The use of the topical route for the treatment of dermatological diseases depends on an effective formulation of products, to optimize drug delivery so as to maximize drug bioavailability at the target site while ensuring minimal adverse effects. Skin barrier function and unsuitable drug physicochemical properties can often combine to create hurdles to effective topical delivery. Systematic development of formulations considering the factors affecting topical delivery together with robust analytical tools to evaluate cutaneous drug delivery from these developed formulations could help to overcome the barriers to cutaneous delivery and to develop effective topical therapies for skin conditions. In this thesis, we wanted to address challenges associated with cutaneous delivery and post-delivery evaluations of small, intermediate and high molecular weight candidates.

The thesis can be divided into two parts. The first part investigated how nanocarrier systems could be used to improve passive cutaneous delivery across intact skin barriers and addressed the question of how different nanosystems compare in terms of delivery efficiency. The cutaneous delivery of a low and an intermediate molecular weight therapeutic was investigated using different nanoformulation-based approaches. The low molecular weight therapeutic, TAK-441, is a cytotoxic that was developed for the treatment of basal cell carcinoma and the aim of the study was to develop and to evaluate an aqueous formulation of this poorly water soluble molecule and thereby enhance its cutaneous delivery. This was successfully achieved through the use of polymeric micelle nanocarriers. Given the positive outcome using this nanoformulation approach, this led us to ask the question whether it was possible to identify the “best” nanoformulation approach and to investigate why certain molecules might be better a better fit for a given technology. To begin to answer this question, we developed and compared different nanoformulations of an intermediate molecular weight immunosuppressant drug, ciclosporin, to better understand how these different nanosystems affected its cutaneous delivery. As a corollary, the results would also lead to the development of a robust and efficient formulation for the treatment of psoriasis – there are no topical formulations of ciclosporin approved for dermatological use. The second part of this thesis focused on the cutaneous delivery of a higher molecular weight species, in this case, mRNA using various physical delivery modalities to better understand the delivery efficiencies of these techniques in targeting different skin layers and to compare the delivery as well as post-delivery protein expression qualitatively and semi-quantitatively.