Injectable formulation of disodium 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), an ultrafast nitric oxide donor prodrug.
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.
Waterhouse
David J
DJ
Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Maryland 21702, USA.
Saavedra
Joseph E
JE
Davies
Keith M
KM
Citro
Michael L
ML
Xu
Xia
X
Powell
Douglas A
DA
Grimes
George J
GJ
Potti
Gopal K
GK
Keefer
Larry K
LK
D004339:Drug Compounding; D004356:Drug Storage; D006868:Hydrolysis; D007275:Injections, Intravenous; D009569:Nitric Oxide / Q000032:analysis; D020030:Nitric Oxide Donors / Q000032:analysis / Q000737:chemistry*; D009589:Nitrogen Oxides / Q000032:analysis / Q000737:chemistry*; D011355:Prodrugs / Q000032:analysis / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry
D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D011355:Prodrugs; C102043:proline-nitric oxide; D009569:Nitric Oxide; D011392:Proline