Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, University of Athens, Panepistimiopolis, 157 71 Athens, Greece.
Int J Pharm. 2010 May 10;390(2):150-9. doi: 10.1016/j.ijpharm.2010.01.038. Epub 2010 Feb 1.
The aim of this study is to develop milk-based formulations for ionized and unionized lipophilic drugs. Solubility studies of the following non-steroidal anti-inflammatory drugs (NSAIDs): mefenamic acid, tolfenamic acid, ketoprofen, meloxicam, tenoxicam and nimesulide in phosphate- and glycine-NaOH buffers at nominal pH 8-12, were performed. The solubilities of cyclosporine and danazol in water-ethanol solutions were studied. NSAIDs-, cyclosporine-, danazol-, aspirin-milk oral liquid formulations were prepared by adding the appropriate volume of (i) NSAIDs-alkaline buffer solutions, (ii) water-ethanol solutions of cyclosporine and danazol and (iii) aspirin aqueous solution to 150-200ml of milk. All the non-steroidal anti-inflammatory drugs exhibited increased solubility in the alkaline buffers. The actual pH values (range 6.7-7.7) of the final NSAIDs-milk formulations were very close to milk pH. The higher ethanol content in ethanol-water mixtures increased the solubility of danazol and cyclosporine. A 15mg meloxicam-, a 100mg cyclosporine- and a 500mg aspirin-milk formulation was administered orally to healthy volunteers. All these formulations showed a satisfactory in vivo performance. The strong buffering capacity of milk that was observed and the high solubility of unionized drugs in ethanol allow the preparation of drug-milk formulations with enhanced pharmacokinetic properties.
本研究旨在开发用于离子化和非离子化亲脂性药物的基于牛奶的配方。在名义 pH 值为 8-12 的磷酸盐和甘氨酸-NaOH 缓冲液中对以下非甾体抗炎药（NSAIDs）：甲芬那酸、托芬那酸、酮洛芬、美洛昔康、替诺昔康和尼美舒利的溶解度进行了研究。环孢素和丹那唑在水-乙醇溶液中的溶解度也进行了研究。通过向 150-200ml 牛奶中添加（i）NSAIDs-碱性缓冲溶液、（ii）环孢素和丹那唑的水-乙醇溶液和（iii）阿司匹林水溶液，制备了 NSAIDs-、环孢素-、丹那唑-和阿司匹林-牛奶口服液制剂。所有非甾体抗炎药在碱性缓冲液中的溶解度均增加。最终 NSAIDs-牛奶配方的实际 pH 值（范围 6.7-7.7）非常接近牛奶的 pH 值。乙醇-水混合物中较高的乙醇含量增加了丹那唑和环孢素的溶解度。给健康志愿者口服 15mg 美洛昔康、100mg 环孢素和 500mg 阿司匹林牛奶制剂。所有这些配方都表现出令人满意的体内性能。观察到牛奶的强缓冲能力和非离子化药物在乙醇中的高溶解度允许制备具有增强药代动力学特性的药物-牛奶配方。
