Matsui Kazuki, Tsume Yasuhiro, Amidon Gregory E, Amidon Gordon L
Pharmacokinetics & Safety Laboratory, Discovery Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, Gotemba, Shizuoka, 412-8524, Japan; College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065.
College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065.
J Pharm Sci. 2016 Sep;105(9):2804-2814. doi: 10.1016/j.xphs.2016.02.020. Epub 2016 Mar 25.
The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, gastrointestinal simulator (GIS), in assessing the drug dissolution of 2 commercially available oral dosage forms for itraconazole (ICZ). The GIS consists of 3 chambers, mimicking the upper gastrointestinal tract. In vitro dissolution of ICZ capsule or oral solution was evaluated in United States Pharmacopeia apparatus II and GIS. To investigate the suitability of fasted state simulated intestinal fluid (FaSSIF) to predict better in vivo, FaSSIF as well as phosphate buffer were used as dissolution media. Area under the dissolved drug amount-time curve (AUDC) was calculated for each dosage form in each apparatus, and the ratios of AUDCoral solution to AUDCcapsule were compared with human pharmacokinetic data. Based on this comparison, GIS with FaSSIF can adequately distinguish the pharmacokinetic profiles of 2 oral dosage forms for ICZ. Additionally, Caco-2 cell transepithelial transport study in combination with GIS revealed that improved drug dissolution by formulations resulted in enhanced permeation of ICZ through cell monolayer, suggesting the observed ICZ concentration in the GIS will directly reflect systemic exposure. These results indicate GIS would be a powerful tool to assess the formulations of ICZ as well as other Biopharmaceutics Classification System class II drug formulations.
本研究的目的是评估一种多隔室体外溶出装置——胃肠道模拟器（GIS），用于评估两种市售伊曲康唑（ICZ）口服剂型的药物溶出度的可行性。GIS由3个腔室组成，模拟上消化道。在美国药典装置II和GIS中评估ICZ胶囊或口服溶液的体外溶出度。为了研究禁食状态模拟肠液（FaSSIF）预测体内情况的适用性，将FaSSIF以及磷酸盐缓冲液用作溶出介质。计算每种装置中每种剂型的药物溶出量-时间曲线下面积（AUDC），并将口服溶液的AUDC与胶囊的AUDC之比与人药代动力学数据进行比较。基于这种比较，使用FaSSIF的GIS能够充分区分两种ICZ口服剂型的药代动力学特征。此外，结合GIS的Caco-2细胞跨上皮转运研究表明，制剂改善的药物溶出导致ICZ透过细胞单层的渗透增强这表明在GIS中观察到的ICZ浓度将直接反映全身暴露情况。这些结果表明，GIS将是评估ICZ制剂以及其他生物药剂学分类系统II类药物制剂的有力工具。
