Targeted skin delivery of topically applied drugs by optimised formulation design

Abstract

Early research concentrated on the relationship between a solute's physicochemical properties and its skin permeation, mostly from simple solutions. Relatively less is known about how vehicles, particularly complex ones, might also affect skin permeation by altering the properties of the skin, although this is an area that has attracted much interest. Key requirements for topical delivery is understanding the relationships between drug-vehicle, drug-skin or drug -vehicle -skin interaction. In this project, understanding this relationship was crucial to designing novel formulations able to deliver drugs with different lipophilicity topically or systemically. The first aim was to explore the impact of various solution compositions on skin permeation of some model drugs. I compared in vitro maximum penetration fluxes (Jmax) and solubilities of the vehicles (Sv) and of the stratum corneum (SSC) and derived diffusivities (D*) for four drugs (caffeine, minoxidil, lidocaine and naproxen) having a range of lipophilicities. I used a range of solvent vehicles that were hypothesised to affect the skin to differing degrees to evaluate vehicle effects on permeability parameters.If neither the vehicle nor the solute alters the properties of the skin, maximum (or saturated) solute flux is independent of both the vehicle composition and the solute's saturated solubility in that vehicle. These findings were confirmed in this study for all four drugs used.The permeation of caffeine, minoxidil, lidocaine and naproxen were found to be selectively enhanced by vehicles containing specific excipients that were hypothesised to alter the properties of the skin. The greatest effects were seen on flux and diffusivity by the eucalyptol (EU) and oleic acid (OA) vehicles on the more hydrophilic compounds, caffeine and minoxidil. We concluded that enhanced solute fluxes were mainly driven by increased diffusivity in the stratum corneum.I also examined the extent of skin permeation enhancement of the hydrophilic drug caffeine and lipophilic drug naproxen applied in nanoemulsions incorporating skin penetration enhancers. Infinite doses of fully characterised oil-in-water nanoemulsions containing the skin penetration enhancers oleic acid or eucalyptol as oil phases and caffeine (3%) or naproxen (2%) were applied to full-thickness skin and human epidermal membranes in Franz diffusion cells, along with aqueous control solutions. Caffeine and naproxen fluxes were determined over 8 h. Solute solubility in the formulations and in the stratum corneum, as well as the uptake of product components into the stratum corneum were measured.The nanoemulsions significantly enhanced the skin penetration of caffeine and naproxen compared to aqueous control solutions. The maximum flux enhancement of caffeine was III associated with a synergistic increase in both its solubility in the stratum corneum and skin diffusivity. Enhanced skin penetration in these systems is largely driven by uptake of formulation excipients containing the active compounds into th...

Application of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs – a PEARRL review

“…The HSP approach within LBDDS has only been investigated to a limited extend, potentially due to the variability and complexity of the lipid excipient composition and the multitude of drug–excipient interactions. However, there are further pharmaceutical applications that are to some extent linked to lipids in general such as intestinal drug absorption, skin penetration of topically applied drugs, and prediction of drug–nail interactions . The available studies suggest that partial solubility parameters have the potential to be a useful tool in early development of LBDDS.…”