School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, and MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology , Tsinghua University , Beijing 100084 , P.R. China.
Chemical and Pharmaceutical Development, Research and Development , Bayer AG , 13342 Berlin , Germany.
Mol Pharm. 2018 Jul 2;15(7):2754-2763. doi: 10.1021/acs.molpharmaceut.8b00253. Epub 2018 May 30.
Amorphous solid dispersion (ASD) is one of the most versatile supersaturating drug delivery systems to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. PVP based ASD formulation of nimodipine (NMD) has been marketed and effectively used in clinic for nearly 30 years, yet the mechanism by which PVP maintains the supersaturation and subsequently improves the bioavailability of NMD was rarely investigated. In this research, we first studied the molecular interactions between NMD and PVP by solution NMR, using CDCl as the solvent, and the drug-polymer Flory-Huggins interaction parameter. No strong specific interaction between PVP and NMD was detected in the nonaqueous state. However, we observed that aqueous supersaturation of NMD could be significantly maintained by PVP, presumably due to the hydrophobic interactions between the hydrophobic moieties of PVP and NMD in aqueous medium. This hypothesis was supported by dynamic light scattering (DLS) and supersaturation experiments in the presence of different surfactants. DLS revealed the formation of NMD/PVP aggregates when NMD was supersaturated, suggesting the formation of hydrophobic interactions between the drug and polymer. The addition of surfactants, sodium lauryl sulfate (SLS) or sodium taurocholate (NaTC), into PVP maintained that NMD supersaturation demonstrated different effects: SLS could only improve NMD supersaturation with concentration above its critical aggregation concentration (CAC) value while not with lower concentration. Nevertheless, NaTC could prolong NMD supersaturation independent of concentration, with lower concentration outperformed higher concentration. We attribute these observations to PVP-surfactant interactions and the formation of PVP/surfactant complexes. In summary, despite the lack of specific interactions in the nonaqueous state, NMD aqueous supersaturation in the presence of PVP was attained by hydrophobic interactions between the hydrophobic moieties of NMD and PVP. This hydrophobic interaction could be disrupted by surfactants, which interact with PVP competitively, thus hindering the capability of PVP to maintain NMD supersaturation. Therefore, caution is needed when evaluating such ASDs in vitro and in vivo when various surfactants are present either in the formulation or in the surrounding medium.
无定形固体分散体（ASD）是最通用的超饱和药物传递系统之一，可提高水溶性差的药物的溶解速率和口服生物利用度。基于 PVP 的尼莫地平（NMD）ASD 制剂已上市，并在临床上有效使用近 30 年，但 PVP 维持过饱和状态并随后提高 NMD 生物利用度的机制很少被研究。在这项研究中，我们首先通过溶液 NMR 研究了 NMD 和 PVP 之间的分子相互作用，使用 CDCl 作为溶剂和药物-聚合物 Flory-Huggins 相互作用参数。在非水状态下，未检测到 PVP 和 NMD 之间的强特异性相互作用。然而，我们观察到 PVP 可显著维持 NMD 的水相过饱和度，这可能是由于 PVP 的疏水性部分与 NMD 在水介质中的疏水性部分之间存在疏水相互作用。这一假设得到了在不同表面活性剂存在下的动态光散射（DLS）和过饱和度实验的支持。DLS 显示当 NMD 过饱和时会形成 NMD/PVP 聚集体，这表明药物和聚合物之间形成了疏水相互作用。表面活性剂十二烷基硫酸钠（SLS）或牛磺胆酸钠（NaTC）的加入可维持 PVP 中 NMD 的过饱和度，表现出不同的效果：SLS 仅能在其临界聚集浓度（CAC）值以上的浓度下改善 NMD 的过饱和度，而在较低浓度下则不能。然而，NaTC 可以独立于浓度延长 NMD 的过饱和度，较低浓度的效果优于较高浓度。我们将这些观察归因于 PVP-表面活性剂相互作用和 PVP/表面活性剂复合物的形成。总之，尽管在非水状态下缺乏特异性相互作用，但通过 NMD 和 PVP 的疏水性部分之间的疏水相互作用，在 PVP 存在下实现了 NMD 的水相过饱和度。这种疏水相互作用可被与 PVP 竞争相互作用的表面活性剂破坏，从而阻碍 PVP 维持 NMD 过饱和度的能力。因此，当在存在各种表面活性剂的制剂或周围介质中评估此类 ASD 时，无论是在体外还是体内，都需要谨慎。
