Ready-to-use tranexamic acid intravenous solution

• US 10,980,757 B2
• Filed: 04/24/2019
• Issued: 04/20/2021
• Est. Priority Date: 09/06/2018
• Status: Active Grant

• Current Assignee: RTU Pharma SA
• Original Assignee: RTU Pharma SA
• Inventors: Jacobsen, Thomas, Dubois, Eric
• Primary Examiner(s): Henley, III, Raymond J
• Application Number:
  US16/392,865
• Publication Number:
  US 20200078326A1
• Time in Patent Office: 727 Days
• Field of Search: 514567
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• 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 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

Ready-to-use, stable aqueous intravenous tranexamic acid compositions are provided.

Claims

1. An aqueous pharmaceutical composition in the form of a solution for parenteral administration comprising:

tranexamic acid or a pharmaceutically acceptable salt thereof; and

a tonicity agent, wherein the composition requires no dilution before administration and has a pH from 6.0 to 8.0.

2. The aqueous pharmaceutical composition of claim 1, comprising from 0.05 to 15 mg/mL tranexamic acid.

3. The aqueous pharmaceutical composition of claim 1, comprising 5 mg/mL tranexamic acid.

4. The aqueous pharmaceutical composition of claim 1, comprising 10 mg/mL tranexamic acid.

5. The aqueous pharmaceutical composition of claim 1, wherein the tonicity agent is selected from the group consisting of sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, and magnesium chloride.

6. The aqueous pharmaceutical composition of claim 1, comprising the tonicity agent in a concentration effective to impart osmolality of from 270 to 340 mOsm/kg.

7. The aqueous pharmaceutical composition of claim 1, wherein the tonicity agent is sodium chloride.

8. The aqueous pharmaceutical composition of claim 7, comprising from 5 to 10 mg/mL sodium chloride.

9. The aqueous pharmaceutical composition of claim 1, wherein the tonicity agent is mannitol.

10. The aqueous pharmaceutical composition of claim 9, comprising from 35 to 45 mg/mL mannitol.

11. The aqueous pharmaceutical composition of claim 1, wherein the composition maintains at least about 95% of the tranexamic acid in undegraded form after storage for 180 days at 25°

C.

12. The aqueous pharmaceutical composition of claim 1, wherein the composition maintains at least about 98% of the tranexamic acid in undegraded form after storage for 180 days at 25°

C.

13. The aqueous pharmaceutical composition of claim 1, further comprising at least one pH adjuster selected from the group consisting of hydrochloric acid, sodium hydroxide and a mixture thereof.

14. The aqueous pharmaceutical composition of claim 1, further comprising water for injection having conductivity at 25°

C. of 0.6 to 1.5 mS/cm.

21. A method for reducing or preventing hemorrhage associated with tooth extraction in a patient with coagulopathy comprising steps of:

(a) administering the composition of claim 1 to the patient immediately before tooth extraction; and

(b) administering the composition of claim 1 to the patient for 2 to 8 days following tooth extraction.

22. The method of claim 21, wherein step (a) further comprises concomitant administration of replacement therapy.

23. The method of claim 21, wherein step (a) comprises intravenous administration of the composition at a dose of 10 mg tranexamic acid per kg body weight of the patient.

24. The method of claim 21, wherein step (b) comprises intravenous administration of the composition at a dose of 10 mg tranexamic acid per kg body weight of the patient three to four times per day.

15. A pharmaceutical composition for parenteral administration comprising a ready-to-use aqueous solution with a pH from about 6.0 to about 8.0 comprising:

from 0.05 to about 15 mg/mL tranexamic acid or a pharmaceutically acceptable salt thereof;

a tonicity agent selected from (i) about 35 mg/mL to about 45 mg/mL mannitol or (ii) about 6.8-8.2 mg/mL sodium chloride; and

a pH adjuster in an amount to provide initial pH from about 6.0 to about 8.0.

16. The aqueous pharmaceutical composition of claim 15, further comprising water for injection having conductivity at 25°

C. of 0.6 to 1.5 mS/cm.

17. The pharmaceutical composition of claim 15, wherein the aqueous solution is contained in a pharmaceutically acceptable container.

18. The pharmaceutical composition of claim 15, wherein the aqueous solution when stored in the container for at least one year at room temperature exhibits (i) less than a 10% decrease in the concentration of tranexamic acid and (ii) a total impurity formation of less than about 3%.

19. The aqueous pharmaceutical composition of claim 15, comprising 5 mg/mL tranexamic acid.

20. The aqueous pharmaceutical composition of claim 15, comprising 10 mg/mL tranexamic acid.