title: Synergetic skin targeting effect of hydroxypropyl-β-cyclodextrin combined with microemulsion for ketoconazole.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Junxiu
authors.initials: J
authors.lastname: Che
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Zushuai
authors.initials: Z
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Shao
authors.affiliation: Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Penghao
authors.initials: P
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Pan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Guoguang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Chuanbin
authors.initials: C
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: lssxyh@mail.sysu.edu.cn.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000279:Administration, Cutaneous; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D002175:Candida / Q000187:drug effects / Q000254:growth & development; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004655:Emulsions; D005026:Ethylene Glycols / Q000737:chemistry; D005989:Glycerides / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007654:Ketoconazole / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D018613:Microscopy, Confocal; D010316:Particle Size; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D012995:Solubility; D013229:Stearic Acids / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D014783:Viscosity; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D004655:Emulsions; D005026:Ethylene Glycols; D005989:Glycerides; C514708:Labrafil M 1944 CS; D013229:Stearic Acids; D013501:Surface-Active Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011092:Polyethylene Glycols; C067028:Solutol HS 15; C010111:carbitol; D007654:Ketoconazole
keywords: 2D (1)H NMR; CLSM; HP-β-CD; Hydroxypropyl-beta-cyclodextrin (PubChem CID: 44134771); Ketoconazole; Ketoconazole (PubChem CID: 5702077); MST; Microemulsion; Skin targeting; Synergetic effect