Polymeric micelles for cutaneous delivery of resveratrol

Purpose: The efficacy of resveratrol (RES) in preventing skin aging and protecting epidermis from damages induced by UVA and UVB has been recently demonstrated (Soeur et al., 2015). Considering the low skin penetration of UV rays, the design of delivery systems able to promote the RES localization into the epidermis resulted of interest to guarantee skin protection. The present study aimed to evaluate the feasibility of poloxamer micelles for enhancing the RES penetration in the upper skin layers. Methods: 0.1% w/v RES-loaded polymeric micelles were prepared using solvent diffusion method (acetone solution/water: 1/10 v/v). Poloxamer 118 (P118) and 407 (P407) were selected as excipients because of their high solubility in water, other than the different molecular weight and HLB value. To study the impact of polymer composition on the physical properties and stability of RES-loaded polymeric micelles, different formulations were prepared using different concentrations of polymers (0.1-1.0% w/v), as single polymer or 1:1 mixture. The resulting nanosystems were characterized in terms of particle size, ζ-potential and apparent solubility of RES in water. Their physical stability was also checked over 1 month at room temperature. Release studies through artificial membrane (i.e., Cuprophan®) and in vitro permeation studies through full-thickness porcine ear skin were performed over 24 h by using Franz cells. Results: Poloxamers can auto-assemble in nano-micelles when RES was added to the formulation. The size of micelles ranged from 30 to 300 nm, as function of their compositions; ζ-potential was almost neutral for all formulations. In micellar systems containing P407, the RES apparent solubility significantly increased (1.05±0.7 mg/mL) with respect to a saturated solution (0.04±0.00 mg/mL). Similar results were observed with P118, but it had a lower solubilizing efficiency (0.36±0.33 mg/mL). The release study suggested that micelles could act as nano-reservoir systems for RES. Indeed, the RES amount diffused through Cuprophan® membrane within 8h (<5%) was six-time lower for polymeric micelles in comparison to the control solution (≈30%). Among micellar systems, the diffused RES amounts increased in the order: P407 < P118/P407 (1:1) ≈ P118. In vitro permeation study demonstrated that the RES permeation through full-thickness porcine skin was negligible for all tested formulations and the RES retention in the deep epidermal and dermal layers resulted lower than 1% of total RES loaded. Nevertheless, the stripping technique revealed that micellar formulations were more efficient in promoting the penetration and retention of RES than control (p < 0.01) in the upper epidermal layers. Interestingly, micelles made of P188 and P407 (1:1) could enhance the permeation of RES in the lower epidermal layers more than other micellar systems and control (p < 0.05). Conclusions: Poloxamers can auto-assemble in presence of RES to form micellar systems, enhancing significantly its apparent solubility in water. Micelles made of P188 and P407 resulted promising nanocarriers for enhancing the skin partition of RES and its localization in the upper skin layers. References Soeur J et al. Skin resistance to oxidative stress induced by resveratrol: From Nrf2 activation to GSH biosynthesis. Free Radical Biology and Medicine 2015, 78, 213-223.