Lee Jaehyeok, Lee Chul Haeng, Lee Jong-Geon, Jeon So Yeon, Choi Min-Koo, Song Im-Sook
BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea.
College of Pharmacy, Dankook University, Cheonan-si 31116, Korea.
Pharmaceutics. 2022 May 11;14(5):1037. doi: 10.3390/pharmaceutics14051037.
Ursodeoxycholate (UDCA) has low oral bioavailability and pH-dependent solubility and permeability. Thus, we developed a pH-modified extended-release formulation of UDCA using NaCO as the alkalizing agent and hydroxypropyl methylcellulose (HPMC) as the release-modifying agent. The optimized pH-modified controlled-release UDCA formulation, with the UDCA:HPMC:NaCO ratio of 200:600:150 (//), was prepared using a spray-drying method. Then, the formulation's solubility, dissolution, and pharmacokinetic properties were characterized. In a pH-modified extended-release formulation of UDCA, the solubility of UDCA was increased to 8 mg/mL with a sustained dissolution for 12 h. Additionally, the spray-dried formulation exhibited amorphous states without molecular interaction among UDCA, NaCO, and HPMC. Moreover, the plasma UDCA concentration of the formulation maintained a higher UDCA concentration for up to 48 h than that of UDCA itself or the non-extended-release UDCA formulation. Consequently, the formulation significantly increased the AUC compared to UDCA or the non-extended-release UDCA formulation in rats. In conclusion, we have improved UDCA's solubility and dissolution profile by preparing a pH-modified extended-release formulation with the UDCA:HPMC:NaCO ratio of 200:600:150 (//), which effectively increased the oral bioavailability of UDCA by 251% in rats.
熊去氧胆酸（UDCA）口服生物利用度低，且具有pH依赖性溶解性和渗透性。因此，我们以碳酸钠作为碱化剂、羟丙基甲基纤维素（HPMC）作为释放调节剂，开发了一种pH修饰的UDCA缓释制剂。采用喷雾干燥法制备了优化的pH修饰控释UDCA制剂，其UDCA:HPMC:碳酸钠的比例为200:600:150（//）。然后，对该制剂的溶解度、溶出度和药代动力学性质进行了表征。在pH修饰的UDCA缓释制剂中，UDCA的溶解度提高到8mg/mL，并持续溶解12小时。此外，喷雾干燥制剂呈现无定形状态，UDCA、碳酸钠和HPMC之间没有分子相互作用。而且，该制剂的血浆UDCA浓度在长达48小时内保持比UDCA本身或非缓释UDCA制剂更高的UDCA浓度。因此，与UDCA或非缓释UDCA制剂相比，该制剂在大鼠体内显著增加了曲线下面积（AUC）。总之，我们通过制备UDCA:HPMC:碳酸钠比例为200:600:150（//）的pH修饰缓释制剂，改善了UDCA的溶解度和溶出曲线，这有效地使UDCA在大鼠体内的口服生物利用度提高了251%。
