Stable pharmaceutical compositions of 5,10-methylenetetrahydrofolate

Abstract

This invention relates to stable pharmaceutical compositions of 5,10-methylene-(6R)-, -(6S)-, or -(6R,S)-tetrahydrofolate (MTHF), by adjusting a basic pH and the simultaneous use of citrate. Stabilisation is effected even in the absence of a reducing agent. The present invention is particularly suitable for producing lyophlisation solutions and lyophilisates or dry powders and dry mixtures, since the stable MTHF solutions can be used in high concentrations for filling corresponding vessels such as vials, ampoules, etc. The lyophilisates have a surprisingly long shelf life and are surprisingly stable. They can be reconstituted without problems by adding wateror aqueous solutions, and the final clear injection solutions again exhibit excellent stability properties. Moreover, the present invention even makes it possible to prepare difficulty soluble calcium 15 or acidic salts of MTHF in high concentrations and as physiologically compatible isotonic solutions.

1 . Stable pharmaceutical compositions of 5,10-methylene-(6R)-, -(6S)-or -(6R,S)-tetrahydrofolate, characterised in that the composition comprises 5,10-methylene-(6R)-, -(6S)-or -(6R,S)-tetrahydrofolic acid or a pharmaceutically acceptable salt of 5,10-methylene-(6R)-, -(6S)-or -(6R,S)-tetrahydrofolic acid together with citrate, and has a pH between 7.5 and 10.5, preferably between 8.5 and 9.5. 
     
     
         2 . Stable pharmaceutical compositions according to  claim 1  together with further pharmaceutically acceptable active ingredients and adjuvants. 
     
     
         3 . A pharmaceutical composition according to  claim 2 , characterised in that it comprises formaldehyde as an adjuvant. 
     
     
         4 . A pharmaceutical composition according to  claim 2 , characterised in that it comprises a further folate as a further active ingredient. 
     
     
         5 . A pharmaceutical composition according to  claim 4 , characterised in that it comprises tetrahydrofolic acid and salts thereof as a further folate. 
     
     
         6 . A pharmaceutical composition according to  claim 1 , characterised in that the calcium salt or an acidic salt is used as the pharmaceutically acceptable salt of 5,10-methylene-(6R)-, -(6S)- or -(6R,S)-tetrahydrofolic acid. 
     
     
         7 . A pharmaceutical composition according to  claim 2 , characterised in that it comprises a cytostatic agent as a further active ingredient. 
     
     
         8 . A pharmaceutical composition according to  claim 2 , characterised in that it comprises a fluorinated pyrimidine derivative as a further active ingredient. 
     
     
         9 . A pharmaceutical composition according to  claim 8 , characterised in that it comprises 5-fluoruracil or a 5-fluoruracil prodrug , particularly capecitabine (xeloda) as a fluorinated pyrimidine derivative. 
     
     
         10 . A pharmaceutical composition according to  claim 1 , additionally comprising at least one antioxidant or a radical scavenger. 
     
     
         11 . A pharmaceutical composition according to  claim 10 , characterised in that it comprises vitamin C or reduced glutathione as an antioxidant or radical scavenger. 
     
     
         12 . A pharmaceutical composition according to  claim 1 , characterised in that the composition exists as a lyophilisate, dry powder or dry mixture. 
     
     
         13 . A pharmaceutical composition according to  claim 1 , characterised in that the composition exists as a lyophilisation solution. 
     
     
         14 . A method of stabilising compositions comprising 5,10-methylene-(6R)-, -(6S)-or -(6R,S)-tetrahydrofolate, characterised in that 5,10-methylene-(6R)-, -(6S)-or -(6R,S)-tetrahydrofolic acid is treated with citrate and is brought to a pH between 7.5 and 10.5, preferably between 8.5 and 9.5. 
     
     
         15 . Use of compositions comprising a pharmaceutically acceptable salt of 5,10-methylene-(6R)-, -(6S)-or -(6R,S)-tetrahydrofolic acid and citrate at a pH between 7.5 and 10.5, preferably between 8.5 and 9.5, for producing a pharmaceutical preparation suitable for use for corresponding medical indications.