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The objective was to develop a ternary skin targeting system for ketoconazole (KET) using a combined strategy of microemulsion (ME) and cyclodextrin (HP-β-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-β-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-β-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-β-CD inclusion solution (KET-CD), KET aqueous suspension, and commercial KET cream; the results showed that the combination of ME with HP-β-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-β-CD on KET in the ternary system. Moreover, the interactions between HP-β-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-β-CD with KET in the ternary system and a deep insight into the interactions between KET and HP-β-CD were obtained by means of 2D (1)H NMR spectroscopy. The results indicate that the ternary system of ME combination with HP-β-CD may be a promising approach for skin targeting delivery of KET. Copyright © 2015 Elsevier B.V. All rights reserved.


Junxiu Che, Zushuai Wu, Weiyan Shao, Penghao Guo, Yuanyuan Lin, Wenhui Pan, Weidong Zeng, Guoguang Zhang, Chuanbin Wu, Yuehong Xu. Synergetic skin targeting effect of hydroxypropyl-β-cyclodextrin combined with microemulsion for ketoconazole. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V. 2015 Jun;93:136-48

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PMID: 25845772

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