1,3-Dicyclohexyl urea nanosuspension for intravenous steady-state delivery in rats

Aqueous insolubility is recognized throughout the pharmaceutical industry as a major hurdle for pre-clinical and clinical drug delivery. Pre-clinical, early efficacy, and proof of concept studies oftentimes rely on model compounds that have less than ideal physiochemical properties, and the in vivo results from these studies often have critical impact on the future of the project. As such, effective delivery of prototype compounds with sub-optimal properties is important in target validation. 1,3-Dicyclohexyl urea (DCU), a potent inhibitor of soluble epoxide hydrolase (sEH) has been shown to lower systemic blood pressure in spontaneously hypertensive rats. This compound has limited aqueous solubility that makes in vivo delivery difficult. In such situations, co-solvents, complexation reagents, and emulsions are commonly used to increase the bioavailability of a prototype compound. However, these approaches are often limited by their capacity to get and keep a compound in solution and can have unwanted placebo effects, which can confound the interpretation of animal efficacy results. Nanosuspension formulations of DCU have been utilized for both intravenous injection and infusion to reach steady-state (Css) plasma concentrations in rat enabling the investigation of the target, chemistry space, and PK/PD in a timely manner without encountering confounding efficacy results.