METHOD FOR PRODUCING A LIQUID PHARMACEUTICAL PREPARATION

Abstract

A method for producing a liquid pharmaceutical preparation which contains a complex consisting of DOTA and gadolinium and a base such as L-lysine or meglumine, includes the following steps: a) An aqueous solution containing free DOTA, free gadolinium and a base such as L-lysine or meglumine is produced. b) The yield of free DOTA and free gadolinium is determined in the solution obtained according to step a). c) Free gadolinium and/or free DOTA is added in order to adjust a stoichiometric excess of free DOTA in the solution. d) The complexation is executed at an increased temperature. e) Additional base such as L-lysine or meglumine is added in order to adjust the pH value. f) The final volume of the preparation is adjusted.

Claims

1. Method for producing a liquid pharmaceutical preparation that contains a complex that consists of DOTA and gadolinium as well as a base, such as, for example, L-lysine or meglumine, the method comprising the following steps: a) An aqueous solution that consists of DOTA, gadolinium, and a base is produced, b) In the solution obtained according to step a), the content of free DOTA and free gadolinium is determined, c) Free gadolinium and/or free DOTA is/are added in order to adjust a content of free DOTA of 200-1500 ppm in the solution that is obtained according to step a), relative to the complex, whereby the addition of free DOTA and free gadolinium is carried out in such a way that there is no free gadolinium in the preparation, d) The complexing is carried out at elevated temperature, e) Another base is added in order to adjust the pH, and f) The final volume is set.

2. Method according to claim 1, wherein for producing the solution according to step a), first DOTA is dissolved in water at elevated temperature, and then gadolinium is added.

3. Method according to claim 1, wherein the complexing is completed by further addition of a base.

4. Method according to claim 1, wherein step a) is carried out at a temperature of between 60° C. and 95° C.

5. Method according to claim 1, wherein the solution is stirred when steps a) and/or d) is/are carried out.

6. Method according to claim 1, wherein in step c), the addition of free gadolinium and/or free DOTA is carried out in two or more than two partial amounts.

7. Method according to claim 1, wherein free DOTA is added in the form of a solution and/or free gadolinium is added in the form of a solution.

8. Method according to claim 1, wherein the gadolinium is added as an oxide (Gd.sub.2O.sub.3) and in the oxidation stage +III.

9. Method according to claim 1, wherein the concentration of free DOTA in the preparation is 180-2000 ppm, preferably 200 to 1500 ppm, relative to the complex.

10. Method according to claim 1, wherein the concentration of free gadolinium in the preparation is less than 10 ppm.

11. Method according to claim 1, wherein the pH in step e), in particular at room temperature, is adjusted to a value of between 7.0 and 7.2.

12. The method of claim 1, wherein the base produced is meglumine or L-lysine.

13. The method of claim 3, wherein the base added is meglumine or L-lysine.

14. Method according to claim 2, wherein the complexing is completed by further addition of a base.

15. Method according to claim 2, wherein step a) is carried out at a temperature of between 60° C. and 95° C.

16. Method according to claim 3, wherein step a) is carried out at a temperature of between 60° C. and 95° C.

17. Method according to claim 2, wherein the solution is stirred when steps a) and/or d) is/are carried out.

18. Method according to claim 3, wherein the solution is stirred when steps a) and/or d) is/are carried out.

19. Method according to claim 4, wherein the solution is stirred when steps a) and/or d) is/are carried out.

20. Method according to claim 2, wherein in step c), the addition of free gadolinium and/or free DOTA is carried out in two or more than two partial amounts.

Description

EXAMPLE 1:

[0050] 40.5 g of DOTA was suspended in 150 ml of water at a temperature of 75° C. 17.8 g of gadolinium oxide was added, and the batch was stirred at 75° C. for 2 hours. The solution that was produced was mixed with 19.5 g of meglumine and stirred at 75° C. for one hour. Then, the content of free DOTA, free gadolinium, and complex was determined, and the final content of excess free DOTA was set. The concentration of free gadolinium was equal to zero, and the concentration of excess free DOTA was adjusted to a value of between 200 and 1500 ppm, relative to the complex. The reaction batch was made up to a total volume of 200 ml and filtered.

EXAMPLE 2:

[0051] 7.8 g of gadolinium oxide was suspended in 150 ml of water at a temperature of 75° C. 40.5 g of DOTA was added, and the batch was stirred at 75° C. for 2 hours. Another 10.0 g of gadolinium oxide was added and again stirred at 75° C. for 15 minutes. The solution that was produced was mixed with 19.5 g of meglumine and stirred at 75° C. for one hour. Then, the content of free DOTA, free gadolinium, and complex was determined, and the final content of excess free DOTA was set. The concentration of free gadolinium was equal to zero, and the concentration of excess free DOTA was adjusted to a value of between 200 and 1500 ppm, relative to the complex. The reaction batch was made up to a total volume of 200 ml and filtered.

EXAMPLE 3:

[0052] 13.5 g of DOTA was suspended in 150 ml of water at a temperature of 75° C. 5.9 g of gadolinium oxide was added, and the batch was stirred at 75° C. for 30 minutes. In addition, 13.5 g of DOTA and 5.9 g of gadolinium oxide were added and stirred at 75° C. for 30 minutes. Once again, 13.5 g of DOTA and 6.0 g of gadolinium oxide were added and stirred at 75° C. for 30 minutes. The solution that was produced was mixed with 19.5 g of meglumine and stirred at 75° C. for one hour. Then, the content of free DOTA, free gadolinium, and complex was determined, and the final content of excess free DOTA was set. The concentration of free gadolinium was to be equal to zero, and the concentration of excess free DOTA was adjusted to a value of between 200 and 1500 ppm, relative to the complex. The reaction batch was made up to a total volume of 200 ml and filtered.

[0053] As shown in the examples, with the method according to the invention, the final content of excess DOTA can be set to 200-1500 ppm.

[0054] When the method according to the invention is carried out, the content of free gadolinium is always zero, since the procedure is performed with an excess of DOTA. When the method according to the invention is carried out, gadolinium is added in order to adjust the proportion of DOTA to the above-mentioned range.

[0055] When the method according to the invention is carried out, the substances gadolinium and DOTA can be added alternately. For example, one-third each of the target quantity is added at half-hour intervals.

[0056] At the beginning of the method according to the invention, gadolinium can be introduced. Then, a portion, e.g., one-fourth of the target quantity, of DOTA, is added.

[0057] The thus obtained solution is stirred, for example, at 80° C., e.g., for 2 hours, and then the remaining amount of DOTA is added to the solution.

[0058] In summary, an embodiment of the invention can be described as follows:

[0059] A method for producing a liquid pharmaceutical preparation, which contains a complex that consists of gadolinium and DOTA as well as a base such as L-lysine or meglumine, comprises, for example, the following steps: [0060] a) An aqueous solution, consisting of DOTA, gadolinium, and a base such as meglumine or L-lysine, is produced. [0061] b) The content of free DOTA and free gadolinium in the solution that is obtained according to step a) is determined. [0062] c) Free gadolinium and/or free DOTA is/are added in order to adjust the content of free DOTA to 200-1500 ppm, relative to the complex. [0063] d) The complexing can be carried out at elevated temperature. [0064] e) To set the final pH, another base is added. [0065] f) The final volume of the preparation is set.