Effect of penetration enhancers and amorphization on transdermal permeation flux of raloxifene-encapsulated solid lipid nanoparticles: an ex vivo study on human skin

Despite 60% oral absorption, high first-pass metabolisms resulted in 2% oral bioavailability of raloxifene and also suffer poor water solubility. In this study, we developed the penetration enhancer rich hydrogel containing raloxifene-loaded solid lipid nanoparticles (RL-SLNs) for transdermal route. Interestingly, SLN offers higher solubility and thermodynamic activity due to amorphization of drug and evasion of first-pass metabolism by transdermal route. Cumulative effect will contribute to enhanced permeation flux, controlled drug release and enhanced bioavailability. Nanoparticles were synthesized using solvent emulsification-evaporation method and evaluated further for various physicochemical properties, ex vivo permeation and hydration studies. RL-SLN3 with particle size 227.9 +/- 12.6 nm, polydispersity index 0.283 +/- 0.021, zeta potential 15.4 +/- 1.7 mV and entrapment efficiency 77.04 +/- 5.08% was selected for further studies as optimized formulation. Differential scanning calorimetric method revealed that 54.75% of RL had changed to amorphous state adding to enhanced solubility. Furthermore, the results of ex vivo permeation studies on human skin elucidated that 10% d-limonene in combination with RL-SLN had excellent permeation flux (7.24 +/- 0.49 mu g/cm(2) h) compared to RL-SLN alone and other penetration enhancers tested. Thus, the output of above studies suggested that transdermal delivery of RL-SLN using d-limonene as penetration enhancer can be a promising approach to evade the first-pass metabolism and increase the systemic bioavailability of RL.