Lin Hai-Shu, Leong Wendy Wen Yi, Yang Jie An, Lee Pei, Chan Sui Yung, Ho Paul C
Department of Pharmacy, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore.
Int J Pharm. 2007 Aug 16;341(1-2):238-45. doi: 10.1016/j.ijpharm.2007.03.050. Epub 2007 Apr 5.
13-cis-Retinoic acid (13-cis-RA), also known as isotretinoin, is commonly used in the management of severe acne. Its clinical efficacy in oncology has also been documented. As a vitamin A derivative, it is not soluble in water. This solubility barrier not only affects its oral absorption but also makes parenteral delivery difficult. Recently, water-soluble formulations of 13-cis-RA have been attempted with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and randomly methylated-beta-cyclodextrin (RM-beta-CD). In this study, the pharmacokinetic profiles of these two formulations were assessed in Sprague-Dawley rats after single intravenous or oral administration. We found that 13-cis-RA was eliminated from the body through a dose-independent process after intravenous injection of either sodium salt or the HP-beta-CD formulation within the tested dosage range (2.0-7.5mg/kg). Furthermore, HP-beta-CD did not alter the kinetic profile of 13-cis-RA after intravenous administration in comparison with 13-cis-RA sodium salt. We also found that RM-beta-CD dramatically enhanced the oral absorption of 13-cis-RA. At 10.0mg/kg, the bioavailability of 13-cis-RA formulated with RM-beta-CD was about three-fold higher than that of the control (13-cis-RA suspended in 0.5% carboxymethylcellulose (CMC)). Similarly, the oral absorption of 13-cis-RA was not saturated within our tested range (2.5-10.0mg/kg) and the bioavailability remained unchanged. These results demonstrated that HP-beta-CD and RM-beta-CD were suitable excipients for the delivery of 13-cis-RA.
13-顺式维甲酸（13-cis-RA），也被称为异维甲酸，常用于重度痤疮的治疗。其在肿瘤学方面的临床疗效也有文献记载。作为一种维生素A衍生物，它不溶于水。这种溶解性障碍不仅影响其口服吸收，也使得肠胃外给药困难。最近，已尝试用2-羟丙基-β-环糊精（HP-β-CD）和随机甲基化-β-环糊精（RM-β-CD）制备13-顺式维甲酸的水溶性制剂。在本研究中，对这两种制剂在单次静脉注射或口服给药后的Sprague-Dawley大鼠体内的药代动力学特征进行了评估。我们发现，在测试剂量范围（2.0 - 7.5mg/kg）内，静脉注射13-顺式维甲酸的钠盐或HP-β-CD制剂后，13-顺式维甲酸通过非剂量依赖性过程从体内消除。此外，与13-顺式维甲酸钠盐相比，HP-β-CD在静脉给药后并未改变13-顺式维甲酸的动力学特征。我们还发现，RM-β-CD显著增强了13-顺式维甲酸的口服吸收。在10.0mg/kg时，用RM-β-CD配制的13-顺式维甲酸的生物利用度比对照组（13-顺式维甲酸悬浮于0.5%羧甲基纤维素（CMC）中）高约三倍。同样，在我们的测试范围（2.5 - 10.0mg/kg）内，13-顺式维甲酸的口服吸收未达到饱和，生物利用度保持不变。这些结果表明，HP-β-CD和RM-β-CD是用于递送13-顺式维甲酸的合适辅料。
