Understanding the in vivo dynamics of non-occlusive drug delivery systems

Over the years, many studies have focused on characterising the penetration behaviour of drugs across the skin in order to develop methods to improve transdermal drug delivery. However, very few studies have been able to account for the fact that the process of drug penetration into the skin’s major barrier, the stratum corneum (SC), occurs in tandem with the process of lateral diffusion across the skin surface. Furthermore, the exact distance that drugs spread radially from their application site, as well as the extent of their lateral diffusion within the SC bilayers, has been poorly defined. Lateral diffusion from the application site increases the area of drug exposure and for potent drugs, this may increase the risk of secondary drug contact to third parties. Therefore, the aim of this thesis was to develop a method sensitive enough to determine both the lateral diffusion and penetration behaviour of topically applied drugs across the SC, as well as evaluate the impact of formulation excipients on the fate of drugs applied topically to humans. Specially designed concentric adhesive tapes perforated into four sections of known diameter were developed to follow the distribution behaviour of small volumes of ethanolic solutions of drugs across the SC. Repeated stripping of the concentric tapes allowed for assessment of the three–dimensional distribution of three model compounds with different lipophilicities across human SC in vivo. Caffeine (CAF), a hydrophilic drug, formed a flat depot on the surface and in the uppermost regions of the SC. Hydrocortisone (HC), a relatively more lipophilic drug compared to CAF, exhibited a lower tendency to spread and instead, formed a narrow drug reservoir in the uppermost regions of the SC. Ibuprofen (IBU), a lipophilic drug, demonstrated greater drug penetration and lateral diffusion across the SC in comparison to CAF and HC. The SC is a heterogeneous system with lipophilic and aqueous domains, and so, lipophilic drugs such as IBU are more soluble in the lipid medium and thus, the SC poses less resistance to their diffusion. In contrast, lateral diffusion across the skin will be less tortuous for hydrophilic drugs, such as CAF. For HC, however, lateral diffusion is reduced compared to CAF owing to its more lipophilic nature and its tendency to form drug reservoirs within the skin. As IBU demonstrated the most significant penetration following topical application, the effect of excipients – propylene glycol (PG), polyethylene glycol 200 (PEG 200) and octisalate (OS), on the lateral diffusion and penetration behaviour of ethanolic solutions of IBU across human skin was also assessed. OS promoted lateral diffusion of IBU while the addition of PG and PEG 200 decreased lateral diffusion of drug and retained the majority of IBU within close proximity to the application area. As PG and PEG 200 are highly viscous materials compared to OS, it is likely that the movement of IBU across the skin surface is dependent on the flow of the vehicle in which it is dissolved. In addition, the larger contact angle formed between droplets of IBU and human skin when mixed with PG and PEG 200 (relative to IBU applied with OS alone) further highlights the resistance of viscous vehicles to spread. After prolonged drug exposure, approximately 55% and 25% of IBU was recovered from the uppermost layers of the skin when applied alone and in the presence of PG, PEG 200 and OS, respectively. To determine whether this significantly lower recovery of IBU (when applied with excipients) was due to enhanced penetration, in vitro permeation studies were carried out to assess the percutaneous absorption of IBU with and without excipients. Following the onset of steady-state delivery, the flux of IBU increased by an average of 2-fold in the presence of PG, PEG 200 and OS compared to IBU applied alone. Therefore, it is likely that the significant loss of IBU from the uppermost region of the skin in vivo was due to enhanced permeation of IBU in the presence of PG, PEG 200 and OS. The research and findings from this thesis demonstrate that following topical application, the competing processes of lateral diffusion and penetration of drug both contribute to the disposition of drugs within the SC. To an extent, drug lipophilicity may govern the distance of lateral diffusion across the SC and hence the level of secondary exposure. Furthermore, the ability to reduce lateral diffusion by increasing formulation viscosity may allow for the development of more safe and effective transdermal drug delivery systems.