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.