Research and Development, PLIVA Croatia Ltd, Prilaz baruna Filipovića 25, 10000, Zagreb, Croatia.
Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.
Pharm Res. 2018 Jun 22;35(8):163. doi: 10.1007/s11095-018-2434-1.
The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC).
Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively. An IVIVC was established by using a direct, differential based method.
Metaxalone has been confirmed as a Class II drug according to BCS. Bioavailability studies performed in humans demonstrated that dissolution was the rate limiting step for bioavailability of the drug and one of the test products had significantly improved bioavailability compared to the marketed product Skelaxin®. An IVIVC model was developed that demonstrated an acceptable internal predictability.
The IVIVC demonstrated that formulation factors play a significant role in dissolution and absorption of metaxalone. A pH 4.5 dissolution medium containing 0.5% NaCl with 0.2% SLS (USP apparatus 2 at 50 rpm) is clinically relevant to predict bioavailability of the drug and is superior to the USP method in terms of the Quality by Design (QbD) concept.
本工作旨在根据生物药剂学分类系统（BCS）对美索巴莫进行分类，开发一种临床相关的溶出度方法，用于预测美索巴莫的口服吸收，并建立体外-体内相关性（IVIVC）。
研究了药物在不同 pH 介质中的溶解度，并使用 Caco-2 细胞模型进行了渗透性研究。使用 USP 2 仪器和单剂量、四交叉生物等效性研究，分别对 3 种不同的美索巴莫速释片剂制剂的体外溶出度和体内处置进行了研究，同时还对药物的口服溶液进行了研究。通过直接、基于差异的方法建立 IVIVC。
美索巴莫已被确认为 BCS 中的 II 类药物。在人体进行的生物利用度研究表明，溶出度是药物生物利用度的限速步骤，其中一种测试产品与市售产品 Skelaxin®相比具有显著改善的生物利用度。建立了 IVIVC 模型，表明具有可接受的内部预测性。
IVIVC 表明，制剂因素在美索巴莫的溶解和吸收中起着重要作用。含有 0.5%NaCl 和 0.2%SDS（USP 仪器 2，转速为 50rpm，pH4.5 溶解介质）的溶出度方法在临床上可用于预测药物的生物利用度，并且在质量源于设计（QbD）概念方面优于 USP 方法。
