Han Dingding, Rahimi Ehsan, Aramideh Soroush, Ardekani Arezoo M
Mechanical Engineering, Purdue University, 585 Purdue Mall Purdue University West Lafayette, IND 47906, United States.
Mechanical Engineering, Purdue University, 585 Purdue Mall Purdue University West Lafayette, IND 47906, United States.
J Pharm Sci. 2022 Mar;111(3):752-768. doi: 10.1016/j.xphs.2021.09.045. Epub 2021 Oct 6.
Drug transport and uptake in the subcutaneous tissue receives increasing attention in biomechanical and pharmaceutical researches, as subcutaneous administration becomes a common approach for the delivery of biotherapeutics, such as monoclonal antibodies. In this paper, high-fidelity numerical simulations are used to investigate the mechanisms governing drug transport and absorption in the subcutaneous tissue, which is expressed as a porous medium modeled by Darcy's law. The effects of tissue properties (permeability and porosity), the injection flow rate, and the vascular permeability of lymphatic vessels on the lymphatic uptake are studied. Additionally, an empirical formula for the lymphatic uptake during the injection is developed based on the numerical results. The roles of lymphatic drainage, blood perfusion, osmotic pressure, and the drug binding to the cells and the extracellular matrix in the lymphatic uptake are systematically studied. Furthermore, the drug distribution and absorption in a multi-layered porous medium are investigated to illustrate the effect of heterogeneity of permeability, as the permeability varies over a wide range in different layers of the tissue (such as dermis, subcutaneous tissue, muscle). While the interstitial pressure plays an essential role in the mechanisms regulating the absorption of free monoclonal antibodies, the binding and metabolism of drug proteins also affect the drug absorption by reducing the total free monoclonal antibodies.
随着皮下给药成为生物治疗药物（如单克隆抗体）递送的常用途径，皮下组织中的药物转运和摄取在生物力学和药学研究中受到越来越多的关注。在本文中，使用高保真数值模拟来研究皮下组织中药物转运和吸收的机制，皮下组织被表示为由达西定律建模的多孔介质。研究了组织特性（渗透率和孔隙率）、注射流速以及淋巴管的血管渗透率对淋巴摄取的影响。此外，基于数值结果建立了注射过程中淋巴摄取的经验公式。系统研究了淋巴引流、血液灌注、渗透压以及药物与细胞和细胞外基质的结合在淋巴摄取中的作用。此外，研究了多层多孔介质中的药物分布和吸收，以说明渗透率非均质性的影响，因为渗透率在组织的不同层（如真皮、皮下组织、肌肉）中变化范围很广。虽然间质压力在调节游离单克隆抗体吸收的机制中起着至关重要的作用，但药物蛋白的结合和代谢也会通过减少总游离单克隆抗体来影响药物吸收。
