Emulsions are the most commonly used skin delivery systems for active ingredients in cosmetic and pharmaceutical applications; as a consequence, they often receive less attention than they deserve from the point of skin delivery. Almost every component in an emulsion has the capability to influence the skin delivery of actives incorporated in the formula, but until recently this capability had not been fully realized to increase the efficacy of active ingredients.
This column will discuss ways in which ingredients can positively affect the partition coefficient of the active between the formula and the skin. By carefully selecting the emollients used in a formulation, formulators can increase the delivery and clinical efficacy of a formulation without increasing the level of the active ingredient. Examples will show that using this so-called “Formulating for Efficacy” formulation strategy can significantly enhance the clinical efficacy of a topically applied emulsion.
Emulsions are a technologically simple yet elegant skin delivery system. The feel,1 stability2,3 and delivery of an emulsion are determined by the combination of emollients and emulsifiers. The choice of the emollients determines the extent of skin delivery while the choice of the emulsifiers determines the rate of skin delivery. To explain these effects, some fundamental skin delivery theory may be useful.
Skin delivery theory: Skin delivery consists of a series of steps of partitioning and diffusion.4
Figure 1 is a schematic representation of the skin penetration process.
Partitioning is defined as the distribution of a chemical over two adjacent but different compartments at equilibrium. These two compartments can be the formulation and the stratum corneum (SC), as in Step 3 in Figure 1; the SC and the viable epidermis, as in Step 6; the viable epidermis and the dermis, Step 10; etc.
The diffusivity is described by the diffusion coefficient and is basically a rate constant within a single compartment (see Steps 2, 5, 9 and 14 in Figure 1).Each of these 17 steps in Figure 1 can be the rate-limiting step, but the diffusivity within the SC, or Step 5, is the main barrier for penetration for the majority of chemicals.
Fick’s first law of diffusion is a simplified way of mathematically describing the skin penetration process through the SC and is shown in Eq. 1.
J = KD . DC Eq. 1
The formulation/SC partition coefficient, or Step 3 in Figure 1,
is designated as K; the diffusivity within the SC, or Step 5, as D; the concentration gradient over the SC as ΔC; and the length of pathway of diffusion through the SC as l. Therefore, in order to increase the flux, J, over the SC—or to get higher levels of penetrant through the SC and into the viable epidermis—one can increase the values of K, D or ΔC.
To optimize the flux of an active ingredient across the SC, all three parameters need to be optimized but the requirements to do so seem contradictory. For instance, the ΔC can be increased by increasing the absolute concentration in the formulation, whereas the K can be increased by reducing the concentration of active ingredient in the formulation relative to that in the SC. This contradiction can be explained by emphasizing the words absolute and relative.
In order to obtain clinical efficacy of a molecule with a given intrinsic activity, two requirements need to be met. The first requirement is that there needs to be enough active ingredient or drug in the formula to allow the minimum effective concentration (MIC) at the target site to be reached. This means that one needs to have a high absolute solubility of the active ingredient in the formulation.
On the other hand, this dissolved active ingredient should also leave the formulation and partition into the SC. This driving force for diffusion can be increased by making the active ingredient more soluble in the SC than in the formulation. In other words, it should have a low solubility in the formulation relative to that in the SC.
It is therefore necessary to pay attention to the solubility of an active ingredient in the formulation as well as in the SC. A high solubility of a solid in a solvent is generally achieved if the polarity of the solvent is similar or close to that of the chemical to be dissolved. In skin delivery, there are three polarities to take into account: that of the active ingredient, that of the SC, and that of the formulation. Not all of these can be freely changed.
Whereas the polarity of an active is something that cannot be changed, and the polarity of the SC can only be marginally changed, the polarity of the formulation can be freely changed. The Formulating for Efficacy concept, as described in previous publications,4,5 was developed to calculate the ideal polarity of a formulation so that the right balance is found between incorporating as much as possible active ingredient in a formulation, requiring the highest possible absolute solubility of an active ingredient in the formulation, and ensuring the best driving force for the active to partition out of the formulation into the skin—requiring a low solubility of the active in the formulation relative to that in the SC.
The optimal polarity of the formulation that would allow 50% of the active ingredient to penetrate the skin was found to be:
Polarity Polarity Penetrant
of = of active + Polarity
formulation ingredient Gap
where the Penetrant Polarity Gap (PPG) is defined as the difference in polarity between the active ingredient and the SC (see literature5 for further details). In reality, it is even more complex because the polarity also depends on the phase ratio and concentration of the active ingredient.
Whereas theory says that a formulation prepared according to these principles should deliver 50% of the active ingredient that is applied on skin into the SC, the more skeptical formulator will ask at least two questions before accepting this new formulation strategy: Why 50% and not 100%? and: Is skin delivery really increased?
Why 50% and not 100%? The value of 50% was chosen because it results in an easy equation. Other degrees of penetration would be possible but it should be realized that most cosmetic and pharmaceutical formulations generally do not deliver more than 1% to 10% at best. Therefore, aiming for a value of 50% seems reasonable from the point of simplicity and practicality. The ultimate target of 100% skin delivery, however, would have been unrealistic. A concentration gradient would be needed—actually, a difference in thermodynamic activity of the active ingredient in the formulation and the SC, to be scientifically correct6—to create a driving force for diffusion; once 100% delivery was achieved, that implies that there is 0% left on the application area, which would reverse any gradient that might exist over the barrier, so 100% would be an unrealistic target.
When aiming for 50% delivery, there will never be a situation in which there is more in the SC than on top of the skin in the formulation; however, there is another issue that comes into play when skin delivery exceeds 10%. Once such values are exceeded, the “loss” of active ingredient from the application site, i.e., the drop in concentration or thermodynamic activity of the active, can no longer be ignored.
In in vitro skin penetration experiments, this depletion is noticeable as a deviation from steady-state flux. In other words, the steady-state flux is no longer constant because the drop in concentration can no longer be ignored. This is another reason why the skin penetration of a formulation made according to these principles will be lower than the theoretical 50%. But the skin delivery from formulations prepared according to the Formulating for Efficacy principles will be increased relative to formulations that have been composed without taking skin delivery considerations into account; by how much will depend on how good or bad the original formulation was.
Is skin delivery really increased? What the Formulating for Efficacy concept really does is two things. On the one hand, it optimizes the thermodynamic activity of the active ingredient in the formulation by selecting the right polarity and hence solubility profile of the active in the formulation. On the other hand, it ensures that this is not done at the expense of too high loadings of active ingredient.
The article of Twist and Zatz6 beautifully demonstrates the importance of thermodynamic activity. In this article, the authors study the skin penetration of methyl-, ethyl-, propyl-, and butylparaben through artificial membranes from a wide series of vehicles. Every penetrant was studied at its level of saturation in each of 11 very different solvents. The flux of methylparaben from these 11 different vehicles was basically the same (0.619 ± 0.020 x 10-6 mole/cm2/h) despite a 100-fold difference in solubility of methylparaben in these solvents (3.53–334 mg/mL) and therefore a roughly 100-fold difference in concentration applied.6
This work can be summarized as follows: As long as there is no interaction between the vehicle components and the membrane, the degree of skin penetration is determined by its fraction of maximum solubility. This has been known for some time,7 but the capability to calculate the optimal polarity of a formulation is novel.
Two skin whitening formulations were made, both containing 2% octadecenedioic acid. One was prepared with the usual physical stability and sensory considerations, whereas the second formulation was prepared with the Formulating for Efficacy concept in mind. Details on the tested formulations and skin penetration methodology employed are available in the literature.5
It suffices here to say that there were three types of samples: tape strips, reflecting the penetration into the first layers of the SC; the skin fraction, comprising the rest of the SC, the viable epidermis and the dermis; and the aliquots collected from the receptor fluid at regular intervals, representing systemic delivery as a function of time. The skin delivery of octadecenedioic acid from the two formulations determined via this method is shown in Figure2.
As this skin whitener needs to go into the skin, special attention is paid to increasing the skin fraction where the melanocytes are located on which this chemical is exerting its action.8 It can be seen from Figure 2 that the skin delivery is increased by a factor of 3.5 without an increase in the concentration of the active. The original formulation was obviously not optimized for skin delivery. In order to obtain the penetration of octadecenedioic acid from that nonoptimized formulation, the concentration of active would need to be quadrupled from 2% to 8%. The fact that this is possible is shown in Figure 3, illustrating the effect of concentration on skin delivery from the nonoptimized formulation in Figure 2.
It can be seen that one needs about 8% of octadecenedioic acid in that formulation to obtain the same skin delivery of active as from the 2% octadecenedioic acid-containing optimized formulation.
Cosmetic formulations are not made to show the consumer how well formulators understand the theory of skin penetration but to deliver a consumer-perceivable effect; however, to obtain this effect, it is important to understand and utilize the principles of skin penetration to the formulator’s advantage. The nonoptimized formulation containing 2% octadecenedioic acid from Figure 2 was tested for its skin-whitening effect on 20 Indian and Pakistani subjects using a chromametera. Further details of this experiment are available in the literature.9
This study was repeated on 20 subjects of Chinese descent a few years later using the same protocol with respect to application regimen, amounts applied as well as application times, inclusion and exclusion criteria, time of year to perform the study, etc. This allowed a direct comparison of the data from the two studies—so long as one normalizes to the start of each of the two studies. Therefore, the differences in the L-values obtained with the chromameter relative to the start of the study were plotted against time for both formulations.
Figure 4 shows that the optimized formulation was clinically superior to the original formulation in a statistically significant way (p<0.05).
Moreover, after eight weeks of twice daily application, the 2% octadecenedioic acid in the original formula reached a change in L-value of around 0.5 that, although clearly detectable for the chromameter, is only just visible for the human eye.10 After only two weeks, the skin delivery-optimized formula change in L-value, relative to the start of the study, was significantly greater and consumer perceivable. This change in L-value continued to rise until the end of the application phase at week 8. By this time, the whitening effect of the optimized formulation was very obvious for every subject in the study. It can therefore be concluded that the use of the Formulating for Efficacy concept does not only result in more skin delivery, but also in more clinical efficacy.
Reducing the Dose Without Affecting Efficacy
What the above example of the nonoptimized formulation demonstrates is that the dose can be reduced without necessarily losing clinical efficacy. Both of these two formulations, 8% octadecenedioic acid in the original formulation and 2% in the optimized formulation, were close to or at maximum solubility. Hence, they would have shown the same skin delivery in line with the methylparaben paper discussed above6 and therefore also the same clinical efficacy. To prove this point, the oil phase of the skin delivery optimized formula was halved so that the oil phase was reduced by 50% but the ratio between primary and secondary emollient remained the same. The driving force also remained the same since the fraction of maximum solubility also remained the same.
Skin delivery experiments were not performed with this new formulation but it was clinically tested simultaneously in the same lab and on the same type of subjects and protocol as the 2% optimized formulation. When the clinical results were combined with the results already shown in Figure 4, Figure 5 is obtained, which shows that relative to the 2% nonoptimized formulation, the 1% optimized formulation is 3.9-fold more effective. However, there is no statistical difference between the 2% optimized formulation and the 1% optimized formulation. This is therefore an example of reducing an applied concentration without reducing the clinical effect.
This does not suggest that one can simply keep reducing the topically applied concentration as long as the maximum driving force by formulating is maintained close to the maximum solubility of the active ingredient in the formula. The reason for this is that at very small doses, the residence time on the skin starts to become the new rate-limiting step. Skin penetration is not only determined by the applied concentration or thermodynamic activity difference, but also by the time during which this difference is maintained. Especially on arms, hands, body and face where physical contact and movement will remove the formulation, this is likely to happen. At a normal “overdose” level, this is rarely problematic and goes unnoticed. However, when applying the absolute minimum amount, the percentage of accidentally removed material will become excessive and—similar to what was said above for skin penetration values above 10%—cause a reduction in skin penetration. Research into where exactly this point is still ongoing but it is likely that this will be a constant value and therefore apply to many active ingredients.
Hopefully it is obvious that the Formulating for Efficacy concept has many benefits for the delivery of active ingredients from topically applied emulsions, but there are many additional considerations. In fact, the only thing that this concept accomplishes is to optimize the driving force of the active ingredient into the SC without affecting the SC. It assumes that the barrier for diffusion is in the SC, that the SC is constant and uniform, and that the intercellular route is the only penetration route into SC. The industry knows that this is not true in all cases. Therefore, this model will be refined in the nearby future to differentiate between the various routes of penetration and consider the differences in the SC between summer and winter months.11
In addition, some refinements to this concept have already been made* in consideration of factors such as the influence of chemicals that affect the SC, the influence of the emulsifier, and others: super-saturation, liposomes, hard and soft encapsulation systems, and electrical means of enhancing skin penetration. It is only amazing that the emulsion, one of the oldest skin delivery systems in the world, used since the days of Queen Cleopatra, still has not been optimized for skin delivery.
1. JW Wiechers, M-C Taelman, V A-L Wortel, C Verboom and JC Dederen, Emollients and emulsifiers exert their sensory impact in different phases of the sensory evaluation process but how does one demonstrate the absence of such an influence? IFSCC Magazine 5 99–105 (2002)
2. W Griffin, Classification of surface active agents by HLB, J Soc Cosmet Chem 1 311–326 (1949)
3. CD Vaughan and D Rice, Predicted o/w-emulsion stability by the required HLB equation, J Disp Sci Technol 11 83–91 (1990)
4. BW Barry, in Dermatological Formulations: Percutaneous Absorption, New York: Marcel Dekker, ch 4 (1983) pp 127–233
5. JW Wiechers, CL Kelly, TG Blease and JC Dederen, Formulating for Efficacy, Cosmet & Toil 119(3) 49–62 (2004); IFSCC Magazine, 7 13–20 (2004); Int J Cosmet Sci 26 173–182 (2004)
6. JN Twist and JL Zatz, Influence of solvents on paraben permeation through idealized skin model membranes, J Soc Cosmet Chem 37 429–444 (1986)
7. GL Flynn and RW Smith, Membrane diffusion III: Influence of solvent composition and permeant solubility on membrane transport, J Pharm Sci 49 598–606 (1960)
8. JW Wiechers et al, A new mechanism of action for skin whitening agents: Binding to the peroxisome proliferator-activated receptor, Int J Cosmet Sci 27 123–132 (2005)
9. JW Wiechers, CJ Oakley, VAL Wortel and A Barlow, Looking at the skin: Skin color, Cosmet & Toil 113(8) 61–69 (1998)
10. J Hewitt, personal communication (2005)
11. AV Rawlings, Trends in stratum corneum research and the management of dry skin conditions, Int J Cosmet Sci 25 63–95 (2003)