Mellaerts Randy, Mols Raf, Kayaert Pieterjan, Annaert Pieter, Van Humbeeck Jan, Van den Mooter Guy, Martens Johan A, Augustijns Patrick
Centre for Surface Chemistry and Catalysis, Kasteelpark Arenberg 23, Catholic University of Leuven, BE-3001 Heverlee, Belgium.
Int J Pharm. 2008 Jun 5;357(1-2):169-79. doi: 10.1016/j.ijpharm.2008.01.049. Epub 2008 Feb 3.
The majority of innovative drug candidates are poorly water soluble and exhibit basic properties. This makes them highly dependent on the in vivo encountered acid-neutral pH sequence to achieve a sufficient dissolution and thus absorption. In this study, we evaluated the pH-independent generation of intraluminally induced supersaturation of the model compound itraconazole and its beneficial effect on the extent of absorption in the Caco-2 system and the rat in situ perfusion system. Local supersaturation was obtained by means of a solvent shift method and a novel formulation strategy based on ordered mesoporous silica (OMS) as a carrier. In vitro results evidenced that both methods were capable of creating a supersaturated state of itraconazole in fasted state simulated intestinal fluid (FaSSIF) when no preceding acidic dissolution was simulated. The extent of supersaturation exceeded 21.9 and 9.6 during at least 4h for the solvent shift method and OMS as a carrier, respectively. As compared to saturation conditions (0.09+/-0.01 microg), supersaturation induced by the solvent shift method as well as by the use of OMS increased transport across a Caco-2 cell monolayer more than 16-fold, resulting in the basolateral appearance of 2.20+/-0.29 microg and 1.46+/-0.03 microg itraconazole after 90 min, respectively. In the absence of an acid-neutral pH sequence, the performance of the marketed product Sporanox was inferior with total transport amounting to 0.12+/-0.03 microg after 90 min. Enhanced absorption was confirmed in the in situ perfusion model where OMS was able to boost total transport of itraconazole after 60 min from 0.03+/-0.01 nmol cm(-1) to 0.70+/-0.09 nmol cm(-1) compared to saturated equilibrium conditions in FaSSIF. The solid dosage form Sporanox again failed to achieve a similar extent of absorption enhancement (0.29+/-0.01 nmol cm(-1)). These findings suggest that intraluminal supersaturation can be created by the use of OMS and that preceding dissolution of basic compounds in the acidic medium of the stomach is not required to allow for efficient intestinal absorption. The use of OMS appears to be a promising strategy for the delivery of especially basic low solubility compounds in patients suffering from hypochlorhydria; the pH independency may also result in a more reproducible systemic exposure.
大多数创新药物候选物水溶性差且具有碱性。这使得它们高度依赖于体内遇到的酸 - 中性pH序列来实现足够的溶解从而吸收。在本研究中，我们评估了模型化合物伊曲康唑腔内诱导的过饱和的pH无关生成及其对Caco - 2系统和大鼠原位灌注系统中吸收程度的有益影响。通过溶剂转移法和基于有序介孔二氧化硅（OMS）作为载体的新型制剂策略获得局部过饱和。体外结果表明，当未模拟先前的酸性溶解时，两种方法都能够在禁食状态模拟肠液（FaSSIF）中产生伊曲康唑的过饱和状态。对于溶剂转移法和以OMS作为载体，过饱和程度在至少4小时内分别超过21.9和9.6。与饱和条件（0.09±0.01μg）相比，溶剂转移法以及使用OMS诱导的过饱和使伊曲康唑跨Caco - 2细胞单层的转运增加了16倍以上，90分钟后分别在基底外侧出现2.20±0.29μg和1.46±0.03μg伊曲康唑。在没有酸 - 中性pH序列的情况下，市售产品斯皮仁诺的性能较差，90分钟后总转运量为0.12±0.03μg。在原位灌注模型中证实了吸收增强，与FaSSIF中的饱和平衡条件相比，OMS能够在60分钟后将伊曲康唑的总转运量从0.03±0.01 nmol cm(-1)提高到0.70±0.09 nmol cm(-1)。固体剂型斯皮仁诺再次未能实现类似程度的吸收增强（0.29±0.01 nmol cm(-1)）。这些发现表明，使用OMS可以产生腔内过饱和，并且碱性化合物在胃的酸性介质中的先前溶解对于有效的肠道吸收不是必需的。对于胃酸过少患者中特别碱性的低溶解度化合物的递送，使用OMS似乎是一种有前途的策略；pH无关性也可能导致更可重复的全身暴露。
