Injectable formulation of disodium 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), an ultrafast nitric oxide donor prodrug

✍ Scribed by David J. Waterhouse; Joseph E. Saavedra; Keith M. Davies; Michael L. Citro; Xia Xu; Douglas A. Powell; George J. Grimes; Gopal K. Potti; Larry K. Keefer

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 105 KB
• Volume: 95
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.20486

✦ Synopsis

PROLI/NO is an agent of structure XN(O)==NONa (X = L-prolyl) whose 2-s half-life for nitric oxide (NO) release at physiological pH makes it an excellent prodrug for localizing NO's therapeutic effects at the site of application, but a difficult one to formulate and certify as pure. Despite its extraordinary thermal and hydrolytic instability, however, PROLI/NO could be formulated as an injectable drug by dissolving it in cold 0.1 M sodium hydroxide containing 5% D-mannitol, then quickly ultrafiltering and lyophilizing it in evacuated septum vials. No evidence for decomposition was seen in the contents of these evacuated vials when stored at -20 degrees C over a 140-day observation period, as judged by quantifying NO release in simulated infusate solutions (10 mM carbonate/bicarbonate, pH 10.5). The only hydrolysis products detected were NO, nitrite ion, proline, and N-nitrosoproline, all products of normal human physiological processes.