Various studies have been performed to compare different types of emulsions (Dal Pozzo and Pastori 1996; Förster et al. 1997; Wiechers 2005). However, not only the type of emulsion was different, the formulation ingredients also varied, and their interactions with the active ingredients (e.g. solubilisation in micelles, supramolecular complex formation) may therefore have impacted on the dermal and transdermal delivery of the active ingredients (Dal Pozzo and Pastori 1996). Consequently, due to the complexity of topical emulsions, the investigation of the emulsion type effects on dermal and transdermal delivery requires a systematic approach.

A study by Lalor et al. (1995), for example, showed the effects of the incorporation of surfactants in o/w and w/o emulsions (polysorbate 60 (Tween® 60) in o/w emulsion and sorbitan sesquioleate (Arlacel® 83) in w/o emulsion) on the partitioning and permeation of three model compounds (methyl-, ethyl- and butyl-p-aminobenzoate), due to the solubilisation capabilities of the emulsifiers. It was demonstrated that the emulsifier (surfactant) and its distribution between the oil and water phase played an important role in the solubility and therefore thermodynamic activity of the permeants in the vehicle, i.e. the thermodynamic activity of the compounds in the external phase of the emulsions was found to be the driving force for permeation through the polydimethylsiloxane membranes. Polysorbate 60 (Tween® 60), the surfactant used in the o/w emulsion, was mainly available in the external aqueous phase of the emulsion, where it formed micelles and solubilised the three test permeants, methyl-, ethyl- and butyl-p-aminobenzoate, thereby reducing their thermodynamic activity and the permeability coefficient. The permeability coefficient between the o/w emulsion and its corresponding, externally isolated aqueous phase was equal, signifying the importance of the thermodynamic activity of the permeants in the external phase for promoting the permeation process. However, the solubility of the three compounds in the oil phase of the same o/w emulsion was similar to the solubility in the oil without surfactant, indicating no solubilising effect of polysorbate 60 (Tween® 60) in the oil phase of the o/w emulsion, hence resulting in similar permeability coefficients between the internal oil phase and the pure oil. Analogous results were obtained with the w/o emulsion in which the emulsifier, sorbitan sesquioleate (Arlacel® 83), was nearly entirely distributed in the oil phase of the emulsion, whereas the aqueous phase was in effect free of sorbitan sesquioleate (Arlacel® 83). This yielded no solubility increase in the internal aqueous phase and thus no reduction in permeability, when compared with water. However, the solubility of each compound increased in the oil phase, because of the formation of inverse micelles. Consequently, the permeability of the three test permeants was reduced from both the w/o emulsion and from the corresponding isolated external oil phase, when compared with the pure oil.

Several studies have been reported, involving different emulsion types with identical composition (e.g. o/w, w/o and w/o/w), hence allowing for the systematic investigation of the effect of the type of emulsion on dermal and transdermal delivery only. These study outcomes are summarised in Table 16.1.

The results in Table 16.1 demonstrate that the type of emulsion significantly influenced both skin penetration and skin permeation of the active ingredients. The effect of the type of emulsion on dermal and transdermal delivery was furthermore dependent on the dosing condition (finite non-occluded vs. infinite occluded). With finite dosing under non-occluded conditions, the physicochemical and thermodynamic properties of the formulation modified rapidly after application onto the skin, whereas at infinite dosing under occluded conditions, the thermodynamic properties did not alter significantly (Laugel et al. 1998b).

In summary, it can be concluded that the percutaneous absorption, as well as the skin penetration of hydrophilic drugs (e.g. glucose, metronidazole and lactic acid), is generally superior for o/w emulsions, compared to w/o/w and w/o emulsions (Fig. 16.3). Various suggestions were made for the differences in performance between the diverse emulsion types. For example, the higher skin uptake from o/w emulsions could have been due to a higher concentration of free hydrophilic actives in the external aqueous phase of the emulsions being directly in contact with the skin, whilst the actives were encapsulated in the internal phase of the w/o/w and w/o emulsions and as a result not readily available to the stratum corneum (Ferreira et al. 1995b; Youenang Piemi et al. 1998; Sah et al. 1998). It was hence suggested that w/o/w and w/o emulsions could be utilised for the controlled release of water-soluble actives (Sah et al. 1998). As shown by Ferreira et al. (1994, 1995b), the release of glucose and metronidazole through cellulose membranes and silicone membranes was in the following order: o/w > w/o/w > w/o. The release from the w/o/w emulsion was higher than from the w/o emulsion, due to the leakage of glucose and metronidazole into the external aqueous phase, resulting in a higher effective concentration of the hydrophilic actives in the external aqueous phase of w/o/w emulsions than in the external oil phase of w/o emulsions (Ferreira et al. 1995a, b). It should also be noted that the differences in polarity of the active ingredients further impacted on the performances of the various emulsions. So the difference between the various emulsions was more pronounced for glucose (high polarity) than for metronidazole (intermediate polarity), due to a smaller oil-water partitioning coefficient of glucose, indicating a higher concentration of glucose in the aqueous phase, when compared with metronidazole (Ferreira et al. 1995b). Furthermore, the partitioning between the oil and water phases in the emulsion was better for metronidazole, which in turn yielded a decrease in the internal release barrier and therefore a less pronounced difference in performance between the various metronidazole emulsions (Ferreira et al. 1995a).

Differences in dermal and transdermal delivery could also have occurred as a result of different partitioning coefficients between the stratum corneum and the various emulsions, e.g. a higher partitioning between the stratum corneum and external aqueous phase (for o/w and w/o/w emulsions) than between the stratum corneum and external oil phase (for w/o emulsions). In addition, the external aqueous phase may have contributed to the hydration of the stratum corneum, which in turn may have enhanced the permeability of hydrophilic compounds (Ferreira et al. 1995b). This effect could be more pronounced for an infinite, occluded dosing condition than for a finite, non-occluded dosing (Sah et al. 1998).

It is also important to consider the fate of the emulsion after application onto the skin and its effect on the delivery of the actives. Following the application onto the skin, volatile components (e.g. water) can evaporate, and therefore phase transitions, inversion, flocculation and coalescence may occur (Friberg and Langlois 1992). In addition, the drug concentration in the residual film could increase, due to water evaporation from a finite dose (Sah et al. 1998). Consequently, consideration of the evaporation of volatile components, as well as the vehicle structure of the remaining film after the evaporation of volatile components, is of importance when investigating skin penetration of actives. Ferreira et al. (1995a) investigated water evaporation from three different emulsions (o/w, w/o/w and w/o) and found that the rate thereof was higher from emulsions with an aqueous continuous phase (o/w and w/o/w) than from emulsions with an oily continuous phase (w/o) (Fig. 16.4), which may partially explain the differences in dermal and transdermal delivery. They also investigated the structure of the residual film after evaporation was completed and its effect on the lipid organisation of the stratum corneum. No differences were detected among the three emulsions (o/w, w/o/w and w/o) though. Youenang Piemi et al. (1998) reasoned in their article that the similar performances of w/o/w and w/o emulsions in the dermal and transdermal delivery of glucose could be due to a similar vehicle structure of the w/o/w and w/o emulsions after application onto the skin, because of the evaporation of the external water phase of the w/o/w emulsion.

It should be noted that most of the studies on hydrophilic compounds, as listed in Table 16.1, were performed with the same synthetic emulsifier system Hypermer™ A60 (a modified polyester)/poloxamer 407 (Synperonic™ PE/F127). However, the one study by Youenang Piemi et al. (1998) incorporated natural soybean phospholipids (lecithin, Emulmetik™ 100/300) as emulsifier in order to obtain different types of emulsions. Overall, the same trend was observed with the soybean phospholipids as with the synthetic emulsifiers. This was indicative of the importance of the nature of the continuous phase of an emulsion on the dermal and transdermal delivery of hydrophilic drugs (Youenang Piemi et al. 1998). Furthermore, the results of the various studies with hydrophilic active ingredients indicated that the type of emulsion (o/w, w/o/w, w/o) may not significantly affect the distribution of the actives between dermal and transdermal delivery, as the order of emulsions was similar for dermal and transdermal delivery (see Table 16.1).

As with the hydrophilic drugs, the encapsulation of the lipophilic actives (hydrocortisone and three different triterpenic derivatives) in the internal oily phase of multiple o/w/o emulsions reduced the percutaneous absorption of these lipophilic actives, compared to that of simple w/o emulsions, when applied as a finite dose. However, the uptake of the lipophilic actives into the epidermis and dermis was higher from the multiple o/w/o emulsion than from the simple w/o emulsion (Laugel et al. 1998a, b). Similarly, a release study showed that the release of hydrocortisone was slower from a multiple o/w/o emulsion than from a simple w/o emulsion, as the active needed to diffuse from the internal phase, across the aqueous phase and into the external phase (Laugel et al. 1998b). Both studies hence confirmed that multiple o/w/o emulsions could be used as prolonged, topical delivery systems for lipophilic drugs, when incorporated in the internal oily phase and applied as a finite dose. Furthermore, these multiple emulsions exhibited the advantages of reducing the transdermal delivery and therefore the systemic effects of the lipophilic drugs, whereas the dermal delivery was increased, thus showing a controlled release of the drugs to the site of action (Laugel et al. 1998b). However, it should be noted that no significant differences in transdermal delivery were observed between w/o and o/w/o emulsions, when an infinite dose of hydroquinone containing emulsions was applied onto the skin (Laugel et al. 1998b).

When investigating the dermal and transdermal delivery of active ingredients from emulsions, consideration of the stabilisation effects of a formulation on delivering degradation-sensitive active ingredients intact into and/or across the skin can prove beneficial. Schmidts et al. (2011) investigated the stabilisation effects of various emulsion systems against enzymatic degradation of topically applied oligonucleotides. They found that the enzymatic degradation of water-soluble DNAzymes, encapsulated in the inner aqueous phase of w/o/w and w/o emulsions, was significantly reduced, compared to DNAzymes, incorporated in the outer aqueous phase of a microemulsion and a submicron emulsion. The outcomes of their study suggested that w/o and w/o/w emulsions are promising formulations for effective encapsulation of DNAzymes with concurrent protection against enzymatic degradation.