College of Pharmaceutical Science, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou, Zhejiang, 310014, People's Republic of China.
AAPS PharmSciTech. 2020 Mar 17;21(3):107. doi: 10.1208/s12249-020-01647-7.
Amorphous solid dispersions (ASD) are one of the most important supersaturating drug delivery systems (SDDS) for poorly water-soluble drugs to improve their bioavailability. As a result of thermodynamic instability, drug molecules tend to precipitate during storage and dissolution in gastrointestinal tract. Various precipitation inhibitors (PI) have been widely used to improve the stability in the past decade. However, most studies have investigated the inhibiting capability of PI on drug precipitation, rarely considering their potential hindering effect on the drug dissolution. The present study designed an ASD of Indomethacin (IND) and Eudragit® EPO by hot melt extrusion to investigate the influence of the added PI (PVP-K30) into ASD both on dissolution and precipitation. The precipitation study by solvent shift method indicated PVP-K30 could inhibit the precipitation of IND significantly. The dissolution study in different concentrations of PVP-K30 showed when the concentration increased above 50 μg/mL, PVP-K30 displayed an acceptable precipitation inhibition without drug concentration decline but an unexpected dissolution impediment with the reduction of maximum concentration platform. The dissolution tests of physical mixtures (PMs) of ASD and PVP-K30 also showed the precipitation inhibition and dissolution impediment when more than 2% PVP-K30 in PMs. This opposed effect of PVP-K30 was strengthen in ternary systems prepared by hot melt extruding the mixtures of IND, Eudragit® EPO and PVP-K30. All of these results proved the PI may be a double-edged sword for the opposed effects of precipitation inhibition and dissolution impediment, which should be carefully considered in the design and development of SDDS.
无定形固体分散体（ASD）是提高难溶性药物生物利用度的最重要的超饱和药物传递系统（SDDS）之一。由于热力学不稳定性，药物分子在储存和胃肠道溶解过程中往往会沉淀。在过去的十年中，各种沉淀抑制剂（PI）已被广泛用于提高其稳定性。然而，大多数研究都调查了 PI 对药物沉淀的抑制能力，很少考虑到它们对药物溶解的潜在阻碍作用。本研究通过热熔挤出设计了吲哚美辛（IND）和 Eudragit® EPO 的 ASD，以研究添加到 ASD 中的 PI（PVP-K30）对溶解和沉淀的影响。溶剂转移法的沉淀研究表明，PVP-K30 能显著抑制 IND 的沉淀。在不同浓度 PVP-K30 中的溶解研究表明，当浓度增加到 50μg/mL 以上时，PVP-K30 显示出可接受的沉淀抑制作用，而不会导致药物浓度下降，但会导致最大浓度平台的降低，从而出现意想不到的溶解阻碍。ASD 和 PVP-K30 的物理混合物（PM）的溶解测试也表明，当 PM 中 PVP-K30 的含量超过 2%时，会出现沉淀抑制和溶解阻碍。PVP-K30 的这种相反作用在通过热熔挤出 IND、Eudragit® EPO 和 PVP-K30 的混合物制备的三元系统中得到了加强。所有这些结果都证明了 PI 可能是一把双刃剑，既具有沉淀抑制作用，又具有溶解阻碍作用，在 SDDS 的设计和开发中应谨慎考虑。
