Towards nanoformulations for skin delivery of poorly soluble API: What does indeed matter?

Abstract Loading sparingly soluble active pharmaceutical ingredients (API) and overcoming biological barriers are two challenging issues in the drug delivery and technology fields. In this work, we assessed the influence of composition on the ability of nanosized ethosomes to increase the apparent solubility and drug incorporation, as well as the skin penetration of two hydrophobic drugs, celecoxib and paclitaxel. Ethosomes were produced through the bottom-up method using ethanol injection, and APIs were added in supersaturated ethanolic solution. Variations in the composition of the aqueous phase (containing or not Tween 80 micelles) and phospholipid content (2 or 4 %, w/v) were included to assess their effect on ethosomes characteristics and drug apparent solubility. Dynamic light scattering enabled monitoring the non-soluble API precipitation and indicated an increase in size (up to 500-1000 nm) and polydispersity (above 0.3). Soft and fast centrifugation at 5000 g for 5 min enabled removal of non-soluble APIs, decreasing size and PDI to ∼300-400 nm and 0.2-0.3, respectively. The nanoformulation incorporated ∼60-90 % of the API added, but short-term stability assays suggested precipitation of paclitaxel at 24-72 h. These results were evaluated by two factorial designs 22, and a significant effect of lecithin concentration on celecoxib solubilization was observed. A tendency of interaction between Tween 80 micelles presence and increased solubilization was observed for celecoxib but not paclitaxel. Higher amounts of celecoxib (∼5-fold) were quantified in the stratum corneum and epidermis (minus stratum corneum) + dermis after treatment with ethosomes containing Tween 80 compared to those without the surfactant, but not in the receptor phase. For paclitaxel, presence of Tween 80 micelles did not affect delivery. This work evidenced the feasibility of the ethosomes developed to load poorly soluble APIs and to deliver them to skin but suggest that this effect vary with composition and the API physicochemical characteristics. Nanocarrier composition and level of molecular complexity and characteristics of APIs are factors that can interact and generate distinctive effects on both API solubilization and delivery to/across the skin.