Department of Pharmaceutical, Chemical & Environmental Science, Faculty of Engineering & Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent ME4 4TB, United Kingdom.
Department of Chemistry, The Hashemite University, P.O. Box 150459, Zarqa 13115, Jordan.
ACS Biomater Sci Eng. 2020 Jan 13;6(1):21-37. doi: 10.1021/acsbiomaterials.8b01028. Epub 2019 Mar 28.
The development and evaluation of a controlled-release (CR) pharmaceutical solid dosage form comprising xanthan gum (XG), low molecular weight chitosan (LCS), and metoprolol succinate (MS) are reported. The research is, partly, based upon the utilization of computational tools: in this case, molecular dynamics simulations (MDs) and the response surface method (RSM) in order to underpin the design/prediction and to minimize the experimental work required to achieve the desired pharmaceutical outcomes. The capability of the system to control the release of MS was studied as a function of LCS (% w/w) and total polymer (LCS and xanthan gum (XG)) to drug ratio (P/D) at different tablet tensile strengths. MDs trajectories, obtained by using different ratios of XG/LCS as well as XG and high molecular weight chitosan (HCS), showed that the driving force for the interaction between XG and LCS is electrostatic in nature, the most favorable complex is formed when LCS is used at 15% (w/w) and, importantly, the interaction between XG and LCS is more favorable than that between XG and HCS. RSM outputs revealed that the release of the drug from the LCS/XG matrix is highly dependent on both the % LCS and the P/D ratio and that the required CR effect can be achieved when using weight fractions of LCS ≤ 20% and P/D ratios ≥2.6:1. Results obtained from in vitro drug release and swelling studies on the prepared tablets showed that using LCS at the weight fractions suggested by MDs and RSM data plays a major role in overcoming the high sensitivity of the controlled drug release effect of XG on ionic strength and pH changes of the dissolution media. In addition, it was found that polymer relaxation is the major contributor to the release of MS from LCS/XG tablets. Using Raman spectroscopy, MS was shown to be localized more in the core of the tablets at the initial stages of dissolution due to film formation between LCS and XG on the tablet surface, which prevents excess water penetration into the matrix. In the later stages of the dissolution process, the film starts to dissolve/erode, allowing full tablet hydration and a uniform drug distribution in the swollen tablet.
报道了一种包含黄原胶（XG）、低分子量壳聚糖（LCS）和琥珀酸美托洛尔（MS）的控释（CR）药物固体制剂的开发和评价。该研究部分基于计算工具的利用：在这种情况下，分子动力学模拟（MDs）和响应面法（RSM），以支持设计/预测，并最小化实现所需药物结果所需的实验工作。研究了系统控制 MS 释放的能力，作为 LCS（%w/w）和总聚合物（LCS 和黄原胶（XG））与药物比（P/D）的函数，在不同片剂拉伸强度下。通过使用不同比例的 XG/LCS 以及 XG 和高分子量壳聚糖（HCS）获得的 MDs 轨迹表明，XG 和 LCS 之间相互作用的驱动力本质上是静电的，当 LCS 以 15%（w/w）使用时，形成最有利的复合物，重要的是，XG 和 LCS 之间的相互作用比 XG 和 HCS 之间的相互作用更有利。RSM 输出表明，药物从 LCS/XG 基质中的释放高度依赖于 LCS 的%和 P/D 比，并且当使用重量分数≤20%的 LCS 和 P/D 比≥2.6:1 时，可以实现所需的 CR 效果。对制备的片剂进行体外药物释放和溶胀研究的结果表明，在 MDs 和 RSM 数据建议的重量分数下使用 LCS 在克服 XG 对溶解介质离子强度和 pH 变化的控释药物释放效果的高敏感性方面起着主要作用。此外，发现聚合物弛豫是 LCS/XG 片剂中 MS 释放的主要贡献者。使用拉曼光谱法，由于片剂表面上 LCS 和 XG 之间形成的薄膜，MS 在溶解的初始阶段更多地定位于片剂的核心，这阻止了过量的水渗透到基质中。在溶解过程的后期，薄膜开始溶解/侵蚀，允许整个片剂水合和在膨胀的片剂中均匀分布药物。
