Che Junxiu, Wu Zushuai, Shao Weiyan, Guo Penghao, Lin Yuanyuan, Pan Wenhui, Zeng Weidong, Zhang Guoguang, Wu Chuanbin, Xu Yuehong
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Eur J Pharm Biopharm. 2015 Jun;93:136-48. doi: 10.1016/j.ejpb.2015.03.028. Epub 2015 Apr 4.
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.
目的是采用微乳（ME）和环糊精（HP-β-CD）的联合策略，即KET-CD-ME，开发一种用于酮康唑（KET）的三元皮肤靶向系统，该系统利用环糊精复合物和微乳的优点来获得协同效应。以Labrafil M 1944 CS为油相、Solutol HS 15为表面活性剂、Transcutol P为助表面活性剂、HP-β-CD溶液为水相来制备KET-CD-ME。对KET-CD-ME的配方进行了优化，并从粒径、粒径分布、pH值和粘度方面对最佳配方进行了表征。长期稳定性实验表明，HP-β-CD可提高三元体系的物理稳定性和KET的化学稳定性。与KET微乳（KET-ME）、KET HP-β-CD包合物溶液（KET-CD）、KET水悬浮液和市售KET乳膏相比，研究了KET-CD-ME中KET在体外通过大鼠皮肤的经皮渗透；结果表明，ME与HP-β-CD的组合对KET在皮肤内的沉积表现出显著的协同效应（29.38±1.79μg/cm²），对KET透过皮肤的渗透表现出轻微的协同效应（11.3μg/cm²/h）。通过共聚焦激光扫描显微镜（CLSM）进一步观察到该组合对皮肤沉积的增强作用。体外对近平滑念珠菌的敏感性试验表明，KET-CD-ME增强了KET的抗真菌活性，主要是由于三元体系中HP-β-CD对KET的增溶作用。此外，通过微量热泳动（MST）和二维¹H NMR光谱对三元体系中HP-β-CD与KET之间的相互作用进行了阐明。MST的结果证实了三元体系中HP-β-CD与KET之间的主客体相互作用，并通过二维¹H NMR光谱对KET与HP-β-CD之间的相互作用有了深入了解。结果表明，ME与HP-β-CD的三元体系可能是一种有前景的KET皮肤靶向递送方法。
