Coamorphous Solid Dispersion of a Soluble Epoxide Hydrolase Inhibitor t-TUCB with Amino Acid l-Arginine

Abstract

Inhibitors of soluble epoxide hydrolase (sEHIs) have been of interest for treating various diseases in humans and animals. Therefore, various sEHIs have been investigated in several clinical trials. Here, we report the development of a coamorphous solid dispersion of an sEHI t-TUCB with the amino acid l-arginine. t-TUCB has a very low aqueous equilibrium solubility (0.031 ± 0.013 μg/mL in pH 6.6 DI water) but possesses free carboxylic acid. Thus, converting t-TUCB to the corresponding sodium salt improved the water solubility (1.2 mg/mL). However, the sodium salt tended to form insoluble t-TUCB sodium salt aggregates, which is problematic for the scale-up of the sodium salt. However, adding l-arginine can deaggregate t-TUCB sodium salt aggregates. Moreover, the basicity of l-arginine allows us to prepare solid dispersion of t-TUCB directly, which forms a coamorphous system. The coamorphous solid dispersion of t-TUCB with l-arginine at a ratio of 1:3 (t-TUCB/Arg (1:3) solid dispersion) not only improved the water solubility (2.2 mg/mL) and dissolution profile (>80% in 10 min) of t-TUCB but also solved the problem of forming insoluble heavy aggregates associated with the sodium salt of t-TUCB. Therefore, the t-TUCB/Arg (1:3) solid dispersion obtained showed 87.1% bioavailability and alleviated LPS-induced pain in rats when orally administered.