Eprova Ag

Aprofol Ag

Eprova Akteingesellschaft

Merck Eprova Ag

Martin Ulmann

Josef Conti

Hans R Muller

Gerd Wiesler

Rudolf Moser

Hans R Mueller

Thomas Ammann

Gunter Muerdel

Arthur Bodenmüller

Hans Rudolf M&uuml;ller

Gunter Murdel

Markus Müller

Hans Dutler

Guenter Muerdel

Hans Rudolf Müller

Josef Flammer

The invention relates to crystalline folate salts. The salt consists of a folate anion and an organic cation. The folate anion is 5-methyl-(6S)-tetrahydrofolic acid, and the cation is an organic compound which is an alkanolamine selected from the group consisting of choline, N-methylaminoethanol, 2-amino-2-methylpropanol and 2-dimethylaminoethanol.

Folate salts

The present invention relates to preparations of folate salts and their topical use for the treatment of epithelial tissue irritations and skin disorders.

Folate preparations

Preparations of folate for use in the treatment of eye disorders in the presence of elevated intraocular pressure. Methods of reducing intraocular pressure in a patient having an eye disease.

The invention relates to amorphous folate salt. The salt consists of a folate anion and an organic cation. The folate anion is selected from the group consisting of 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, (6S)-tetrahydrofolic acid, 5,10-Methylene-(6R)-tetrahydrofolic acid, and its oxidized derivatives JK12A and Mefox, and the cation is an organic compound selected from the group arginine, choline, acetylcholine, 1,1-dimethyl-biguanidin and phenylethylbiguanidin. The cation is an organic compound with a complementary pharmacological activity.

Folate salts for medical use

The administration of leucovorin as well as other active, reduced folates is useful as an antidote to drugs which act as folic acid antagonists and in combination chemotherapy with 5-FU. The most often used calcium salts of the folates have a low solubility in water and form almost insoluble degradation products. Therefore, aqueous solutions are unstable and precipitates result. Precipitates in injectable products present an unacceptable safety risk to patients. Stable high strength pharmaceutical aqueous compositions are formed containing calcium salts, magnesium or zinc salts of the reduced folates leucovorin, (6R,S)-tetrahydrofolic acid, (6S)-tetrahydrofolic acid, 5,10-methylene-(6R,S)-tetrahydrofolate, 5,10-methylene-(6R)-tetrahydrofolate, 5-methyl-(6R,S)-tetrahydrofolate or 5-methyl-(6S)-tetrahydrofolate and one or more of the compounds sodium gluconate, potassium gluconate, glycerophosphate disodium salt or glycerophosphate dipotassium salt.

Stable pharmaceutical composition containing folates

The administration of levoleucovorin is useful as an antidote to drugs which act as folic acid antagonists and in combination chemotherapy with 5-FU. The most often used calcium salt of levoleucovorin has a limited solubility in water and forms almost insoluble degradation products. Therefore aqueous solutions are unstable and precipitates are resulting. Precipitates in injectable products present an unacceptable safety risk to patients. Stable high strength pharmaceutical aqueous compositions containing calcium salts, magnesium or zinc salts of levoleucovorin and one or more of the compounds sodium gluconate, potassium gluconate, glycerophosphate disodium salt or glycerophosphate dipotassium salt are disclosed.

Stable high strength pharmaceutical composition of levoleucovorin

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

The invention relates to a process for preparing (6S)-folinic acid and its salts by recrystallization of alkaline-earth salts of (6R,S)-folinic acid and, where necessary, liberation of the acid from the alkaline-earth folinates and/or, where necessary, conversion into the alkali salts by at least one recrystallization in the presence of a base. The invention also relates to calcium-, magnesium-, potassium- and sodium-(6S)-folinates and to (6S)-folinic acid prepared in accordance with the invention.

Sodium salt of (6S)-folinic acid

This invention relates to the use of tetrahydrofolates in natural stereoisomeric form for the production of a pharmaceutical preparation suitable for influencing the homocysteine level, particularly for assisting the remethylation of homocysteine. Clinical areas of application include all anomalies of the homocysteine level, particularly the prevention and treatment of cardiovascular diseases and the prevention of neural tube deficiencies. The present invention also relates to pharmaceutical preparations comprising at least one compound selected from the group consisting of 5-formyl-(6S)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydrofolic acid, 5,10-methenyl-(6R)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino-(6S)-tetra-hydrofolic acid or (6S)-tetrahydrofolic acid or pharmaceutically compatible salts thereof, together with pharmaceutically compatible active and adjuvant substances, for influencing the homocysteine level, particularly when a methylene tetrahydrofolate reductase deficiency exists, such as when thermolabile methylene tetrahydrofolate reductase exists for example.

Use of tetrahydrofolates in natural stereoisomeric form for the

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.

Stable crystalline tetrahydrofolic acid salts

The invention relates to novel cyclodextrin inclusion compounds of 5,10-methylenetetrahydrofolic acid. The surprisingly good stability of these compounds makes possible their pharmaceutical use for the first time. The invention additionally relates to a process for the preparation of the said substances and their use for the preparation of medicaments.

5,10-methylenetetrahydrofolic acid-cyclodextrin inclusion compounds

Pharmaceutical compositions containing (65)-folinic acid and salts

For the preparation of (6S)- and (6R)-tetrahydrofolic acid and their addition salts with a sulfonic acid or with sulfuric acid, (6R,S)-tetrahydrofolic acid is reacted with a sulfonic acid or with sulfuric acid, the resulting acid addition salt is fractionally crystallized and, if desired, the (6S)- or (6R)-tetrahydrofolic acid is liberated from the resulting diastereomeric acid addition salts by treatment with a base and isolated.

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Dachsen, Switzerland

Martin Ulmann