Preclinical evaluation of modern oral dosage forms requires more advanced in vitro devices as the trend of selecting low solubility, high permeability compounds for commercial development continues. Current dissolution methodologies may not always be suitable for such compounds due to excessive fluid volume, high fluid shear rates, heterogeneity of shear rates, suboptimal fluid flow, and, ultimately, the lack of absorption ability (Gray The Science of USP 1 and 2 Dissolution: Present Challenges and Future Relevance; Pharmaceutical Research, 2009; Vol. 26; pp 1289−1302). Herein, a new dissolution apparatus is introduced in combination with an ultrathin, semipermeable polymer membrane that mimics human passive absorption for lipophilic compounds. The ultrathin large-area polydimethylsiloxane (PDMS) membrane (UTLAM) absorption system is designed to mimic the dissolution and passive transcellular diffusion process representing the oral absorption pathway. A simple spin-casting method was developed to fabricate the ultrathin highly uniform membranes. To minimize membrane resistance to diffusion and maximize transport across the polymer membrane, 10–40 μm PDMS membranes were successfully prepared. A new diffusion cell was designed and tested to support the UTLAM and incorporates a hydrofoil impeller for more desirable hydrodynamics and mixing, using ibuprofen as a model weak acidic drug. UTLAM permeability was sufficiently high that the aqueous boundary layer contributed to the overall permeability of the system. This diffusion cell system demonstrated that, when the aqueous diffusion layer contributes to the overall resistance to transport, the pH at which absorption is 50% of maximum (pH_50%) shifts from the pK_a to higher values, demonstrating why weak acid drugs can exhibit high absorption at pH’s significantly greater than their pK_a. High rates of transport across the UTLAM are possible for drugs with high partition coefficients (i.e., BCS II compounds even under mostly ionized conditions), and PDMS UTLAMs may be tailored to simulate human intestinal passive absorption rates.

中文翻译：

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超薄型大面积膜扩散池，用于pH依赖的同时溶解和吸收研究。

随着为商业发展选择低溶解度，高渗透性化合物的趋势不断发展，现代口服剂型的临床前评估需要更先进的体外装置。由于过多的流体体积，高的流体剪切速率，剪切速率的非均质性，次优的流体流动以及最终缺乏吸收能力，当前的溶出方法可能并不总是适用于此类化合物（USP 1和2溶出度的灰色科学） ：当前的挑战和未来的相关性；药物研究，2009年；第26卷; 1289−1302页）。在此，引入了一种新的溶解设备，该设备与模仿人类被动吸收亲脂性化合物的超薄半透性聚合物膜结合使用。超薄大面积聚二甲基硅氧烷（PDMS）膜（UTLAM）吸收系统旨在模拟代表口服吸收途径的溶解和被动跨细胞扩散过程。开发了一种简单的旋转浇铸方法来制造超薄，高度均匀的膜。为了最大程度地减少膜的扩散阻力并最大程度地跨聚合物膜运输，已成功制备了10–40μmPDMS膜。设计并测试了新的扩散池以支持UTLAM，并使用布洛芬作为模型弱酸性药物，并结合了水翼式叶轮以实现更理想的流体动力学和混合。UTLAM渗透性足够高，以至于水界面层有助于系统的总体渗透性。该扩散池系统证明，当水扩散层有助于总体传输阻力时，在该pH处的吸收为最大值的50％（pH_50％的值从p K _a移至更高的值，这说明了为什么弱酸药物在pH值明显大于其p K _a时能表现出高吸收。对于具有高分配系数的药物（即，即使在大多数电离条件下，BCS II化合物也是如此）而言，跨UTLAM的高传输速率是可能的，并且PDMS UTLAM可以定制为模拟人体肠道被动吸收率。