Markovic Milica, Zur Moran, Fine-Shamir Noa, Haimov Ester, González-Álvarez Isabel, Dahan Arik
Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
Department of Pharmacokinetics and Pharmaceutical Technology, Miguel Hernandez University, 03550 San Juan de Alicante, Spain.
Pharmaceutics. 2020 Mar 24;12(3):295. doi: 10.3390/pharmaceutics12030295.
The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high P marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol's solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product.
影响口服药物吸收的主要因素是溶解度和渗透性，它们因位置而异，且可能沿胃肠道（GIT）发生变化。本研究的目的是调查肠道吸收的节段依赖性及其在控释（CR）药物产品开发中的作用。对卡维地洛（与美托洛尔相比）的溶解度/溶出度和渗透性进行了全面研究，包括体外/体内研究（辛醇-缓冲液分配系数（Log D）、平行人工膜渗透性测定（PAMPA）、大鼠肠道灌注），重点关注位置依赖性效应。由于其两性离子性质，卡维地洛在整个胃肠道的不同条件下表现出溶解度的变化。卡维地洛速释（IR）与CR情况的生物相关pH-稀释溶出度研究表明，虽然IR剂量（25mg）可能在胃肠道腔内条件下溶解，但CR产品中使用的较高剂量如果一次性给药会沉淀，从溶解度/溶出度角度突出了CR的优势。同样，节段依赖性渗透性也很明显，在整个胃肠道中，卡维地洛的渗透性高于低/高渗透性标记物美托洛尔，证实其为生物药剂学分类系统（BCS）II类药物。相关理化性质的理论分析也证实了这些结果。CR产品可能会将卡维地洛的溶解度行为从II类转变为I类，因为在给定时间点只需溶解一小部分剂量。卡维地洛的渗透性在整个胃肠道（包括结肠）中超过了美托洛尔空肠渗透性的阈值，使其成为CR产品开发的合适候选者。总之，这项工作可作为CR制剂开发决策过程中的分析模型，并可能增进我们对成功的CR药物产品的生物药剂学理解。
