2005 ANNUAL SCIENTIFIC MEETING 191 FORMULATING FOR FAST EFFICACY Johann W. Wiechers1, Ph.D., Caroline L. Kelley2, Ph.D., Trevor G. Blease2, Ph.D. and J. Chris Dederen3, Ph.D Introduction: Uniqema Applied Research, 1 The Netherlands Uniqema Applied Research, 2 United Kingdom Uniqema Applied Research, 1 Belgium SOlulliHty penelrant\ The underlying issue in not delivering the promise of cosmetic products in a consumer-noticeable and fast way is very often the lack of sufficient skin delivery of active ingredients into the skin. Our previous work has indicated that the choice of the emollients determines the quantity of active ingredient penetrating the skin. The polarity of the phase in which the active ingredient is solubilized can be calculated and is a compromise between the solubility of the active ingredient in the formulation on the one hand and the driving force for penetration into the skin on the other hand. For details of this so-called Formulating for Efficacy concept, see Figure 1 and ref. l. -s1l penelnlnl I l110l'fJ hydrophilic -PPG polarity + PPG penetrant more lipophilic Figure 1: Schematic representation of the "Formulating for Efficacy" Co11cept Whereas this approach helps to increase the quantity of active ingredient penetrating the skin, it does not guarantee that at any given time, there is also sufficient active ingredient at the site of action to achieve levels above the minimal effective concentration. To achieve this, the deposition of active ingredient in skin - the so-called drug targeting - should also be taken into account. Deposition of ingredients is influenced by both the rate and extent of the percutaneous absorption process. Whereas the choice of emollients regulates the extent to which active ingredients penetrate the skin, the choice of the emulsifier influences the rate of skin penetration, probably due to the interaction of enmlsifiers with skin lipids. In order to investigate the influence of emulsifiers on the rate and extent of skin penetration of cosmetically active ingredients, two types of studies were performed: 1. Clinical studies in which the emollient was used as the active ingredient (either acting as a skin moisturizer or as a skin elasticity provider both emollients were lipophilic) 2. Skin penetration studies in which a hydrophilic or a 1ipophilic active ingredient were included in formulations using emulsifiers that formed either liquid-crystalline emulsions or not. Results: In the clinical trials in which 36 formulations were tested for either skin moisturization ( 18 formulations 9 containing a good moisturizing emollient and another 9 containing a poorly moisturizing emollient) or skin elasticity (another 18 formulations also 9 with a good elasticity-providing emollient and another 9 with a poor elasticity-providing emollient). All formulations were applied for 6 hours. Formulations with a liquid-crystalline structure gave better skin moisturization or skin elasticity as measured by the Comeometer or Dermal Torque meter, respectively (see Figure 2). From this, we concluded that these formulations deliver more of the lipophilic moisturizer or elasticity-provider into the (epi)dermal layers of the stratum comeum at 6 hours. Figure 1: (Epi)deNlf#I hlivery (ond tJ,us moisturization) is better from lifuid-crystallineforWJulations. In the skin delivery studies, the total skin penetration of the lipophilic octadecenedioic acid was the same after 24 hours from a liquid-crystalline and a non-liquid crystalline formulation. However, while the dennal delivery was high and the transdermal delivery low from the non-liquid crystalline formulation, this was reversed for liquid-crystalline fomrulation, suggesting the skin penetration of lipophilic ingredients to be faster from liquid crystalline systems (see Figure 3). In contrast, the total skin penetration of the hydrophilic propagermanium increased significantly from a liquid-crysta1line fonnulation but the transdermal delivery was low from both formulations types. From this, we conclude that the skin

192 JOURNAL OF COSMETIC SCIENCE penetration process is prolonged (hence more penetration) for hydrophilic active ingredients but enhanced □ ■Tapes Skin for the lipophilic active ingredients (hence more transderrnal delivery). ■ Tran.clermal Fonnulatlon Fonnulatlon Discussion: A B At first glance, the results seem somewhat inconsistent but sense can be made if the factor time is brought into consideration. For hydrophilic active ingredients, the water in liquid-crystalline formulations is structured (see b in Figure 4) and as a consequence, it evaporates less, keeping the active ingredient in solution and therefore to penetrate for longer. This explains the increased penetration of hydrophilic active ingredients from liquid- crystalline formulations at 24 hours. Figure 4: Figure 3: Skin delivery of tl,e lipophilic octadecenedioic acid is Jaster from a liquid- crystalline formulation (BJ than from a non- liquid crystalline formulation (A). a: hydrophobic part b: trapped water c: hydrophilic part d: bulk water e: oil Hydroplri/ic chemicals remain solubi/ized longer in trapped water within liquid-crystalline emulsion structures For lipophilic active ingredients, we postulate a shift in the skin lipid packing from orthorhombic to hexagonal (see Figure 5). This will result in an increased skin permeability of active ingredients of all polarities, explaining the observed increase in (epi)derrnal delivery of the moisturizing and elasticity-providing emollients at six hours and the increased transdermal delivery of the lipophilic active ingredient octadecenedioic acid at 24 hours. Transdermal delivery of the hydrophilic propagermanium had indeed increased but was still low, suggesting that for hydrophilic ingredients the time-extension is more prominent than the increase in skin permeability. Figure 5: A shift from orthorhombic to hexagonal skin lipid lacking will increase tJ,e skin permeability of all active ingredients. Liquid-crystalline emulsion structures may therefore be used when increased efficacy (and thus increased skin delivery) is needed for hydrophilic active ingredients and when faster efficacy (and thus faster delivery) is needed for lipophilic active ingredients. In the latter case, however, it may be necessary to change from single daily dosing to multiple daily dosing to maintain clinical efficacy over a prolonged period of time. References: I. Wiechers, J.W., Kelly, C.L., Blease, T.G., and Dederen, J.C., Formulating for Efficacy, Int. J Cosm. Sci., 26, 173-182 (2004).