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

Author:

Waterhouse, D. J.

Saavedra, J. E.

Davies, K. M.

Citro, M. L.

Xu, X.

Powell, D. A.

Grimes, G. J.

Potti, G. K.

Keefer, L. K.
Author Address

Natl Canc Inst, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Data Management Serv Inc, Ft Detrick, MD 21702 USA. NCI, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA Keefer, LK, Natl Canc Inst, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA

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. (c) 2005 Wiley-Liss, Inc

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