Mol Pharm. 2020 Jan 6;17(1):180-189. doi: 10.1021/acs.molpharmaceut.9b00889. Epub 2019 Dec 6.
Recently published studies have proposed that amorphous drug nanoparticles in gastrointestinal fluids may be beneficial for the absorption of poorly soluble compounds. Nanosized drug particles are known to provide rapid dissolution rates and, in some instances, a slight increase in solubility. However, in recent studies, the differences observed in vivo could not be explained solely by these attributes. Given the high dose and very low aqueous solubility of the study compounds, rapid equilibration to the drug-saturated solubility in gastrointestinal fluid would occur independent of the presence of nanoparticles. Alternatively, it has been proposed that drug nanoparticles (ca. ≤ 200 to 300 nm) may provide a "shuttle" for drug across the unstirred water layer (UWL) adjacent to the intestinal epithelium, particularly for low solubility/lipophilic compounds where absorption may be largely UWL-limited. This transport mechanism would result in a higher unbound drug concentration at the surface of the epithelium for absorption. This study evaluates this mechanism using a simple modification of the effective permeability to account for the effect of drug nanoparticles diffusing across the UWL. The modification can be made using inputs for solubility and nanoparticle size. The permeability modification was evaluated using three published case studies for amorphous formulations of itraconazole, anacetrapib, and enzalutamide, where the formation of amorphous drug nanoparticles upon dissolution resulted in improved drug absorption. Absorption modeling was performed using GastroPlus to assess the impact of the nanomodified permeability method on the accuracy of model prediction compared to in vivo data. Simulation results were compared to those for baseline simulations using an unmodified effective permeability. The results show good agreement using the nanomodified permeability, which described the data better than the standard baseline predictions. The nanomodified permeability method can be a suitable, fit-for-purpose in silico approach for evaluating or predicting oral absorption of poorly soluble, UWL-limited drugs from formulations that produce a significant number of amorphous drug nanoparticles.
最近发表的研究表明，胃肠道液中无定形药物纳米颗粒可能有利于吸收难溶性化合物。众所周知，纳米级药物颗粒能提供快速的溶解速率，在某些情况下还能略微提高溶解度。然而，在最近的研究中，体内观察到的差异不能仅用这些特性来解释。鉴于研究化合物的高剂量和极低的水溶解度，药物在胃肠道液中的饱和溶解度会与纳米颗粒的存在与否无关而迅速达到平衡。或者，有人提出药物纳米颗粒（约 200 至 300nm）可能为药物穿过与肠上皮相邻的未搅动水层（UWL）提供“穿梭”，特别是对于低溶解度/亲脂性化合物，其吸收可能主要受到 UWL 的限制。这种转运机制将导致上皮表面的游离药物浓度更高，从而有利于吸收。本研究使用有效渗透系数的简单修改来评估这种机制，以考虑药物纳米颗粒穿过 UWL 扩散的影响。可以使用溶解度和纳米颗粒尺寸的输入来进行修改。使用伊曲康唑、阿昔单抗和恩扎卢胺的三种已发表的无定形制剂的案例研究来评估渗透系数的修改，其中溶解时形成无定形药物纳米颗粒导致药物吸收改善。使用 GastroPlus 进行吸收建模，以评估与体内数据相比，纳米改性渗透率方法对模型预测准确性的影响。将模拟结果与使用未修改的有效渗透率进行的基线模拟结果进行比较。结果表明，使用纳米改性渗透率可获得良好的一致性，其描述数据的能力优于标准基线预测。纳米改性渗透率方法可作为一种合适的、适合目的的计算方法，用于评估或预测从产生大量无定形药物纳米颗粒的制剂中吸收难溶性、受 UWL 限制的药物的口服吸收。
