Clinical Proof for Validity of the 'Formulating for Efficacy' Concept: Enhanced Skin Delivery Results in Enhanced Skin Efficacy and Both Can Be Predicted

摘要

The Formulating for Efficacy concept is a systematic approach to simultaneously optimize the driving force of the active ingredient (so that it partitions in larger quantities into the stratum corneum) and reduce its concentration in the formulation without a loss of clinical efficacy. Its ultimate aim is to optimize the clinical efficacy via enhancement of the skin delivery of the active principle at the lowest possible concentration, i.e. at minimal cost. The validity of this approach was initially demonstrated through the use of in vitro skin penetration methodology. A formulation containing 2% octadecenedioic acid that was optimized in this way for skin delivery resulted in 3.5-fold higher concentrations in the viable skin layers than those obtained from a non-delivery optimized formulation containing the same amount of active ingredient.In this paper, clinical studies using the same optimized and non-optimized formulations, as those in the in vitro experiments described above were used to assess whether an enhanced skin delivery also resulted in enhanced clinical efficacy. In addition, a second optimized formulation containing 1 % octadecenedioic acid was prepared and compared with the optimized formulation containing 2% of the same active ingredient. All studies consisted of an 8-week application phase. In the two studies with optimized octadecenedioic acid delivery this was followed by a 4-week regression phase. Skin whitening efficacy was assessed using chromamet-ric analysis of skin color. Comparison of the non-optimized and optimized formulations showed that the previously assessed 3.5-fold increase in skin delivery resulted in a 3.2 to 3.9-fold increase in clinical activity of the delivery-optimized formulation. This increase was statistically significant (p < 0.05 and p < 0.002, respectively), whereas the difference between the two delivery-optimized formulations was statisti-cally insignificant (p > 0.05). This confirms the validity of using the "Formulating for Efficacy"guidelines for selecting emollients in topical formulations, as enhanced skin delivery of the incorporated active ingredient corresponds to a similarly enhanced clinical efficacy of the formulation.The enhanced skin delivery from the optimized formulation could be predicted by assessment of the maximum solubility of the active in the non-optimized formulation. It was calculated that the level of active in the non-optimized formulation was only 25% that of maximum solubility and therefore the skin delivery and skin efficacy could be improved by a factor of 4. In addition, the maximization of clinical efficacy could also be predicted by studying the binding curves of the active ingredient to its receptor. Likewise, theory predicts that the skin delivery of two independently optimized formulations containing either 1 % or 2% oc-tadecenedioic acid should result in the same delivery of the active ingredient and therefore also the same clinical efficacy. The reality of a clinical study confirmed this theory: the 1% and 2% formulations resulted in equal skin whitening efficacy. It can therefore be concluded that the formulation guidelines of the "Formulating for Efficacy" concept are not only valid in theory or only in in vitro skin delivery set-ups but also in in vivo clinical situations. Moreover, the potential increases in clinical efficacies can be predicted from simple solubility experiments of the active in the formulation.