Department of Chemistry, College of Natural Science, Seoul National University, Seoul, 151-747, Republic of Korea.
Int J Pharm. 2011 Oct 31;419(1-2):114-20. doi: 10.1016/j.ijpharm.2011.07.027. Epub 2011 Jul 22.
Ion-paired solutions of risedronate (RIS) with L-arginine (ARG), L-lysine (LYS), and diethylenetriamine (DETA) were tested in vitro for their potential to enhance the penetration of RIS across the skin of hairless mouse. The xylene solubilities of RIS paired with ARG, LYS, and DETA in molar ratios of 1:2, 1:2, and 1:1 were 8.9%, 12.0%, and 2.1%, respectively, in comparison with the solubility in deionized water, but non-ion-paired RIS was not detected in xylene. In vitro permeation tests were performed on the skin of hairless mice, and the results indicated that ion-paired RIS could penetrate mice skin about 36 times more effectively than RIS alone. The cumulative amount of ion paired RIS after 24 h resulted in 475.18±94.19 μg/cm(2) and 511.21±106.52 μg/cm(2) at molar ratio of 1:2 and 1:1. The cumulative amount of RIS alone was as low as 14.13±5.49 μg/cm(2) in 24h. The hairless mice showed no skin irritation after a single administration of RIS alone and ion-paired RIS (1:2 molar ratio with ARG, and 1:1 molar ratio with DETA). In this study, we found that RIS can be delivered transdermally, and the ion-paired system in an aqueous solution showed an enhanced flux through the skin barrier.
将利塞膦酸钠（RIS）与 L-精氨酸（ARG）、L-赖氨酸（LYS）和二亚乙基三胺（DETA）形成离子对溶液，用于测试其潜在的增强 RIS 穿过无毛小鼠皮肤渗透的能力。RIS 与 ARG、LYS 和 DETA 以摩尔比 1:2、1:2 和 1:1 形成的离子对在二甲苯中的溶解度分别为 8.9%、12.0%和 2.1%，与去离子水中的溶解度相比，但在二甲苯中未检测到非离子化的 RIS。在无毛小鼠皮肤进行了体外渗透试验，结果表明，与单独的 RIS 相比，离子化的 RIS 能够使 RIS 更有效地渗透到小鼠皮肤约 36 倍。在摩尔比为 1:2 和 1:1 时，离子对 RIS 在 24 小时后累积量分别为 475.18±94.19μg/cm(2)和 511.21±106.52μg/cm(2)。单独的 RIS 在 24 小时内累积量仅为 14.13±5.49μg/cm(2)。单次给予 RIS 单独和离子对 RIS（与 ARG 摩尔比为 1:2，与 DETA 摩尔比为 1:1）后，无毛小鼠皮肤均无刺激反应。在这项研究中，我们发现 RIS 可以经皮给药，并且水溶液中的离子对系统显示出增强的皮肤屏障通透性。
