Department of Chemistry , Michigan State University , 578 South Shaw Lane , East Lansing , Michigan 48824 , United States.
Mol Pharm. 2018 Apr 2;15(4):1607-1617. doi: 10.1021/acs.molpharmaceut.7b01143. Epub 2018 Mar 19.
In this study, a multipronged approach of in vitro experiments, in silico simulations, and in vivo studies was developed to evaluate the dissolution, supersaturation, precipitation, and absorption of three formulations of Compound-A, a BCS class 2 weak base with pH-dependent solubility. In in vitro 2-stage dissolution experiments, the solutions were highly supersaturated with no precipitation at the low dose but increasing precipitation at higher doses. No difference in precipitation was observed between the capsules and tablets. The in vitro precipitate was found to be noncrystalline with higher solubility than the crystalline API, and was readily soluble when the drug concentration was lowered by dilution. A gastric transit and biphasic dissolution (GTBD) model was developed to better mimic gastric transfer and intestinal absorption. Precipitation was also observed in GTBD, but the precipitate redissolved and partitioned into the organic phase. In vivo data from the phase 1 clinical trial showed linear and dose proportional PK for the formulations with no evidence of in vivo precipitation. While the in vitro precipitation observed in the 2-stage dissolution appeared to overestimate in vivo precipitation, the GTBD model provided absorption profiles consistent with in vivo data. In silico simulation of plasma concentrations by GastroPlus using biorelevant in vitro dissolution data from the tablets and capsules and assuming negligible precipitation was in line with the observed in vivo profiles of the two formulations. The totality of data generated with Compound-A indicated that the bioavailability differences among the three formulations were better explained by the differences in gastric dissolution than intestinal precipitation. The lack of intestinal precipitation was consistent with several other BCS class 2 basic compounds in the literature for which highly supersaturated concentrations and rapid absorption were also observed.
在这项研究中，采用了体外实验、计算机模拟和体内研究的多管齐下的方法，评估了三种化合物 A 制剂的溶解、过饱和、沉淀和吸收，化合物 A 是一种 BCS 分类 2 的弱碱，其溶解度随 pH 值变化。在体外两阶段溶解实验中，在低剂量下溶液高度过饱和，没有沉淀，但在高剂量下沉淀增加。胶囊和片剂之间没有观察到沉淀的差异。体外沉淀被发现是非晶态的，比晶态 API 的溶解度更高，并且在药物浓度通过稀释降低时很容易溶解。开发了胃转运和两相溶解（GTBD）模型，以更好地模拟胃转移和肠吸收。在 GTBD 中也观察到沉淀，但沉淀重新溶解并分配到有机相中。来自 I 期临床试验的体内数据表明，制剂的 PK 呈线性和剂量比例，没有体内沉淀的证据。虽然在两阶段溶解中观察到的体外沉淀似乎高估了体内沉淀，但 GTBD 模型提供的吸收曲线与体内数据一致。使用 GastroPlus 进行的基于生理的体外溶解数据的体内浓度的计算机模拟以及假设可忽略不计的沉淀，与这两种制剂的观察到的体内曲线一致。使用化合物 A 生成的全部数据表明，三种制剂之间的生物利用度差异更好地解释为胃溶解的差异，而不是肠沉淀的差异。缺乏肠沉淀与文献中其他几种 BCS 分类 2 的碱性化合物一致，这些化合物也观察到了高度过饱和的浓度和快速吸收。
