先进的计算机仿真工具,如基于生理的生物制药模型(PBBM)或基于生理的药代动力学模型(PBPK),在模型知情配方开发中发挥关键作用。这种方法已成功地实施在目前的情况下,用于开发新的奥美拉唑延迟释放口腔崩解片(ODT)制剂。旨在提高患者的依从性。PBBM是用物理化学方法开发的,生物制药,和溶解数据。中试制剂的溶出研究在生物预测介质中在禁食(0.1NHCl,随后pH6.8)和进料(pH5,随后pH6.8)条件下进行。该模型分三个阶段进行了广泛验证:飞行员禁食,试点饲喂虚拟生物等效性和食品效应评估。令人印象深刻的是,该模型能够适当地预测通过和失败的批次。根据试点研究的见解,优化了更高规模的关键配方。使用经过验证的模型对关键配方进行了前瞻性预测,发现生物结果与禁食条件下的模型预测一致。总的来说,使用创新的建模方法开发了基本原理和患者依从性的配方,并提交给监管机构。新的奥美拉唑制剂通过易于给药从而规避常规制剂的挑战而增强了患者的依从性。
The advanced in silico simulation tools, such as physiologically based biopharmaceutics models (PBBM) or physiologically based pharmacokinetic models (PBPK), play critical role in model informed formulation development. This approach has been successfully implemented in the present
case for development of novel omeprazole delayed-release orally disintegrating tablets (ODT) formulation, aimed to enhance patient compliance.PBBM was developed using physicochemical, biopharmaceutical, and dissolution data. The dissolution studies for pilot formulations were conducted in bio predictive media in fasting (0.1N HCl followed by pH 6.8) and fed (pH 5 followed by pH 6.8) conditions. The model was extensively validated in three stages: pilot fasted, pilot fed virtual bioequivalence and food effect assessments. Impressively, the model was able to predict both passed and failed batches appropriately.Based on insights from the pilot study, a higher scale pivotal formulation was optimized. Prospective predictions were made for pivotal formulations using validated model and bio results were found to be in line with model predictions in fasting condition.Overall, a rationale and patient compliant formulation was developed using innovative modeling approach and filed to regulatory agency. The novel omeprazole formulation enhanced patient compliance through ease of administration thereby circumventing challenges of conventional formulation.