Merck & Cie

Eprova Ag

Merck Patent Gmbh

Thomas Ammann

Rudolf Moser

Viola Groehn

Thomas Egger

Martin Ulmann

Hans Rudolf M&uuml;ller

Hans R Muller

The present invention is directed towards the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, preferably in substantially crystalline form, as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy.

Stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid

The invention is directed towards stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid and its hemisulfate salt as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy.

Stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid

The present invention is directed to stable lyophilisates comprising 5,10-methylene-(6R)-tetrahydrofolic acid or a pharmaceutically acceptable salt thereof and a dicarboxylic acid, or a salt thereof, as well as, a processes of obtaining the same, and the use of such products.

Stable lyophilisates comprising 5,10-methylene-(6R)-tetrahydrofolic acid

This invention relates to stable pharmaceutical compositions of 5,10-methylene-(6R)-, -(65)- or -(6R,S)-tetrahydrofolate (MTHF), by adjusting to 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 lyophilisation 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 water or aqueous solutions, and the final clear injection solutions again exhibit excellent stability properties. Moreover, the present invention even makes it possible to prepare difficultly soluble calcium 15 or acidic salts of MTHF in high concentrations and as physiologically compatible isotonic solutions.

Stable pharmaceutical compositions of 5,10-methylene tetrahydrofolate

Pure and extremely stable crystalline (6R)-tetrahydrofolic acids, absolutely inert even when exposed to air and elevated temperature without stabilizers being added, are prepared by a crystallization process at a pH of &gE;2.

Stable crystalline (6R) -tetrahydrofolic acid

Pure and extremely stable crystalline (6S)- and (6R)-tetrahydrofolic acids, absolutely inert even when exposed to air and elevated temperature without stabilizers being added, are prepared by a crystallization process at a pH of &gE;3.5 for the preparation of crystalline (6S)-tetrahydrofolic acid and at a pH of &gE;2 for the preparation of crystalline (6R)-tetrahydrofolic acid.

Stable crystalline (6S)-  and (6R)-tetrahydrofolic acid

This invention relates to stable crystalline salts of (6R,S)-, (6S)- and (6R)-tetrahydrofolic acid, to methods of preparing these salts and to their use as an ingredient for the production of drugs and pharmaceutical preparations.

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Marthalen, Switzerland

Thomas Ammann