The present invention relates to pharmaceutical compositions for oral administration comprising substantially pure polymorphic form I of levosimendan, the (xe2x88x92) enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, as an active ingredient. Levosimendan is useful in the treatment of congestive heart failure.
The racemic mixture of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile (I) has been described earlier in the applicant""s European Patent No. 383449 B1. It was shown that compound (I) is potent in the treatment of congestive heart failure and has significant calcium dependent binding to troponin. 
Optically active enantiomers of (I) have been earlier described in the applicant""s European Patent No. 565546 B1. It was shown that the cardiotonic potency is predominantly due to the (xe2x88x92) enantiomer of (I), i.e. levosimendan.
Oral administration of levosimendan has proved difficult since levosimendan is susceptible to metabolization in the lower gastrointestinal tract by intestinal bacteria. The metabolites formed in the lower gastrointestinal tract may contribute to the observed side effects of orally administered levosimendan, such as headache and palpitation. Therefore methods and compositions for administering levosimendan orally which would avoid or reduce the accumulation of levosimendan in the lower gastrointestinal tract would be highly desirable.
It has now been found that levosimendan is rapidly dissolved and absorbed into plasma from oral compositions which comprise substantially pure crystalline polymorphic form I of levosimendan as the active ingredient. The rapid absorption reduces the accumulation of levosimendan in the lower gastrointestinal tract and thereby reduces gastrointestinal metabolization of levosimendan.
Thus the present invention provides an oral composition comprising a substantially pure crystalline polymorphic form I of levosimendan as the active ingredient together with a pharmaceutically acceptable carrier.
USPTO Backgrounds
USPTO Backgrounds