Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
Mol Pharm. 2020 Apr 6;17(4):1352-1362. doi: 10.1021/acs.molpharmaceut.0c00061. Epub 2020 Mar 5.
The polymer used in an amorphous solid dispersion (ASD) formulation plays a critical role in dosage form performance. Herein, drug-polymer interactions in aqueous solution were evaluated in order to better understand the dispersion stability of the colloidal drug-rich phase generated when the amorphous solubility is exceeded. The amorphous solubility () of ibuprofen (IBP) decreased when hypromellose (HPMC) or polyvinylpyrrolidone/vinyl acetate (PVP-VA) were present in solution. Solution nuclear magnetic resonance (NMR) spectroscopy revealed that a large amount of HPMC and PVP-VA distributed into the IBP-rich phase. The mixing of HPMC and PVP-VA with the IBP-rich phase led to the decreased . In contrast, the charged amino methacrylate copolymer (Eudragit E PO, EUD-E) showed minimal mixing with the IBP-rich phase; however, this polymer did lead to solubilization of IBP in the bulk aqueous phase. Although the IBP-rich phase generated by dissolving IBP at concentrations above rapidly coarsened followed by creaming in the absence of polymer, all of the polymers stabilized the IBP dispersion to some extent. The droplet size of the IBP-rich phase immediately after formation was around 300 nm in HPMC and PVP-VA solutions, and around 800 nm in the EUD-E solution. The mixing of the former two polymers with the drug-rich phase is thought to account for the smaller droplet size. Despite a smaller initial size, the dispersion stability of the IBP-rich droplets was relatively poor in the presence of PVP-VA. In contrast, the coalescence of the IBP-rich droplets was effectively suppressed by the steric repulsion and electrostatic repulsion derived from adsorbed HPMC and EUD-E, respectively. The present study highlights the complex effects of a polymer on the drug amorphous solubility and colloidal stability, which should be considered when optimizing ASD formulations with the goal of maximizing drug absorption.
无定形固体分散体（ASD）配方中使用的聚合物对剂型性能起着至关重要的作用。本文通过评估药物-聚合物在水溶液中的相互作用，以便更好地了解当无定形溶解度超过时生成的胶体药物富相的分散稳定性。当溶液中存在羟丙甲纤维素（HPMC）或聚乙烯吡咯烷酮/醋酸乙烯酯（PVP-VA）时，布洛芬（IBP）的无定形溶解度（）降低。溶液核磁共振（NMR）光谱表明，大量的 HPMC 和 PVP-VA 分布在 IBP 富相。HPMC 和 PVP-VA 与 IBP 富相混合导致下降。相比之下，带电荷的甲基丙烯酸共聚物（Eudragit E PO，EUD-E）与 IBP 富相的混合作用最小；然而，该聚合物确实导致 IBP 在水相主体中的溶解。尽管在没有聚合物的情况下，浓度高于的 IBP 迅速粗化并随后产生乳状液，但所有聚合物都在一定程度上稳定了 IBP 分散体。在 HPMC 和 PVP-VA 溶液中，形成后立即形成的 IBP 富相的液滴尺寸约为 300nm，而在 EUD-E 溶液中约为 800nm。前两种聚合物与药物富相的混合被认为是导致较小液滴尺寸的原因。尽管初始尺寸较小，但在存在 PVP-VA 的情况下，IBP 富相分散体的稳定性相对较差。相比之下，HPMC 和 EUD-E 分别吸附的空间排斥和静电排斥有效地抑制了 IBP 富相液滴的聚并。本研究强调了聚合物对药物无定形溶解度和胶体稳定性的复杂影响，在优化旨在最大程度提高药物吸收的 ASD 配方时应考虑这些影响。
