Ionic Liquid Versus Prodrug Strategy to Address Formulation Challenges

被引：32

作者：

Balk, Anja ^{[1
]}

Widmer, Toni ^{[1
,2
]}

Wiest, Johannes ^{[1
]}

Bruhn, Heike ^{[3
]}

Rybak, Jens-Christoph ^{[1
]}

Matthes, Philipp ^{[4
]}

Mueller-Buschbaum, Klaus ^{[4
]}

Sakalis, Anastasios ^{[1
]}

Luehmann, Tessa ^{[1
]}

Berghausen, Joerg ^{[2
]}

Holzgrabe, Ulrike ^{[1
]}

Galli, Bruno ^{[2
]}

Meinel, Lorenz ^{[1
]}

机构：

[1] Univ Wurzburg, Inst Pharm, D-97074 Wurzburg, Germany

[2] Novartis Pharma AG, CH-4002 Basel, Switzerland

[3] Inst Mol Infect Biol, D-97080 Wurzburg, Germany

[4] Univ Wurzburg, Inst Inorgan Chem, D-97074 Wurzburg, Germany

来源：

PHARMACEUTICAL RESEARCH | 2015年 / 32卷 / 06期

关键词：

active pharmaceutical ingredient; bioavailability; mechanism of supersaturation; migraine; ionic liquid; QUINAZOLINEDIONE SULFONAMIDES; DRUG DISCOVERY; NUCLEATION; PERMEABILITY; ANTAGONISTS; SOLUBILITY; ABSORPTION;

D O I：

10.1007/s11095-014-1607-9

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

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 mu M / 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.

引用

页码：2154 / 2167

页数：14

共 34 条

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