Indulkar Anura S, Slade Russell, Jana Navendu, Frey Robin R, Penning Thomas D, Lai Albert, Leblanc Alix F
Small Molecule CMC Drug Product Development, Research & Development, AbbVie Inc., North Chicago, IL, USA.
Small Molecule CMC Drug Product Development, Research & Development, AbbVie Inc., North Chicago, IL, USA.
J Pharm Sci. 2025 Jan;114(1):279-288. doi: 10.1016/j.xphs.2024.09.012. Epub 2024 Oct 3.
With an increasing number of Biopharmaceutical Classification System (BCS) II/IV pipeline compounds, solubilizing and supersaturating formulation strategies are becoming prevalent. Beyond formulation and solid form strategies, prodrugs are also employed to overcome solubility-limited absorption of poorly water-soluble compounds. Prodrugs can potentially yield supersaturated systems upon conversion to the parent drug intraluminally and thus enhance absorption. However, supersaturation also increases the driving force for crystallization, resulting in low solution concentrations, which can potentially negate the advantage of prodrugs. In this work, two unique solubility-enhancing prodrugs, phosphate and glycine esters, were investigated for a rapidly crystallizing parent drug. Ex vivo absorption studies using rat tissue and in vivo studies in dogs were performed. Conversion rate of the phosphate prodrug to the parent was dependent on the milieu and increased ∼24-fold in the presence of intestinal contents as medium and tissue relative to neat buffer. In contrast, conversion of the glycine prodrug was minimal under any conditions tested, suggesting that the conversion occurs after absorption into the enterocytes. Phosphate prodrug showed a non-linear increase in parent drug absorptive flux across rat intestinal tissue with concentration when intestinal contents were used as donor media. This was attributed to rapid conversion and high supersaturation of the parent drug which subsequently resulted in crystallization at high doses in the donor chamber. Glycine prodrug did not undergo complete conversion at high doses and was absorbed unchanged on the basolateral side, indicating saturation of the converting enzymes in the enterocytes. The combined flux (parent drug and glycine) showed a linear increase with dose and crystallization was not observed. Under physiological conditions, glycine prodrug that is absorbed unchanged from the intestine can potentially undergo complete conversion in hepatocytes after absorption and make the parent drug systemically available. Thus, glycine prodrug provided overall higher absorption compared to phosphate prodrug. The observed flux levels for both the prodrugs were higher compared to the parent drug alone, highlighting an advantage to use of a prodrug strategy to improve absorption of such compounds. Oral dosing in a dog PK study revealed that the bioavailability using the phosphate prodrug was ∼50% whereas, it was ∼100% with glycine prodrug, supporting the in vitro observations.
随着越来越多的生物药剂学分类系统（BCS）II/IV类在研化合物的出现，增溶和过饱和制剂策略正变得越来越普遍。除了制剂和固体形态策略外，前药也被用于克服难溶性化合物的溶解度限制吸收问题。前药在腔内转化为母体药物时可能会产生过饱和系统，从而增强吸收。然而，过饱和也增加了结晶的驱动力，导致溶液浓度降低，这可能会抵消前药的优势。在这项研究中，针对一种快速结晶的母体药物，研究了两种独特的增溶前药，即磷酸酯和甘氨酸酯。进行了使用大鼠组织的体外吸收研究和犬体内研究。磷酸前药向母体药物的转化率取决于环境，在以肠内容物为介质和组织的情况下，相对于纯缓冲液，转化率增加了约24倍。相比之下，在任何测试条件下，甘氨酸前药的转化都极少，这表明转化发生在吸收进入肠细胞之后。当以肠内容物作为供体介质时，磷酸前药在大鼠肠道组织中的母体药物吸收通量随浓度呈非线性增加。这归因于母体药物的快速转化和高过饱和度，随后在供体室中高剂量时导致结晶。甘氨酸前药在高剂量时未完全转化，在基底外侧未发生变化地被吸收，表明肠细胞中转化酶饱和。组合通量（母体药物和甘氨酸）随剂量呈线性增加，未观察到结晶现象。在生理条件下，从肠道未发生变化吸收的甘氨酸前药在吸收后可能在肝细胞中完全转化，使母体药物全身可用。因此，与磷酸前药相比，甘氨酸前药总体吸收更高。两种前药观察到的通量水平均高于单独的母体药物，突出了使用前药策略改善此类化合物吸收的优势。犬PK研究中的口服给药显示，使用磷酸前药的生物利用度约为50%，而使用甘氨酸前药时约为100%，支持了体外观察结果。
