AQUEOUS FOLINATE SOLUTION STABLE AT REFRIGERATOR TEMPERATURE, AS WELL AS PROCESS FOR ITS PREPARATION

Abstract: An aqueous folinate solution stable at refrigerator temperature is provided which contains folinate ions, complexed calcium ions, and if desired free calcium ions in a total amount of more than 12 mg/ml, as well as anions of a complexing agent for calcium. This solution is pre­ pared by incorporating the complexing agent therein.

Description: The invention relates to an aqueous folinate solution which is stable at refrigerator temperature. The invention also provides a process for preparing an aqueous calcium folinate solution stable at refrigerator temperature and having a concentration of over 12 mg/ml, which process is characterized by incorporating into the solution a complexing agent for calcium. Folinic acid is a metabolite of folic acid and is the active form to which folic acid is converted in the body. This conversion is inhibited by some cytostatic agents, such as methotrexate. In order to counteract this it is necessary to administer folinic acid, and the form of the folinic acid which should be administered pharmaceutically is the calcium folinate. Usually, the calcium folinate is administered by infusion or injection, and the dosages thereof are ever growing higher. Consequently, there is a demand of more concentrated solutions. Calcium folinate is readily soluble at room temperature, but it is not stable and consequently cannot be stored for a sufficiently long time. At refrigerator temperature, at which it is much more stable, high concentrations cannot be prepared. At the normal refrigerator temperature or 4° C crystallization may already occur at 15 mg/ml, and if by chance the refrigerator has been adjusted somewhat to the cold side and has a temperature of about 0° C, this may already occur at 12 mg/ml. In accordance therewith the publication "Rote Liste", 1989, Editio Cantor, Aulendorf/Württ which discusses a calcium folinate product as number 12022, discloses a content of 127 mg in 10 ml, i.e. 12.7 mg/ml. This composition contains the active compound in combination with sodium chloride and water. Consequently, there is a need of an aqueous folinate solution which is stable at refrigerator temperature, i.e. which will not crystallize at that temperature. It has now been found that much higher concentrations of folinate can be incorporated in the solution without a risk for crystallization in the refrigerator, if the calcium is complexed. Therefore the invention provides an aqueous folinate solution stable at refrigerator temperature, which contains folinate ions and complexed calcium ions and possibly free calcium ions in a total amount of more than 12 mg/l and furthermore anions of a complexing agent for calcium. In this way solutions can be prepared which can be stored in the refrigerator and contain even 50 mg/ml of folinate. If one wishes to store them at room temperature, at which of course the storage time is much shorter, one can even arrive at a maximum of 100 to 120 mg/ml. Of course, the maximum effect of the complexing agent is attained, if this is added in a molar equivalent amount with respect to the calcium folinate. Per se there is no objection against using more of the complexing agent, provided that this has no detrimental side effects, but of course no advantages are obtained from such a greater amount. In principle any complexing agent for calcium can be used which is admissible for therapeutical administration. The agent which is preferred and enters into consideration in the first place is ethylenediamine tetra acetic acid (EDTA) in the form of the di- or tetra-sodium salt. The result of the use thereof is that the obtained solution contains sodium ions, complexed calcium ions and possibly free calcium ions as the cations, and as the anions folinate ions and ethylenediamine tetraacetate ions. Briefly stated, the calcium is thus entirely or partially exchanged for sodium. This has no effect on the activity, because the folinic acid is the active substance. The suitable pH range of the solution is the same as of less concentrated solutions without complexing agent, i.e. generally 4.0-8.8, preferably 5.5-8.8 and especially 6-8. A complexing agent like EDTA has little or no influence on the stability of the obtained solution. For completeness' sake it is remarked that U.S. A 2,695,860, published November 30, 1954, relates to a stabilization of aqueous solutions containing folic acid or derivatives thereof with the aid of EDTA. This patent does mention folinic acid in claim 7, but not calcium folinate, and furthermore, only very low concentrations are involved, and moreover, not only is the active compound different, but also the problem occurring therewith. As has been discussed in column 1 of this patent, the problem is here a stabilization against the precipitation of impurities during storage at room temperature, a problem which does not occur with calcium folinate. The following, non-limiting examples elucidate the invention by way of illustration only. Example I A solution is prepared containing per ml the following ingredients: The obtained solution has a pH of 7.8 Example II A solution is prepared which contains per ml the following: The obtained solution has a pH of 7.8. The solutions of both examples can be made isotonic by addition of NaCl. As appears from example II, addition of sodium EDTA in an amount of about 25 % of the molar equivalent amount already yields a solution which contains considerably more than 20 mg/ml of folinate. This solution does not crystallize in the refrigerator, as has been established experimentally. If desired, considerably greater amounts of folinate can be incorporated in the solution of example I than has been done in this example; the experiment concerned was carried out in the first place for orienting purposes.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE Aqueous folinate solution stable at refrigerator temperature, which contains folinate ions and complexed calcium ions and possibly free calcium ions in a total amount of more than 12 mg/ml and furthermore anions of a complexing agent for calcium. Solution according to claim 1, characterized in that the anions of the complexing agent are present in a molar equivalent amount with respect to the folinate ions. Solution according to claim 1 or 2, characterized in that the anions of the complexing agent are ethylenediamine tetraacetate ions. A process for preparing an aqueous calcium folinate solution stable at refrigerator temperature and having a concentration of over 12 mg/ml, characterized by incorporating in the solution a complexing agent for calcium. A process according to claim 4, characterized by using the complexing agent in a molar equivalent amount with respect to the calcium folinate. A process according to claim 4 or 5, characterized in that a socium salt of ethylenediamine tetra-acetic acid is chosen as the complexing agent. Claims for the following Contracting States : ES, GR A process for preparing an aqueous calcium folinate solution stable at refrigerator temperature and having a concentration of over 12 mg/ml, characterized by incorporating in the solution a complexing agent for calcium. A process according to claim 1, characterized by using the complexing agent in a molar equivalent amount with respect to the calcium folinate. A process according to claim 1 or 2, characterized in that a socium salt of ethylenediamine tetra-acetic acid is chosen as the complexing agent.

Inventors: NIJKER, ALFRED JAMES, VERMEER, JOHANNA MARIA PIETERNELLA
Applicants: PHARMACHEMIE B.V.
Application year: 1990
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K47