Adhikari Saurav, Yang Da Hye, Li Na
Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road Unit 3092, Storrs, CT 06269, United States.
Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road Unit 3092, Storrs, CT 06269, United States; Institute of Materials Science, University of Connecticut, 97 North Eagleville Road Unit 3136, Storrs, CT 06269, United States; Department of Chemical & Biomolecular Engineering, University of Connecticut, 191 Auditorium Road, Unit 3222, Storrs, CT 06269, United States.
J Pharm Sci. 2025 Aug 13;114(10):103937. doi: 10.1016/j.xphs.2025.103937.
Formulations containing colloidal particles, such as micelles, nanocrystals, and amorphous drug nanoparticles, are widely used to enhance the oral absorption of poor soluble drugs. The underlying mechanism was proposed to be the particle drifting effect, where the particles effectively reduce the diffusional resistance of the aqueous boundary layer by releasing the free drug near the surface of the absorption site, such as a membrane, the intestinal mucosa, or an interface. However, it remains challenging to appropriately interpret experimental data or to accurately predict enhanced permeation rate provided by particle drifting effect. In this study, we developed an integrated dissolution-permeation model to quantitatively analyze the particle drifting effect. Using a biphasic experimental setup, amorphous drug nanoparticles of several poorly soluble model drugs were evaluated. The particle drifting effect was modeled by coupling the Wang-Flanagan particle dissolution model with a stagnant-film permeation model. Results suggested that drug nanoparticles at low concentrations did not alter the diffusional profile or the fitted permeability coefficient. At high particle concentrations, a flux plateau was observed, signifying non-sink dissolution of the particles. The fitted interfacial permeability coefficient increased with increasing particle concentration, confirming reduced diffusional resistance of the aqueous boundary layer by the presence of drug particles. High number of particles also altered the fitted partition coefficient of the drug due to saturation of the free drug in the aqueous boundary layer adjacent to the liquid interface. The mass transport model was able to predict the particle drifting effect for systems with high particle concentrations or extremely poorly soluble drugs where experimental evaluations become challenging. Combined with a differential equation-based pharmacokinetic model, in vivo drug absorption of a model drug enzalutamide was predicted at different doses with satisfaction. This work provides mechanistic understanding of the diffusional profiles obtained through the biphasic setup, and may contribute to more accurate oral bioavailability prediction for formulations that contain amorphous drug nanoparticles.
含有胶体颗粒（如胶束、纳米晶体和无定形药物纳米颗粒）的制剂被广泛用于提高难溶性药物的口服吸收。其潜在机制被认为是颗粒漂移效应，即颗粒通过在吸收部位（如膜、肠黏膜或界面）表面附近释放游离药物，有效降低水相边界层的扩散阻力。然而，要恰当地解释实验数据或准确预测颗粒漂移效应所提供的增强渗透速率仍然具有挑战性。在本研究中，我们开发了一个综合的溶解 - 渗透模型来定量分析颗粒漂移效应。使用双相实验装置，对几种难溶性模型药物的无定形药物纳米颗粒进行了评估。通过将王 - 弗拉纳根颗粒溶解模型与停滞膜渗透模型耦合来模拟颗粒漂移效应。结果表明，低浓度的药物纳米颗粒不会改变扩散曲线或拟合的渗透系数。在高颗粒浓度下，观察到通量平台，这表明颗粒的非漏槽溶解。拟合的界面渗透系数随着颗粒浓度的增加而增加，证实了药物颗粒的存在降低了水相边界层的扩散阻力。大量颗粒还会改变药物的拟合分配系数，这是由于与液体界面相邻的水相边界层中游离药物的饱和所致。该传质模型能够预测高颗粒浓度或极难溶性药物系统的颗粒漂移效应，而这些系统的实验评估具有挑战性。结合基于微分方程的药代动力学模型，对模型药物恩杂鲁胺在不同剂量下的体内药物吸收进行了满意的预测。这项工作提供了对通过双相装置获得的扩散曲线的机理理解，并可能有助于更准确地预测含有无定形药物纳米颗粒制剂的口服生物利用度。
