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Ionic Liquid Forms of Weakly Acidic Drugs in Oral Lipid Formulations: Preparation, Characterization, in Vitro Digestion, and in Vivo Absorption Studies
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-10-10 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00442
Yasemin Sahbaz 1 , Tri-Hung Nguyen 1 , Leigh Ford , Claire L. McEvoy 1 , Hywel D. Williams 2 , Peter J. Scammells , Christopher J. H. Porter 1, 3
Affiliation  

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 Cmax 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.

中文翻译:

口服脂质制剂中弱酸性药物的离子液体形式:制备,表征,体外消化和体内吸收研究。

这项研究旨在将弱酸性的水溶性差的药物(PWSD)转变为离子液体(ILs),以促进其在基于脂质的制剂中的溶解度和实用性。离子液体(ILs)是通过与亲脂性抗衡离子配对直接从甲苯磺酸(Tolf),甲氯芬那酸,双氯芬酸和布洛芬形成的。药物-IL以液体或低熔点固体形式获得,与等效的游离酸相比,它们在基于脂质的自乳化药物递送系统(SEDDS)中的溶解度明显更高(完全可混溶或高度溶解)。体内对Tolf二癸基二甲基铵盐的SEDDS脂质溶液制剂和低剂量(18 mg / kg,其中游离酸可溶于SEDDS的Tolf游离酸)的相同制剂的SEDDS脂质溶液配方的评估,导致了相似的吸收曲线和总体暴露。在高剂量(100 mg / kg)下,Tolf ILs的溶液SEDDS配方(二癸基二甲基铵盐,丁基十二烷基二甲基铵盐或二癸基甲基铵盐)是可行的,但是Tolf游离酸的脂质溶解度较低,这表明游离酸只能作为混悬剂给药在SEDDS制剂中或作为水性悬浮液使用。在这些条件下,IL制剂和游离酸的总药物血浆暴露相似,但是血浆分布显着不同,从而导致平坦,更长的暴露分布并减少了暴露。IL制剂的C max。因此,将弱酸性药物作为IL分离可以提供优势,因为它可以将SEDDS制成溶液而不是脂质悬浮液,并且在某些情况下可以提供减缓或维持吸收的手段。目前的研究对弱碱性PWSD进行了补充,并证明了弱酸性化合物也可以转变为高亲脂性IL。
更新日期:2017-10-10
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