Drug Delivery, Disposition and Dynamics and ‡Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
Capsugel R&D Australia, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
Mol Pharm. 2017 Nov 6;14(11):3669-3683. doi: 10.1021/acs.molpharmaceut.7b00442. Epub 2017 Oct 10.
This study aimed to transform weakly acidic poorly water-soluble drugs (PWSD) into ionic liquids (ILs) to promote solubility in, and the utility of, lipid-based formulations. Ionic liquids (ILs) were formed directly from tolfenamic acid (Tolf), meclofenamic acid, diclofenac, and ibuprofen by pairing with lipophilic counterions. The drug-ILs were obtained as liquids or low melting solids and were significantly more soluble (either completely miscible or highly soluble) in lipid based, self-emulsifying drug delivery systems (SEDDS) when compared to the equivalent free acid. In vivo assessment of a SEDDS lipid solution formulation of Tolf didecyldimethylammonium salt and the same formulation of Tolf free acid at low dose (18 mg/kg, where the free acid was soluble in the SEDDS), resulted in similar absorption profiles and overall exposure. At high dose (100 mg/kg), solution SEDDS formulations of the Tolf ILs (didecyldimethylammonium, butyldodecyldimethylammonium or didecylmethylammonium salts) were possible, but the lower lipid solubility of Tolf free acid dictated that administration of the free acid was only possible as a suspension in the SEDDS formulation or as an aqueous suspension. Under these conditions, total drug plasma exposure was similar for the IL formulations and the free acid, but the plasma profiles were markedly different, resulting in flatter, more prolonged exposure profiles and reduced C for the IL formulations. Isolation of a weakly acidic drug as an IL may therefore provide advantage as it allows formulation as a solution SEDDS rather than a lipid suspension, and in some cases may provide a means of slowing or sustaining absorption. The current studies compliment previous studies with weakly basic PWSD and demonstrate that transformation into highly lipophilic ILs is also possible for weakly acidic compounds.
本研究旨在将弱酸性难溶性药物（PWSD）转化为离子液体（IL），以提高其在基于脂质的制剂中的溶解度和应用。通过与亲脂性抗衡离子配对，直接从托芬那酸（Tolf）、甲氯芬那酸、双氯芬酸和布洛芬形成离子液体（IL）。与等量游离酸相比，药物-IL 以液体或低熔点固体形式获得，并且在脂质自乳化药物递送系统（SEDDS）中溶解度显著更高（完全混溶或高度溶解）。Tolf 双十二烷基二甲基氯化铵盐的SEDDS 脂质溶液制剂和 Tolf 游离酸的相同制剂（游离酸可溶于 SEDDS）的低剂量（18mg/kg）的体内评估导致相似的吸收曲线和总体暴露。高剂量（100mg/kg）时，Tolf IL（双十二烷基二甲基铵、正丁基十二烷基二甲基铵或双癸基甲基铵盐）的 SEDDS 溶液制剂是可能的，但 Tolf 游离酸的脂质溶解度较低，使得游离酸的给药只能作为SEDDS 制剂中的混悬液或水性混悬液。在这些条件下，IL 制剂和游离酸的总药物血浆暴露相似，但血浆曲线明显不同，导致 IL 制剂的暴露曲线更平坦、更持久，C 降低。因此，将弱酸性药物分离为 IL 可能具有优势，因为它可以作为溶液 SEDDS 而不是脂质混悬液进行制剂，并且在某些情况下可能提供一种减缓或维持吸收的方法。本研究补充了先前对弱碱性 PWSD 的研究，并证明将弱酸性化合物转化为高亲脂性 IL 也是可行的。
