Ueda Keisuke, Takemoto Shiryu, Higashi Kenjirou, Moribe Kunikazu
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
J Pharm Sci. 2025 Jan;114(1):136-144. doi: 10.1016/j.xphs.2024.06.017. Epub 2024 Jun 26.
This study aimed to investigate the impact of amorphous solubility and colloidal drug-rich droplets on drug absorption. The amorphous solubility of cilnidipine (CND) in AS-HF grade of hypromellose acetate succinate (HPMC-AS) solution was significantly reduced compared to that in non-polymer solution due to AS-HF partitioning into the CND-rich phase. In contrast, AS-LF grade of HPMC-AS has minimal effect on the amorphous solubility. The size of colloidal CND-rich droplets formed in the CND-supersaturated solution was less than 100 nm in the presence of AS-HF, while 200-450 nm in the presence of AS-LF. When the CND concentrations were near the amorphous solubility, CND membrane flux was reduced in the presence of AS-HF due to the decrease in the amorphous solubility of CND. However, the CND flux increased with the increase in CND-rich droplets, especially in the AS-HF solution. The size reduction of the CND-rich droplets led to their effective diffusion into the unstirred water layer, enhancing CND flux. In higher CND concentration regions, the CND flux became higher in the AS-HF solution than in the AS-LF solution. Thus, it is essential to elucidate the drug concentration-dependent impact of the colloidal drug-rich droplets on the drug absorption performance to optimize supersaturating formulations.
本研究旨在探讨无定形溶解度和富含胶体药物的液滴对药物吸收的影响。由于醋酸羟丙甲纤维素琥珀酸酯（HPMC-AS）的AS-HF级分分配到富含西尼地平（CND）的相中，与非聚合物溶液相比，CND在AS-HF级分的HPMC-AS溶液中的无定形溶解度显著降低。相比之下，HPMC-AS的AS-LF级分对无定形溶解度的影响最小。在存在AS-HF的情况下，在CND过饱和溶液中形成的富含胶体CND的液滴尺寸小于100nm，而在存在AS-LF的情况下为200-450nm。当CND浓度接近无定形溶解度时，由于CND无定形溶解度的降低，在存在AS-HF的情况下CND膜通量降低。然而，CND通量随着富含CND的液滴的增加而增加，尤其是在AS-HF溶液中。富含CND的液滴尺寸减小导致它们有效地扩散到未搅拌的水层中，从而提高了CND通量。在较高的CND浓度区域，AS-HF溶液中的CND通量高于AS-LF溶液中的CND通量。因此，阐明富含胶体药物的液滴对药物吸收性能的药物浓度依赖性影响对于优化过饱和制剂至关重要。
