Uhlemann Jens, Diedam Holger, Hoheisel Werner, Schikarski Tobias, Peukert Wolfgang
Bayer SAS, Environmental Science, 16, Rue Jean-Marie Leclair, 69266 Lyon CEDEX 09, France.
Bayer AG, Engineering & Technology, Applied Mathematics, Building B106, 102, 51368 Leverkusen, Germany.
Pharmaceutics. 2020 Dec 24;13(1):22. doi: 10.3390/pharmaceutics13010022.
Crystalline organic nanoparticles and their amorphous equivalents (ONP) have the potential to become a next-generation formulation technology for dissolution-rate limited biopharmaceutical classification system (BCS) class IIa molecules if the following requisites are met: (i) a quantitative understanding of the bioavailability enhancement benefit versus established formulation technologies and a reliable track record of successful case studies are available; (ii) efficient experimentation workflows with a minimum amount of active ingredient and a high degree of digitalization via, e.g., automation and computer-based experimentation planning are implemented; (iii) the scalability of the nanoparticle-based oral delivery formulation technology from the lab to manufacturing is ensured. Modeling and simulation approaches informed by the pharmaceutical material science paradigm can help to meet these requisites, especially if the entire value chain from formulation to oral delivery is covered. Any comprehensive digitalization of drug formulation requires combining pharmaceutical materials science with the adequate formulation and process technologies on the one hand and quantitative pharmacokinetics and drug administration dynamics in the human body on the other hand. Models for the technical realization of the drug production and the distribution of the pharmaceutical compound in the human body are coupled via the central objective, namely bioavailability. The underlying challenges can only be addressed by hierarchical approaches for property and process design. The tools for multiscale modeling of the here-considered particle processes (e.g., by coupled computational fluid dynamics, population balance models, Noyes-Whitney dissolution kinetics) and physiologically based absorption modeling are available. Significant advances are being made in enhancing the bioavailability of hydrophobic compounds by applying innovative solutions. As examples, the predictive modeling of anti-solvent precipitation is presented, and options for the model development of comminution processes are discussed.
如果满足以下条件，结晶有机纳米颗粒及其无定形等效物（ONP）有潜力成为溶出速率受限的生物药剂学分类系统（BCS）IIa类分子的下一代制剂技术：（i）对生物利用度提高的益处与既定制剂技术有定量的理解，并有成功案例研究的可靠记录；（ii）实施高效的实验工作流程，使用最少的活性成分，并通过例如自动化和基于计算机的实验规划实现高度数字化；（iii）确保基于纳米颗粒的口服给药制剂技术从实验室规模扩大到生产规模。由药物材料科学范式提供信息的建模和模拟方法有助于满足这些条件，特别是如果涵盖从制剂到口服给药的整个价值链。药物制剂的任何全面数字化一方面需要将药物材料科学与适当的制剂和工艺技术相结合，另一方面需要将人体中的定量药代动力学和药物给药动力学相结合。药物生产的技术实现模型和药物化合物在人体中的分布模型通过核心目标即生物利用度相互关联。只有通过属性和工艺设计的分层方法才能应对潜在挑战。用于此处所考虑的颗粒过程多尺度建模的工具（例如，通过耦合计算流体动力学、群体平衡模型、诺伊斯 - 惠特尼溶解动力学）和基于生理学的吸收建模是可用的。通过应用创新解决方案，在提高疏水性化合物的生物利用度方面正在取得重大进展。例如，介绍了抗溶剂沉淀的预测建模，并讨论了粉碎过程模型开发的选项。
