Mechanistic Multiscale Modelling Of Drug Release from Immediate Release Tablets

速释片剂药物释放的机制多尺度建模

• 批准号: EP/X032019/1
• 负责人: Mingzhong Li
• 金额: $ 85.99万
• 依托单位: De Montfort University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX032019%2F1
• 关键词: Mechanistic; Multiscale; Modelling; Drug; Release

Immediate release (IR) tablets manufactured via direct compression are the most popular oral solid dosage forms to deliver active pharmaceutical ingredients (APIs) to patients. In order to absorb the drug molecues, the tablet needs to be disintegrated in the gastrointestinal (GI) tract to release the API crystals for dissolution. In vitro dissolution testing plays a vital role throughout the IR tablet product development life-cycle, aiming to probe API release profile to inform selection of formulation candidates and identify the impact of variants of the formulation and/or manufacturing processes on in vivo performance. Current compendial dissolution tests can neither reflect the actual conditions of the GI tract of a patient nor are they suitable to predict the drug release performance in vivo. The best way to achieve this is to model the tablet drug release profile based upon a thorough understanding of the underlying physics. However, the current dissolution model cannot predict the drug release from an IR tablet accurately because it assumes the spherical shape of the dissolving particles, without considering crystal morphology and its face specific dissolution properties. There is no direct connection between the disintegration and dissolution models, where the disintegration process is simply treated as a time delay function to initiate API dissolution, although IR tablet disintegration is considered as the key step in controlling API dissolution. Additionally, there is no mathematical model available which can accurately capture the overall physics of an IR tablet disintegration. The situation is further complicated by diversity of excipients used in the formulation, processing and manufacturing facilities and dissolution environments. This proposal will explore how the drug release profile of an IR tablet in the GI tract can be predicted based on the integrated mechanistic models for disintegration and novel API dissolution models, leading to a step change in our ability to model, analyse, and predict API release profiles. The challenges will be tackled by two leading research groups from De Montfort University and University of Surrey, representing a new multidisciplinary collaboration. The group brings together essential expertise in crystallisation science, molecular dynamics, formulation science, pharmaceutical manufacturing, and Raman spectroscopy/imaging. Through experimental and computational efforts, we will develop a modelling framework that accurately predicts the drug release behaviours of IR tablets in the GI tract. This will enable IR tablets to be designed and tested virtually to provide clinically relevant dissolution specifications for the desired clinical performance, having potential to revolutionise IR product design as well as the opportunity to speed up innovation to bring pharmaceuticals to market more quickly and cost-effectively and save lives.

通过直接压缩制造的立即释放（IR）片剂是最流行的口服固体剂型，可为患者提供活性药物成分（API）。为了吸收药物分子，需要将片剂分解在胃肠道（GI）区以释放API晶体以溶解。体外溶解测试在整个IR片剂产品开发生命周期中起着至关重要的作用，旨在探测API释放曲线，以告知候选配方的选择，并确定配方和/或制造过程对体内性能的影响。当前的汇总溶解测试既不能反映患者的胃肠道的实际条件，也不适合预测体内药物释放性能。实现此目的的最佳方法是基于对潜在物理学的透彻理解来建模药品药物释放概况。 但是，当前的溶解模型无法准确预测药物从IR片剂中释放，因为它假定了溶解颗粒的球形形状，而无需考虑晶体形态及其面部特异性溶解特性。分解模型与溶解模型之间没有直接的连接，尽管IR平板电脑分解被认为是控制API溶解的关键步骤，但崩解过程被简单地视为启动API溶解的时间延迟函数。此外，没有可用的数学模型可以准确捕获IR平板电脑分解的整体物理。在配方，加工和制造设施和溶解环境中使用的赋形剂多样性，这种情况使情况更加复杂。 该提案将探讨如何根据分解和新型API溶解模型的综合机械模型来预测IR片剂在GI道中的药物释放曲线，从而导致我们建模，分析和预测API释放曲线的能力发生了变化。这些挑战将由De Montfort大学和萨里大学的两个领先的研究小组解决，代表了新的多学科合作。该小组汇集了结晶科学，分子动力学，配方科学，药物制造和拉曼光谱/成像的基本专业知识。通过实验和计算工作，我们将开发一个建模框架，该框架准确地预测了GI片中IR片剂的药物释放行为。这将使IR平板电脑实际上可以进行设计和测试，从而为所需的临床性能提供临床相关的溶解规格，并有可能革新IR产品设计以及加快创新的机会，以使药品更快，成本效益，并挽救生命。