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

  1. David J. Waterhouse1,
  2. Joseph E. Saavedra2,
  3. Keith M. Davies3,
  4. Michael L. Citro2,
  5. Xia Xu4,
  6. Douglas A. Powell5,
  7. George J. Grimes6,
  8. Gopal K. Potti6,
  9. Larry K. Keefer1,*

Article first published online: 28 NOV 2005

DOI: 10.1002/jps.20486

Issue

Journal of Pharmaceutical Sciences

Journal of Pharmaceutical Sciences

Volume 95, Issue 1, pages 108–115, January 2006

Total views since August 2010: 44

Additional Information

How to Cite

Waterhouse, D. J., Saavedra, J. E., Davies, K. M., Citro, M. L., Xu, X., Powell, D. A., Grimes, G. J., Potti, G. K. and Keefer, L. K. (2006), 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., 95: 108–115. doi: 10.1002/jps.20486

Author Information

  1. 1

    Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702

  2. 2

    Basic Research Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702

  3. 3

    Department of Chemistry, George Mason University, Fairfax, Virginia 22030

  4. 4

    Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892

  5. 5

    Data Management Services, Inc., National Cancer Institute at Frederick, Frederick, Maryland 21702

  6. 6

    Pharmacy Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892

*Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702. Telephone: 301-846-1467; Fax: 301-846-5946

Publication History

  1. Issue published online: 28 NOV 2005
  2. Article first published online: 28 NOV 2005
  3. Manuscript Accepted: 5 JUL 2005
  4. Manuscript Revised: 20 MAY 2005
  5. Manuscript Received: 27 JAN 2005

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Keywords:

  • nitric oxide;
  • analytical chemistry;
  • lyophilization;
  • stabilization;
  • prodrugs;
  • targeted drug delivery;
  • solvate;
  • kinetics;
  • chirality;
  • chemical stability

Abstract

PROLI/NO is an agent of structure XN(O)[DOUBLE BOND]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°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. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:108–115, 2006

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