Synergetic skin targeting effect of hydroxypropyl-β-cyclodextrin combined with microemulsion for ketoconazole

The objective was to develop a ternary skin targeting system for ketoconazole (KET) using a combined strategy of microemulsion (ME) and cyclodextrin (HP-beta-CD), i.e., MET-CD-ME, which exploits both virtues of cyclodextrin complex and ME to obtain the synergetic effect. MET-CD-ME was formulated using Labrafil M 1944 CS as oil phase, Solutol HS 15 as surfactant, Transcutol P as cosurfactant, and HP-beta-CD solution as aqueous phase. The formulation of MET-CD-ME was optimized and the optimal formulation was characterized in terms of particle size, size distribution, pH value, and viscosity. Long term stability experiment showed that HP-beta-CD could increase the physical stability of ternary system and MET chemical stability. Percutaneous permeation of MET from MET-CD-ME in vitro through rat skin was investigated in comparison with MET microemulsion (MET-ME), MET HP-beta-CD inclusion solution (MET-CD), MET aqueous suspension, and commercial MET cream; the results showed that the combination of ME with HP-beta-CD exhibited significantly synergistic effect on MET deposition within the skin (29.38 +/- 1.79 mu g/cm(2)) and a slightly synergistic effect on MET penetration through the skin (11.3 mu g/cm(2)/h). The enhancement of the combination on skin deposition was further visualized by confocal laser scanning microscope (CLSM). In vitro sensitivity against Candida parapsilosis test indicated that MET-CD-ME enhanced MET antifungal activity mainly owing to the solubilization of HP-beta-CD on MET in the ternary system. Moreover, the interactions between HP-beta-CD and MET in the ternary system were elucidated through microScale thermophoresis (MST) and 2D H-1 NMR spectroscopy. The profiles from MST confirmed the host-guest interactions of HP-beta-CD with MET in the ternary system and a deep insight into the interactions between MET and HP-beta-CD were obtained by means of 2D 1H NMR spectroscopy. The results indicate that the ternary system of ME combination with HP-beta-CD may be a promising approach for skin targeting delivery of MET. (C) 2015 Elsevier B.V. All rights reserved.