Balk Anja, Widmer Toni, Wiest Johannes, Bruhn Heike, Rybak Jens-Christoph, Matthes Philipp, Müller-Buschbaum Klaus, Sakalis Anastasios, Lühmann Tessa, Berghausen Jörg, Holzgrabe Ulrike, Galli Bruno, Meinel Lorenz
Institute for Pharmacy, Am Hubland, University of Würzburg, 97074, Würzburg, Germany.
Pharm Res. 2015 Jun;32(6):2154-67. doi: 10.1007/s11095-014-1607-9. Epub 2014 Dec 23.
A poorly water soluble acidic active pharmaceutical ingredient (API) was transformed into an ionic liquid (IL) aiming at faster and higher oral availability in comparison to a prodrug.
API preparations were characterized in solid state by single crystal and powder diffraction, NMR, DSC, IR and in solution by NMR and ESI-MS. Dissolution and precipitation kinetics were detailed as was the role of the counterion on API supersaturation. Transepithelial API transport through Caco-2 monolayers and counterion cytotoxicity were assessed.
The mechanism leading to a 700 fold faster dissolution rate and longer duration of API supersaturation of the ionic liquid in comparison to the free acid was deciphered. Transepithelial transport was about three times higher for the IL in comparison to the prodrug when substances were applied as suspensions with the higher solubility of the IL outpacing the higher permeability of the prodrug. The counterion was nontoxic with IC50 values in the upper μM / lower mM range in cell lines of hepatic and renal origin as well as in macrophages.
The IL approach was instrumental for tuning physico-chemical API properties, while avoiding the inherent need for structural changes as required for prodrugs.
将一种水溶性差的酸性活性药物成分（API）转化为离子液体（IL），旨在与前药相比实现更快、更高的口服生物利用度。
通过单晶和粉末衍射、核磁共振（NMR）、差示扫描量热法（DSC）、红外光谱（IR）对API制剂进行固态表征，并通过核磁共振和电喷雾电离质谱（ESI-MS）对其溶液进行表征。详细研究了溶解和沉淀动力学以及抗衡离子对API过饱和的作用。评估了API通过Caco-2单层的跨上皮转运和抗衡离子的细胞毒性。
阐明了与游离酸相比，离子液体的溶解速率快700倍且API过饱和持续时间更长的机制。当将物质作为悬浮液应用时，离子液体的跨上皮转运比前药高约三倍，因为离子液体的较高溶解度超过了前药的较高渗透性。在肝源性、肾源性细胞系以及巨噬细胞中，抗衡离子无毒，IC50值处于较高的微摩尔/较低的毫摩尔范围内。
离子液体方法有助于调节API的物理化学性质，同时避免了前药所需的结构变化。
