Stable compositions comprising levosimendan and alginic acid

Details Stable compositions comprising levosimendan and alginic acid Stable compositions comprising levosimendan and alginic acid

2000-12-06

2003-03-11

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S247000

Reexamination Certificate

active

06531458

ABSTRACT:

TECHNICAL FIELD
The present invention relates to pharmaceutical compositions, particularly for oral administration, with improved stability comprising levosimendan, the (−) enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile, as the active ingredient. Levosimendan is useful in the treatment of congestive heart failure.
BACKGROUND OF THE INVENTION
Levosimendan, which is the (−)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, and the method for its preparation is described in EP 565546 B 1. Levosimendan is potent in the treatment of heart failure and has significant calcium dependent binding to troponin. Levosimendan is represented by the formula:
The hemodynamic effects of levosimendan in man are described in Sundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066. Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S57-S62, 1995. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients.
The preparation of pharmaceutical compositions of levosimendan, particularly for oral use, has proved to be difficult. When combined with conventional excipients levosimendan shows poor stability and easily degrades under storage conditions. Therefore, there is a need for pharmaceutical preparations of levosimendan which show improved stability of the active ingredient under storage.
SUMMARY OF THE INVENTION
It has now been unexpectedly found that alginic acid significantly improves the stability of levosimendan in pharmaceutical compositions.
Thus the present invention provides a pharmaceutical composition of levosimendan, particularly for oral administration, with improved stability comprising alginic acid as a stability improving agent.


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Sandell et al., “Pharmacokinetics of Levosimendan in Healthy Volunteers and Patients with Congestive Heart Failure,” J. Cardiovascular Pharmacology, vol. 26, Suppl. 1, pp. S57-S62 (1995).
Sundberg et al., “Hemodynamic and Neurohumoral Effects of Levosimendan, a New Calcium Sensitizer, at Rest and During Exercise in Healthy Men,” American Journal of Cardiology, vol. 75, pp. 1061-1066 (1995).

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