Cyclodextrin inclusion complexes of miconazole and econazole - isolation, toxicity on human cells, and confirmation of a new interpretation of the drug supersaturation phenomenon

作     者：Pedersen, M Jacobsen, J Sorensen, AM 

作者机构：PEDCY DK-7620 Lemvig Denmark Royal Danish Sch Pharm Dept Pharmaceut DK-2100 Copenhagen O Denmark Royal Danish Sch Pharm Dept Analyt & Pharmaceut Chem DK-2100 Copenhagen O Denmark 

出 版 物：《DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY》 (药物开发与工业制药学)

年 卷 期：1999年第25卷第4期

页      面：463-470页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：Danish Health Research Council Generalkonsul Ludvig Tegner og Hustrus Mindelegat 

主　　题：抗真菌药/化学 抗真菌药/分离和提纯 抗真菌药/药理学 细胞培养技术 细胞系 细胞存活 环糊精类/化学 药物相互作用 益康唑/化学 益康唑/分离和提纯 益康唑/毒性 红细胞/药物作用 溶血/药物作用 氢离子浓度 咪康唑/化学 咪康唑/分离和提纯 咪康唑/药理学 咪康唑/毒性 口腔/细胞学 硝酸盐类/毒性 溶解度 温度 水/分析 β环糊精类 人类 

摘      要：Parameters that influence the precipitation of the beta-cyclodextrin (beta-CD) inclusion complexes of the antimycotics miconazole and econazole were investigated. The mechanistic reason for the superior antimycotic activity of the miconazole inclusion complex was studied The toxicity of the complex was estimated. The temperature, the buffer strength, and the effect of the addition of hydrotropic agents on the CD solubility diagrams far the antimycotics were estimated The miconazole and the CD dissolution rate for the complex was measured. The hemolytic activity of the miconazole inclusion complex, the physical mixture, miconazole, and the nitrate salt were compared. The toxicity on TR146 oral cell layers was measured. Lowering the temperature meant that both complexes precipitated at lower CD concentrations. Addition of hydrotropic agents and variation of the buffer strength affected the solubility diagrams. The dissolution medium was supersaturated with miconazole. The supersaturation was not disclosed by the traditional method to analyze for drug supersaturation. The miconazole complex was more toxic to erythrocytes than the physical mixture. On the other hand, the toxic effects of the two products on the TR146 cell layers were similar. Lowering the temperature eased the isolation of genuine CD inclusion complexes of miconazole and econazole. The miconazole supersaturation is likely to be the reason for the superior antimycotic activity of the complex. The complex and the physical mixture had about the same toxicity on TR146 cell layers.