No abstract

18Nasal delivery has become a growing area of interest for drug administration as a consequence of several 19 practical advantages, such as ease of administration and non-invasiveness. Moreover, the avoidance of hepatic 20 first-pass metabolism and rapid and efficient absorption across the permeable nasal mucosa offer a promising 21 alternative to other traditional administration routes, such as oral or parenteral delivery. In fact, nasal delivery 22 has been proposed for a number of applications, including local, systemic, direct nose-to-brain and mucosal 23 vaccine delivery. Nanoemulsions, due to their stability, small droplet size and optimal solubilization properties,

Imiquimod (IMQ) is an immunostimulant drug topically used for the treatment of actinic keratosis and basal cell carcinoma. IMQ formulation and skin delivery is difficult because of its very low solubility in the most of pharmaceutical excipients and very poor skin penetration properties. The purpose of this study was to develop a microemulsion to optimise imiquimod skin delivery using D-α-tocopherol polyethylene glycol-1000 succinate (TPGS) as surfactant (so as to take advantage of its thickening properties) and isostearic acid as oil phase. This fatty acid was selected since it has demonstrated a good solubilizing power for imiquimod and it has also shown to contribute to its therapeutic activity. We have built pseudo-ternary diagrams using two different co-surfactants (Transcutol® and propylene glycol-PG) in a 1:1 ratio with TPGS and then selected microemulsions in the clear and viscous regions of the diagrams. The systems were characterized in terms of rheology and X-ray scattering; additionally, the capability to promote IMQ skin uptake was evaluated ex-vivo on a porcine skin model. All the formulations selected in the gel-microemulsion regions behaved as viscoelastic solids; X-rays scattering experiments revealed in all cases the presence of an ordered lamellar structure, but with differences in terms of interlamellar distance and flexibility between Transcutol® and PG-containing systems. A higher flexibility and a greater hydrophobic volume, possibly interconnected at some point, was associated to the use of Transcutol® and had an impact on the microemulsion capacity to solubilize IMQ as well as on the capability to enhance drug uptake into the skin. The best performing gel-like microemulsion was composed of ≈ 26% of water, ≈21% of isostearic acid, ≈26% of TPGS and ≈27% of Transcutol® and accumulated, after 6h of contact, 3.0 ± 1.1 µg/cm2 of IMQ. This value is higher than the one reported in the literature for the commercial cream (1.9 ± 0.8 µg/cm2), despite the 4-times lower concentration of the vehicle (13 mg/g for the microemulsion vs 50 mg/g for the commercial cream).

The skin has evolved to resist the penetration of foreign substances and particles. Topical therapeutic and cosmeceutical delivery is a growing field founded on selectively overcoming this barrier. Both the biology of the skin and the nature of the formulation/active ingredient must be aligned for efficient transcutaneous delivery. This review discusses the biological changes in the skin barrier that occur with common dermatological conditions. This context is the foundation for the discussion of formulation strategies to improve penetration profiles of common active ingredients in dermatology. Finally, we compare and contrast those approaches to recent advances described in the research literature with an eye toward the future of topical formulation design.