Mechanistic Multiscale Modelling Of Drug Release from Immediate Release Tablets

通过直接压缩生产的立即释放（IR）片剂是最流行的口服固体剂型，用于向患者提供活性药物成分（api）。为了吸收药物分子，片剂需要在胃肠道中分解以释放原料药晶体溶解。体外溶出度测试在IR片剂产品开发生命周期中起着至关重要的作用，旨在探测原料药的释放概况，为候选配方的选择提供信息，并确定配方和/或制造工艺的变体对体内性能的影响。现行药典溶出度试验既不能反映患者胃肠道的实际情况，也不适合预测药物在体内的释放性能。实现这一目标的最佳方法是基于对潜在物理的彻底理解来模拟片剂药物释放概况。然而，目前的溶出度模型不能准确预测红外片剂的药物释放，因为它假设了溶解颗粒的球形，而没有考虑晶体形态和表面特定的溶出性质。虽然红外片剂的崩解被认为是控制原料药溶出的关键步骤，但崩解和溶出模型之间没有直接的联系，崩解过程被简单地视为启动原料药溶出的时滞函数。此外，没有数学模型可以准确地捕捉红外片剂崩解的整体物理。由于制剂中使用的赋形剂、加工和生产设施以及溶出环境的多样性，情况进一步复杂化。本提案将探讨如何基于崩解的综合机制模型和新的原料药溶出模型来预测IR片剂在胃肠道中的药物释放谱，从而使我们的建模、分析和预测原料药释放谱的能力发生重大变化。这些挑战将由德蒙福特大学和萨里大学的两个主要研究小组来解决，这代表了一种新的多学科合作。该小组汇集了结晶科学、分子动力学、配方科学、制药和拉曼光谱/成像方面的基本专业知识。通过实验和计算的努力，我们将开发一个模型框架，准确预测IR片剂在胃肠道中的药物释放行为。这将使IR片剂能够以虚拟方式设计和测试，以提供临床相关的溶出规格，以达到所需的临床性能，有可能彻底改变IR产品设计，并有机会加速创新，以更快、更经济地将药物推向市场，并挽救生命。

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.