences between the TCPs and their corresponding TCs as follows: Dermovate® and CP (F = 30.55;p < 0.0001); Elocon® and MF (F = 39.63; p< 0.0001). Hence, the null hypothesis that theEmax values for any of these comparisons were equal, was rejected (p < 0.05) and the alternative hypothesis that the Emax values of these treatments differed from each other was accepted. The results of these comparisons are summarised in Table 2.
Statistical analysis of the paired comparison of theEmax values of Dermovate® and Elocon® indicated significant differences in theEmax values, where Dermovate®had a greater mean Emax value than Elocon®, indicating a higher potency for that TCP.
The mean Emax value for CP was statistically different from those of MF.
CP had a lower mean Emax value than Dermovate®. MF exhibited a higherEmax value and differed statistically from Elocon®.
Figures 4a-c show composite plots for fitted Ema x model for Dermovate®vs Elocon® creams, Dermovate®cream vs CP, and Elocon® cream vs MF, respectively.
Discussion
Although Dermovate® contains 0.05% CP and Zvidzayiet al (26) used ~0.1% solution of CP, the TCP was found to be more potent than the API solution. This may be attributed to the influence of formulation and associated vehicle properties. The presence of excipients such as permeation enhancers result in better permeation subsequently increasing the potency of the TCP.
MF had a significantly higherEma x value than Elocon® cream which contains the same strength of MFi.e. , 0.1% as the solution used by Zvidzayi et al (26). This too is presumably the result of the influence of formulation and associated vehicle properties. Certain excipients may impede the release of APIs from the formulation, leading to slower permeation and the resultant lower potency.
It is interesting to note that Dermovate® which contains CP was found to be more potent than Elocon®which contains MF whereas the potencies of the corresponding APIs were reversed in the study reported by Zvidzayi et al (26), further implicating formulation effects. However, the potency ranking of the TCPs is in line with the existing classification systems worldwide. The US classification system ranks a 0.05% CP cream as a class I (superpotent) agent and 0.1% MF cream as a class IV (midstrength) agent. The British National Formulary classifies 0.05% clobestasol propionate as class I (very potent) and 0.1% MF as class II (potent) without specifying the type of formulation. New Zealand classifies CP as very potent/ superpotent and MF as potent but does not provide the details about the strength of the TC or the type of formulation. The presence of such discrepancies reiterates the need for the development of a more reliable classification system for TCPs using standardised procedures and validated methods such as the FDA’s VCA (22) which will ensure consistency relating to precision, reproducibility and associated validation parameters. Furthermore, the determination ofEmax values for specific products is a further advantage, whereby a specific metric can be used as a standard potency determinant.