ABSTRACT
The objective was to develop a ternary skin targeting system for ketoconazole (KET) using a combined strategy of microemulsion (ME) and cyclodextrin (HP-ß-CD), i.e., KET-CD-ME, which exploits both virtues of cyclodextrin complex and ME to obtain the synergetic effect. KET-CD-ME was formulated using Labrafil M 1944 CS as oil phase, Solutol HS 15 as surfactant, Transcutol P as cosurfactant, and HP-ß-CD solution as aqueous phase. The formulation of KET-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-ß-CD could increase the physical stability of ternary system and KET chemical stability. Percutaneous permeation of KET from KET-CD-ME in vitro through rat skin was investigated in comparison with KET microemulsion (KET-ME), KET HP-ß-CD inclusion solution (KET-CD), KET aqueous suspension, and commercial KET cream; the results showed that the combination of ME with HP-ß-CD exhibited significantly synergistic effect on KET deposition within the skin (29.38 ± 1.79 µg/cm(2)) and a slightly synergistic effect on KET penetration through the skin (11.3 µg/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 KET-CD-ME enhanced KET antifungal activity mainly owing to the solubilization of HP-ß-CD on KET in the ternary system. Moreover, the interactions between HP-ß-CD and KET in the ternary system were elucidated through microScale thermophoresis (MST) and 2D (1)H NMR spectroscopy. The profiles from MST confirmed the host-guest interactions of HP-ß-CD with KET in the ternary system and a deep insight into the interactions between KET and HP-ß-CD were obtained by means of 2D (1)H NMR spectroscopy. The results indicate that the ternary system of ME combination with HP-ß-CD may be a promising approach for skin targeting delivery of KET.