ABSTRACT

Objectives: This study investigated the impact of polymer excipients on a typical cocrystal for sacubitril (SAC) and valsartan (VAL), aiming to guide optional formulation design and maximize oral bioavailability.

Methods: Poly vinyl pyrrolidone (PVP) and hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) were selected. The dissolution/permeation system was used to predict both the kinetics of drug supersaturation and the simple permeation. The intermolecular interaction was analyzed by ¹H NMR spectroscopy and molecular dynamics simulation. Pharmacokinetic study was performed to assess the impact of polymer excipients in vivo.

Results: Our study found that unappreciated excipients in the formulation, especially some polymers, might compete with the intermolecular hydrogen bonding among the cocrystals components and provide unexpected affinity, and thus leverage the therapeutic benefits. HPMC as a coating excipient used in the Entresto® tablet hampered the supersaturation of API, which led to the poor oral absorption of cocrystals. Conversely, PVP appeared to promote and maintain drug supersaturation, resulting in improved bioavailability of API.

Conclusion: In conclusion, understanding the interplay between the cocrystal components and polymers is the key to optimizing the excipients to maximize the performance of cocrystal based oral drug formulation.

摘要

目的：本研究调查了聚合物赋形剂对沙比特利（SAC）和缬沙坦（VAL）的典型共结晶的影响，旨在指导可选的制剂设计并最大程度地提高口服生物利用度。

方法：选择聚乙烯吡咯烷酮（PVP），羟丙基纤维素（HPC）和羟丙基甲基纤维素（HPMC）。溶解/渗透系统用于预测药物过饱和的动力学和简单渗透。通过¹ H NMR光谱和分子动力学模拟分析分子间的相互作用。进行了药物动力学研究，以评估聚合物赋形剂在体内的影响。

结果：我们的研究发现，配方中未识别的赋形剂，尤其是某些聚合物，可能会与共晶组分之间的分子间氢键竞争，并提供意想不到的亲和力，从而发挥治疗作用。HPMC作为Entresto®片剂中的包衣赋形剂阻碍了API的过饱和，这导致了共晶体的不良口服吸收。相反，PVP似乎促进和维持药物过饱和，从而提高了API的生物利用度。

结论：总而言之，了解共晶成分与聚合物之间的相互作用是优化赋形剂以最大化基于共晶的口服药物制剂性能的关键。