Zhang Miao, Wu Bin, Zhang Shudong, Wang Lin, Hu Qin, Liu Dongyang, Chen Xijing
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China.
Pharmaceutics. 2022 Jan 29;14(2):330. doi: 10.3390/pharmaceutics14020330.
Generally, some weakly basic insoluble drugs will undergo precipitate and redissolution after emptying from the stomach to the small intestinal, resulting in the limited ability to predict the absorption characteristics of compounds in advance. Absorption is determined by the solubility and permeability of compounds, which are related to physicochemical properties, while knowledge about the absorption of redissolved precipitate is poorly documented. Considering that biorelevant media have been widely used to simulate gastrointestinal fluids, sufficient precipitates can be obtained in biorelevant media in vitro. Herein, the purpose of this manuscript is to evaluate the physicochemical properties of precipitates obtained from biorelevant media and active pharmaceutical ingredients (API), and then to explore the potential absorption difference between API and precipitates. Precipitates can be formed by the interaction between compounds and intestinal fluid contents, leading to changes in the crystal structure, melting point, and melting process. However, the newly formed crystals have some advantageous properties compared with the API, such as the improved dissolved rate and the increased intrinsic dissolution rate. Additionally, the permeability of some precipitates obtained from biorelevant media was different from API. Meanwhile, the permeability of rivaroxaban and Drug-A was decreased by 1.92-fold and 3.53-fold, respectively, when the experiments were performed in a biorelevant medium instead of a traditional medium. Therefore, the absorption of precipitate may differ from that of API, and the permeability assay in traditional medium may be overestimated. Based on the research results, it is crucial to understand the physicochemical properties of precipitates and API, which can be used as the departure point to improve the prediction performance of absorption.
一般来说，一些弱碱性不溶性药物从胃排空进入小肠后会发生沉淀和再溶解，导致难以预先预测化合物的吸收特性。吸收取决于化合物的溶解度和渗透性，这与物理化学性质相关，而关于再溶解沉淀的吸收情况记录较少。考虑到生物相关介质已被广泛用于模拟胃肠液，在体外生物相关介质中可获得足够的沉淀。在此，本手稿的目的是评估从生物相关介质和活性药物成分（API）中获得的沉淀的物理化学性质，然后探讨API与沉淀之间潜在的吸收差异。化合物与肠液成分相互作用可形成沉淀，导致晶体结构、熔点和熔化过程发生变化。然而，新形成的晶体与API相比具有一些优势特性，如溶解速率提高和固有溶解速率增加。此外，从生物相关介质中获得的一些沉淀的渗透性与API不同。同时，当在生物相关介质而非传统介质中进行实验时，利伐沙班和药物A的渗透性分别降低了1.92倍和3.53倍。因此，沉淀的吸收可能与API不同，传统介质中的渗透性测定可能被高估。基于研究结果，了解沉淀和API的物理化学性质至关重要，这可作为提高吸收预测性能的出发点。
