Wright Leah, Barnes Timothy J, Joyce Paul, Prestidge Clive A
UniSA: Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia.
Pharmaceutics. 2022 Nov 30;14(12):2659. doi: 10.3390/pharmaceutics14122659.
High-throughput permeation models are essential in drug development for timely screening of new drug and formulation candidates. Nevertheless, many current permeability assays fail to account for the presence of the gastrointestinal mucus layer. In this study, an optimised high-throughput mucus permeation model was developed employing a highly biorelevant mucus mimic. While mucus permeation is primarily conducted in a simple mucin solution, the complex chemistry, nanostructure and rheology of mucus is more accurately modelled by a synthetic biosimilar mucus (BSM) employing additional protein, lipid and rheology-modifying polymer components. Utilising BSM, equivalent permeation of various molecular weight fluorescein isothiocyanate-dextrans were observed, compared with native porcine jejunal mucus, confirming replication of the natural mucus permeation barrier. Furthermore, utilising synthetic BSM facilitated the analysis of free protein permeation which could not be quantified in native mucus due to concurrent proteolytic degradation. Additionally, BSM could differentiate between the permeation of poly (lactic-co-glycolic) acid nanoparticles (PLGA-NP) with varying surface chemistries (cationic, anionic and PEGylated), PEG coating density and size, which could not be achieved by a 5% mucin solution. This work confirms the importance of utilising highly biorelevant mucus mimics in permeation studies, and further development will provide an optimal method for high-throughput mucus permeation analysis.
高通量渗透模型在药物开发中对于及时筛选新的药物和制剂候选物至关重要。然而，目前许多渗透性测定未能考虑胃肠道黏液层的存在。在本研究中，采用高度生物相关的黏液模拟物开发了一种优化的高通量黏液渗透模型。虽然黏液渗透主要在简单的黏蛋白溶液中进行，但通过使用额外的蛋白质、脂质和流变学改性聚合物成分的合成生物相似黏液（BSM）可以更准确地模拟黏液的复杂化学、纳米结构和流变学。利用BSM，观察到与天然猪空肠黏液相比，各种分子量的异硫氰酸荧光素 - 葡聚糖具有等效的渗透性，证实了天然黏液渗透屏障的复制。此外，利用合成BSM有助于分析游离蛋白质的渗透，由于同时存在的蛋白水解降解，在天然黏液中无法对其进行定量。此外，BSM可以区分具有不同表面化学性质（阳离子、阴离子和聚乙二醇化）、聚乙二醇涂层密度和尺寸的聚（乳酸 - 乙醇酸）纳米颗粒（PLGA - NP）的渗透，而5%的黏蛋白溶液无法做到这一点。这项工作证实了在渗透研究中使用高度生物相关的黏液模拟物的重要性，进一步的发展将为高通量黏液渗透分析提供一种优化方法。
