Stable 5,10-methylene-tetrahydrofolate pharmaceutical compounds

A - Human Necessities – 61 – K

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Details

A61K 31/519 (2006.01) A61K 31/191 (2006.01) A61P 35/00 (2006.01)

Patent

CA 2529531

The invention relates to 5,10-methylene-(6R)-,-(6S)-or (6R,S)-tetrahydrofolate (MTHF) pharmaceutical compounds whose stability is due to the adjustment thereof to a basic pH value and to a simultaneous citrate use. Said stabilisation is self-producible in the absence of a reducing agent. Said invention is particularly suitable for preparing lyophilization solution or lyophilisates or dry powders and dry mixtures since the stable MTHF solutions can be filled at the high concentration thereof into corresponding recipients like, for example vials, ampoules etc. Said lyophilisates are surpassingly storable and stable. They are easily reconstituted by adding water or aqueous solutions, thereby providing diluted injection solutions ready for use with an excellent stability. Said invention also makes it possible to produce highly concentrated calcium or acid MTHF salts, even difficult-to-dissolve, in the form of isotonic physiologically compatible solutions.

Compositions pharmaceutiques de 5,10-méthylène-(6R)-, -(6S)- ou -(6R,S)-tétrahydrofolate (MTHF) qui sont stables grâce à leur ajustement à une valeur pH basique et à l'utilisation simultanée de citrate. La stabilisation se produit d'elle-même, en l'absence d'un agent de réduction. La présente invention est particulièrement adaptée pour la préparation de solution de lyophilisation et de lyophilisats ou de poudres sèches et de mélanges secs, étant donné que les solutions stables de MTHF peuvent être transvasées dans des concentrations élevées dans des récipients correspondants, tels que par ex. des flacons, des ampoules, etc. Ces lyophilisats supportent étonnamment bien l'entreposage et sont étonnamment stables. Ils peuvent être reconstitués facilement par ajout d'eau ou de solutions aqueuses, les solutions d'injection diluées prêtes à l'emploi possédant elles aussi une excellente stabilité. La présente invention permet en outre la préparation de sels de calcium ou acides de MTHF, mêmes difficilement solubles, dans de fortes concentrations et en tant que solutions isotoniques physiologiquement compatibles.

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