Freeze-dried pantoprazole preparation and pantoprazole injection

• US 6,780,881 B2
• Filed: 07/15/2002
• Issued: 08/24/2004
• Est. Priority Date: 11/22/2000
• Status: Expired due to Term

• Current Assignee: Takeda GmbH (Takeda Pharmaceutical Company Limited)
• Original Assignee: Altana Pharma AG (Takeda Pharmaceutical Company Limited)
• Inventors: Dietrich, Rango, Linder, Rudolf
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): OSTRUP, CLINTON T
• Application Number:
  US10/195,062
• Publication Number:
  US 20030003058A1
• Time in Patent Office: 771 Days
• Field of Search: 514/338, 514/935, 514/926, 514/927, 514/359, 514/360, 424/46, 548/304.4
• US Class Current: 514/338
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Abstract

Lyophilized pantoprazole preparations which are obtainable by freeze-drying of an aqueous solution of pantoprazole, ethylenediamine tetraacetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbonate are disclosed. The preparations have advantageous properties when reconstituted for injection.

Claims

1. Process for the production of a freeze-dried preparation comprising 5-difluoromethoxy-2-[(3,4-di-methoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (pantoprazole), a salt thereof, a solvate of pantoprazole or a salt thereof, comprising freeze-drying of an aqueous solution of pantoprazole, a salt thereof, a solvate of pantoprazole or a salt thereof, ethylenedlamine tetraacetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbonate, wherein upon dissolution in an aqueous solvent, the preparation has less than 130 subvisible particles per vial, the particles having a size equal to or greater than 10 μ

m, wherein the number of particles is determined according to USP 24 by light obscuration particle test count.

2. Process according to claim 1, wherein the solution is prepared by the following steps:

a. dissolving ethylenediamine tetraacetic acid and/or a suitable salt thereof in water,

b. adjusting the pH of the solution to 8 or above 8 by adding sodium hydroxide and/or sodium carbonate to the solution, and

c. adding pantoprazole, a salt thereof, a solvate of pantoprazole or a salt thereof, to the solution.

3. Process according to claim 1, wherein the ethylenedlamine tetraacetic acid and/or suitable salt thereof is present in an amount from about 0.05 to about 25% by weight, based on the amount of pantoprazole present.

4. Process according to claim 1, wherein the pantoprazole used in the step of freeze-drying is pantoprazole sodium sesquihydrate.

5. Process according to claim 1, wherein the aqueous solution has a pH of between about 10 to about 13.

6. Process according to claim 1, wherein the aqueous solution has a pH of between about 10.5 to about 11.5.

7. Process according to claim 1, wherein the aqueous solution has a pH of between about 10.75 to about 11.25.

8. Process according to claim 1, wherein the aqueous solution has a pH value that is selected from the group consisting of 10.75, 10.8, 10.85, 10.9, 10.95, 11, 11.05, 11.1, 11.15, 11.2, and 11.25.

9. Process according to claim 1, wherein ethylenediamine tetraacetic acid and/or suitable salt thereof is present in an amount from about 0.25 to about 12.5% by weight, based on the amount of pantoprazole present.

10. Process according to claim 1, wherein the ethylenediamine tetraacetic acid and/or suitable salt thereof is present in an amount from about 1 to about 5% by weight, based on the amount of pantoprazole present.

11. Process according to claim 1, wherein the preparation has less than 120 subvisible particles per vial upon dissolution in an aqueous solvent.

12. Process according to claim 1, wherein the pantoprazole used in the step of freeze-drying is pantoprazole sodium.

13. Process according to claim 1, wherein the pantoprazole used in th step of freeze-drying is pantoprazole magnesium.

14. Process according to claim 1, wherein the pantoprazole used in the step of freeze-drying is pantoprazole magnesium dihydrate.

15. Lyophilized pantoprazole preparation obtainable by a process according to claim 1.

16. Injection kit comprising a lyophilized pantoprazole preparation according to claim 15 and an aqueous solvent for bolus administration.

17. Pantoprazole injection for bolus administration obtainable by reconstitution of the pantoprazole preparation according to claim 15 in an aqueous solvent.

18. Pantoprazole injection according to claim 17, wherein the solvent is physiological saline.

19. Pantoprazole injection having less than 130 subvisible particles per vial, the particles having a site equal to or greater than 10 μ

m, wherein the number of particles is determined according to USP 24 by light obscuration particle test count.

20. Pantoprazole injection according to claim 19, having less than 120 subvisible particles per vial.

21. Pantoprazole injection according to claim 19, wherein the pantoprazole is present therein is obtained from pantoprazole sodium sesquihydrate.

22. Pantoprazole injection according to claim 19, wherein the pantoprazole is present therein is obtained from pantoprazole sodium.

23. Pantoprazole injection according to claim 19, wherein the pantoprazole is present therein is obtained from pantoprazole magnesium.

24. Pantoprazole injection according to claim 19, wherein the pantoprazole is present therein is obtained from pantoprazole magnesium dihydrate.