Jeong Hyeong-Mo, Kim Hansol, Jang Taeyeon, Choi Ayoung, Park Jun-Bom, Park Chulhun, Lee Beom-Jin
Department of Pharmacy, College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Central Research Institute, IL-YANG Pharmaceutical Co., Ltd., Yongin 17096, Republic of Korea.
Central Research Institute, IL-YANG Pharmaceutical Co., Ltd., Yongin 17096, Republic of Korea.
Int J Pharm. 2025 Jan 25;669:125091. doi: 10.1016/j.ijpharm.2024.125091. Epub 2024 Dec 17.
Bethanechol chloride (BTC), a quaternary ammonium compound used in bladder dysfunction treatment, requires challenges in developing optimal oral dosage forms due to its high water-solubility, short half-life, rapid elimination and four times a day administration. The aim of this study was to develop optimal BTC-loaded oral dosage forms that could provide both rapid onset and sustained therapeutic effects while reducing the frequency of conventional four-times-daily dosing (Mytonin® tablets). Four different BTC-loaded oral dosage forms were designed including gastro-retentive tablet (GRT), controlled-release tablet (CRT), bilayer tablet (BLT), and tablet-in-tablet (TIT). Then, release-modulating mechanism and in vivo pharmacokinetics in beagle dogs were compared. The release profiles of the four BTC-loaded dosage forms varied according to system design and formulation composition. The optimized GRT F-5 showed rapid buoyancy within 15 s and floated for 12 h, while continuously releasing the drug. CRT showed Fickian diffusion release, whereas BLT and TIT exhibited biphasic immediate and sustained release profiles. Polymer swelling behavior was analyzed using the Vergnaud model, where GRT F-5 and CRT showed n values < 0.5, confirming diffusion-controlled polymer hydration mechanism. In the instrumental analysis, the hydrogen bonding formation of BTC with release-modulating polymers, such as hydroxypropyl methylcellulose and polyethylene oxide and loosening of the polymer structure was crucial as the water influx increased. In pharmacokinetic studies in beagle dogs, the area under the plasma concentration-time curve (AUC) by normalizing dose for 48 h for GRT, CRT, BLT, and TIT were 90.2 %, 108.6 %, 83.8 %, and 76.4 %, respectively, compared with that of the reference drug (Mytonin® tablets, immediate release, four times a day). Interestingly, the plasma maximum concentration (C) and AUC) of GRT F-5 and and Mytonin® tablets for the first 12-h period were much higher compared with that of other BTC-loaded CRT, BLT, and TIT. BTC was absorbed throughout the gastrointestinal tract, but is preferably absorbed in the stomach and upper intestinal sites. However, the GRT F-5 could provide more therapeutic potential for improving patient compliance in bladder dysfunction treatment by achieving both rapid onset and sustained drug release with reduced dosing frequency.
氯贝胆碱（BTC）是一种用于治疗膀胱功能障碍的季铵化合物，由于其高水溶性、短半衰期、快速消除以及每日四次给药，在开发最佳口服剂型方面面临挑战。本研究的目的是开发最佳的载BTC口服剂型，既能提供快速起效又能提供持续治疗效果，同时减少传统每日四次给药（Mytonin®片）的频率。设计了四种不同的载BTC口服剂型，包括胃滞留片（GRT）、控释片（CRT）、双层片（BLT）和片内片（TIT）。然后，比较了比格犬体内的释放调节机制和药代动力学。四种载BTC剂型的释放曲线根据系统设计和制剂组成而有所不同。优化后的GRT F-5在15秒内迅速漂浮并漂浮12小时，同时持续释放药物。CRT显示菲克扩散释放，而BLT和TIT表现出双相速释和缓释曲线。使用韦尔尼奥模型分析聚合物溶胀行为，其中GRT F-5和CRT的n值<0.5，证实了扩散控制的聚合物水合机制。在仪器分析中，随着水流入增加，BTC与释放调节聚合物（如羟丙基甲基纤维素和聚环氧乙烷）形成氢键以及聚合物结构的松弛至关重要。在比格犬的药代动力学研究中，与参比药物（Mytonin®片，速释，每日四次）相比，GRT、CRT、BLT和TIT在48小时内将剂量归一化后的血浆浓度-时间曲线下面积（AUC）分别为90.2%、108.6%、83.8%和76.4%。有趣的是，在最初12小时内，GRT F-5和Mytonin®片的血浆最大浓度（C）和AUC）比其他载BTC的CRT、BLT和TIT高得多。BTC在整个胃肠道均有吸收，但在胃和上肠道部位吸收较好。然而，GRT F-5通过实现快速起效和持续药物释放并减少给药频率，可为改善膀胱功能障碍治疗中的患者依从性提供更大的治疗潜力。
