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

J Pharm Sci. 2006 Jan;95(1):108-15. doi: 10.1002/jps.20486.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Drug Compounding
  • Drug Storage
  • Hydrolysis
  • Injections, Intravenous
  • Nitric Oxide / analysis
  • Nitric Oxide Donors / analysis
  • Nitric Oxide Donors / chemistry*
  • Nitrogen Oxides / analysis
  • Nitrogen Oxides / chemistry*
  • Prodrugs / analysis
  • Prodrugs / chemistry*
  • Proline / analogs & derivatives*
  • Proline / analysis
  • Proline / chemistry

Substances

  • Nitric Oxide Donors
  • Nitrogen Oxides
  • Prodrugs
  • proline-nitric oxide
  • Nitric Oxide
  • Proline