Faculty of Pharmaceutical Sciences, Setsunan University.
Biol Pharm Bull. 2022;45(10):1452-1457. doi: 10.1248/bpb.b22-00219.
In this study, we investigated the effects of ingested water volume on the oral absorption of fenofibrate (FEN) with several formulations to confirm the applicability of rats for oral formulation screening. Oral absorption of suspended crystalline FEN was significantly improved by increasing ingested water volume (from 0.5 to 2 mL). FEN absorption improvement by particle size reduction and the linearity in oral absorption by dose escalation suggested that the rate-limiting step of FEN absorption in rats was the dissolution rate, consistent with that in humans. When FEN, as an amorphous solid dispersion (ASD) formulation, was suspended in water followed by immediate administration, oral FEN absorption was significantly higher than when administered in crystalline form and was not influenced by the differences in ingested water volume. Oral absorption of FEN from encapsulated ASD formulation in 1 or 2 mL of water was comparable with that of the suspension form. However, 0.5 mL of water significantly reduced the oral absorption of the solid ASD FEN formulation. These results indicate that to improve the oral absorption of poorly water-soluble drugs when performing a preclinical study with rats, 1 mL of water is the minimum preferable ingested volume to evaluate in vivo formulation performance.
在这项研究中，我们考察了摄入水量对几种制剂的非诺贝特（FEN）口服吸收的影响，以确认大鼠适用于口服制剂筛选。悬浮结晶 FEN 的口服吸收通过增加摄入水量（从 0.5 毫升增加到 2 毫升）而显著提高。通过粒径减小和剂量递增的口服吸收线性改善，提示 FEN 在大鼠中的吸收限速步骤是溶解速率，与在人体中的情况一致。当 FEN 作为无定形固体分散体（ASD）制剂混悬在水中并立即给药时，其口服 FEN 吸收明显高于结晶形式给药，且不受摄入水量差异的影响。在 1 或 2 毫升水中给予包封的 ASD 制剂的 FEN 口服吸收与混悬液形式相当。然而，0.5 毫升水显著降低了固体 ASD FEN 制剂的口服吸收。这些结果表明，在使用大鼠进行临床前研究时，为了改善水溶性差的药物的口服吸收，1 毫升水是评估体内制剂性能的最小优选摄入体积。
