The propensity of poorly water-soluble drugs to aggregate at supersaturation impedes their bioavailability. The emergence of supersaturated amorphous drug-salt-polymer systems provides a new approach to this problem. However, the effects of polymers on drug-drug interactions in aqueous phase are largely unexplored and it is unclear how to choose an optimal salt-polymer combination for a particular drug. We describe a comparative experimental and computational characterization of amorphous solid dispersions containing the drug celecoxib, and PVP-VA or HPMCAS polymers with or without Na+/K+ salts. Classical models for drug-polymer interactions fail to identify the best drug-salt-polymer combination. In contrast, more stable drug-polymer interaction energies computed from molecular dynamics simulations correlate with prolonged stability of supersaturated amorphous drug-salt-polymer systems, along with better dissolution and pharmacokinetic profiles. The celecoxib-salt-PVP-VA formulations exhibit excellent biopharmaceutical performance, offering the prospect of less frequent administration and lower doses of this widely used anti-inflammatory, thereby increasing cost-effectiveness, and reducing side-effects.

中文翻译：

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通过实验和分子模拟对药物-盐-聚合物相互作用进行比较分析，提高生物制药性能

水溶性差的药物在过饱和时聚集的倾向阻碍了它们的生物利用度。过饱和无定形药物-盐-聚合物体系的出现为解决这一问题提供了新的途径。然而，聚合物对水相中药物-药物相互作用的影响很大程度上尚未被探索，并且尚不清楚如何为特定药物选择最佳的盐-聚合物组合。我们描述了含有药物塞来考昔和 PVP-VA 或 HPMCAS 聚合物（含或不含 Na+/K+ 盐）的无定形固体分散体的比较实验和计算表征。药物-聚合物相互作用的经典模型无法确定最佳的药物-盐-聚合物组合。相比之下，通过分子动力学模拟计算出的更稳定的药物-聚合物相互作用能与过饱和无定形药物-盐-聚合物系统的长期稳定性以及更好的溶出度和药代动力学曲线相关。塞来昔布-盐-PVP-VA制剂表现出优异的生物制药性能，有望减少这种广泛使用的抗炎药物的给药频率和剂量，从而提高成本效益并减少副作用。