Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Mol Pharm. 2024 Apr 1;21(4):1745-1755. doi: 10.1021/acs.molpharmaceut.3c01078. Epub 2024 Mar 19.
Drug-rich droplets formed through liquid-liquid phase separation (LLPS) have the potential to enhance the oral absorption of drugs. This can be attributed to the diffusion of these droplets into the unstirred water layer (UWL) of the gastrointestinal tract and their reservoir effects on maintaining drug supersaturation. However, a quantitative understanding of the effect of drug-rich droplets on intestinal drug absorption is still lacking. In this study, the enhancement of intestinal drug absorption through the formation of drug-rich droplets was quantitatively evaluated on a mechanistic basis. To obtain fenofibrate (FFB)-rich droplets, an amorphous solid dispersion (ASD) of FFB/hypromellose (HPMC) was dispersed in an aqueous medium. Physicochemical characterization confirmed the presence of nanosized FFB-rich droplets in the supercooled liquid state within the FFB/HPMC ASD dispersion. An in situ single-pass intestinal perfusion (SPIP) assay in rats demonstrated that increased quantities of FFB-rich nanodroplets enhanced the intestinal absorption of FFB. The effective diffusion of FFB-rich nanodroplets through UWL would partially contribute to the improved FFB absorption. Additionally, confocal laser scanning microscopy (CLSM) of cross sections of the rat intestine after the administration of fluorescently labeled FFB-rich nanodroplets showed that these nanodroplets were directly taken up by small intestinal epithelial cells. Therefore, the direct uptake of drug-rich nanodroplets by the small intestine is a potential mechanism for improving FFB absorption in the intestine. To quantitatively evaluate the impact of FFB-rich droplets on the FFB absorption enhancement, we determined the apparent permeabilities of the FFB-rich nanodroplets and dissolved FFB based on the SPIP results. The apparent permeability of the FFB-rich nanodroplets was 110-130 times lower than that of dissolved FFB. However, when the FFB-rich nanodroplet concentration was several hundred times higher than that of dissolved FFB, the FFB-rich nanodroplets contributed significantly to FFB absorption improvement. The present study highlights that drug-rich nanodroplets play a direct role in enhancing drug absorption in the gastrointestinal tract, indicating their potential for further improvement of oral absorption from ASD formulations.
富药物液滴通过液-液相分离（LLPS）形成，有可能增强药物的口服吸收。这可以归因于这些液滴扩散到胃肠道的未搅动水层（UWL）中，并维持药物过饱和的储库效应。然而，对于富药物液滴对肠道药物吸收的影响，仍缺乏定量理解。在这项研究中，从机制上定量评估了通过形成富药物液滴来增强肠道药物吸收的效果。为了获得富非诺贝特（FFB）液滴，将非诺贝特/羟丙甲纤维素（HPMC）的无定形固体分散体（ASD）分散在水性介质中。物理化学特性证实，在 FFB/HPMC ASD 分散体的过冷液体状态下存在纳米级 FFB 富液滴。在大鼠体内的原位单次通过肠灌注（SPIP）测定中，增加 FFB 富纳米液滴的数量增强了 FFB 的肠道吸收。FFB 富纳米液滴通过 UWL 的有效扩散将部分有助于改善 FFB 吸收。此外，对大鼠肠道给药后经荧光标记的 FFB 富纳米液滴的横截面进行共聚焦激光扫描显微镜（CLSM）观察显示，这些纳米液滴被小肠上皮细胞直接摄取。因此，小肠对富药物纳米液滴的直接摄取是改善肠道内 FFB 吸收的潜在机制。为了定量评估 FFB 富液滴对 FFB 吸收增强的影响，我们根据 SPIP 结果确定了 FFB 富纳米液滴和溶解 FFB 的表观渗透率。FFB 富纳米液滴的表观渗透率比溶解 FFB 低 110-130 倍。然而，当 FFB 富纳米液滴浓度比溶解 FFB 高几百倍时，FFB 富纳米液滴对 FFB 吸收的改善有显著贡献。本研究强调了富药物纳米液滴在增强胃肠道药物吸收方面发挥了直接作用，表明它们有可能进一步改善 ASD 制剂的口服吸收。
