“SKIN DELIVERY AND CLINICAL EVIDENCE VALIDATING THE FORMULATING
FOR EFFICACY CONCEPT
We have used the formulating for efficacy concept to make skin delivery–optimized
formulations containing octadecenedioic acid, a novel skin whitener. Formulation
A was made without using the Formulation for Efficacy concept and contained
2% active ingredient. Formulation B was made using the formulating for efficacy
concept and also contained 2% octadecenedioic acid. The exact composition of the
formulations is provided in Table 1. The only difference between the formulations
is the choice of the emollients. Propylene glycol isostearate is used as the primary
emollient in formulation B, whereas triethylhexanoin was used as the secondary
emollient. Skin delivery experiments using the two formulations on full-thickness
pig skin were performed and showed a statistically significant, 3.5-fold increase in
dermal delivery (Fig. 5) (5).
The delivery result (Fig. 5) illustrates that the formulating for efficacy concept
delivers significantly more octadecenedioic acid into the skin. The fact that this increase was 3.5-fold is accidental because this depends on the extent of skin delivery
from the formulation that was not optimized for skin delivery. Therefore, it cannot
in general be stated by what factor skin delivery will increase using the formulating
for efficacy concept. But both formulations contained 2% active, yet the delivery was
much more effective from the second optimized formulation.
In both studies, 20 subjects applied either formulation
A or B for a period of eight weeks twice a day. The chromameter measures the L, a,
and b values that characterize the color of any object. The L scale is the luminosity scale and its extreme colors are black and white; the ΔL value represents the color
difference on the L scale relative to the start of the study. The results of these two
studies are compared in Figure 6.
The skin delivery–optimized formulation B showed not only an increased skin
delivery but also an increased skin efficacy. Theoretically, there should be a direct
correlation between skin delivery and clinical efficacy, and this was confirmed in the
enhancement factors, 3.5-fold for skin delivery and 3.2-fold for clinical efficacy.
However, there is more that the formulating for efficacy concept can achieve.
In a delivery-optimized formulation, it is the ratio between the primary emollient,
the secondary emollient, and the drug, active ingredient, or cosmeceutical that optimizes the flux of the penetrant relative to its concentration. What will happen to
the skin delivery of the active ingredient if the percentage of the oil phase is reduced
and in doing so the amount of a lipophilic active in the formulation is also reduced?
Because the ratio between the three constituents of the oil phase is not changed by
this reduction, delivery expressed as μg/cm2
/hr should remain the same, although
delivery expressed as a percentage would increase.
To prove this point, a third formulation was prepared, formulation C, in which
the oil phase was halved relative to formulation B (see Table 1 for composition), and
this formulation was also clinically tested for its skin whitening efficacy. The clinical
results of formulations A, B, and C are shown in Figure 7. Relative to formulation
A (which contained 2% octadecenedioic acid and was not optimized for skin delivery), the clinical effect of formulation C (which contained 1% octadecenedioic acid
but was optimized for skin delivery) was enhanced by a factor of 3.9. There was no
statistically significant difference in clinical efficacy between formulations B and C, whereas there was between formulations A and B (P < 0.05) and formulations A and
C (P < 0.002). This proves that it is the ratio between drug, primary emollient, and
secondary emollient that is of importance, and not the absolute concentration of the
drug in a formulation, that determines the clinical efficacy. However, this does not
mean that one can infinitely reduce the concentration of the cosmeceutical in the
formulation because there will be point that there is simply not enough drug left in
the vehicle to obtain the minimum effective concentration at the target site. Studies in which the concentration is continuously reduced, that is, from 1.0% down to
0.05% octadecenedioic acid, are underway to determine the optimal concentration
in the formulation. The optimal concentration (or OC100) in the formulation is defined here as the minimum concentration of the active ingredient at which maximal
efficacy can be obtained and should not be confused with the minimum effective
concentration (or MEC) at the target site(…)”