Ready-to-use bivalirudin compositions
View Patent ↗Ready-to-use bivalirudin compositions, methods of using the ready-to-use bivalirudin compositions, and methods of preparing the ready-to-use bivalirudin compositions. The ready-to-use bivalirudin compositions comprise bivalirudin and one or more stabilizing agents. The one or more stabilizing agents may be buffering agents having a pKa of about 2.5 to about 6.5, pH-adjusting agents, polymers, preservatives, antioxidants, sugars or polyols, or a combination thereof. The ready-to-use bivalirudin compositions may also comprise [9-10]-cycloimido bivalirudin, [11-12]-cycloimido bivalirudin, or a combination thereof. The method of using the ready-to-use bivalirudin compositions comprises administering the ready-to-use compositions to a patient in need thereof. Further, the method of preparing the ready-to-use bivalirudin compositions comprises mixing bivalirudin with one or more stabilizing agents.
1. An aqueous, injectable composition that has not been reconstituted from a lyophilizate, comprising:
(i) bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;
(ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is a buffering agent having a pKa of about 2.5 to about 6.5;
(iii) a pH of about 4 to less than 5; and
(iv) total impurities in an amount less than about 1.5% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 215 nm after storage at 25° C. for 1 month.
2. The composition of claim 1 , wherein the bivalirudin is at a concentration of about 5 mg/mL.
3. The composition of claim 1 , wherein the bivalirudin is at a concentration of about 10 mg/mL.
4. The composition of claim 1 , wherein the buffering agent is selected from a group consisting of acetate, tartrate, ascorbate, lactobionate, gentisate, succinate, lactate, α-lipoic acid, and any combination thereof.
5. The composition of claim 4 , wherein the buffering agent is acetate.
6. The composition of claim 1 , wherein the buffering agent has a pKa of about 3.5 to about 5.
7. The composition of claim 6 , wherein the buffering agent has a pKa of about 4.2 to about 4.5.
8. The composition of claim 1 , wherein the pH is obtained by a pH-adjusting agent.
9. The composition of claim 8 , wherein the pH-adjusting agent comprises an acid or base.
10. The composition of claim 9 , wherein the pH-adjusting agent comprises acetic acid or sodium hydroxide.
11. The composition of claim 1 , wherein the pH is about 4.2 to about 4.5.
12. The composition of claim 1 , wherein the total impurities are less than about 10% AUC as determined by HPLC after storage at 25° C. for 1 month.
13. The composition of claim 1 , comprising at least one preservative.
14. The composition of claim 13 , wherein the preservative is methyl-paraben.
15. The composition of claim 1 , comprising at least one antioxidant.
16. The composition of claim 15 , wherein the antioxidant is selected from a group consisting of histidine, methionine, and any combination thereof.
17. The composition of claim 1 , comprising at least one inorganic salt.
18. The composition of claim 17 , wherein the inorganic salt is sodium chloride.
19. An aqueous, injectable composition that has not been reconstituted from a lyophilizate, comprising:
(i) bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;
(ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is a buffering agent having a pKa of about 2.5 to about 6.5;
(iii) a pH of about 4 to less than 5; and
(iv) total impurities in an amount less than about 12% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 215 nm after storage at about 2° C. to about 8° C. for 12 months.
20. The composition of claim 19 , wherein the bivalirudin is at a concentration of about 5 mg/mL.
21. The composition of claim 19 , wherein the bivalirudin is at a concentration of about 10 mg/mL.
22. The composition of claim 19 , wherein the buffering agent is selected from a group consisting of acetate, tartrate, ascorbate, lactobionate, gentisate, succinate, lactate, α-lipoic acid, and any combination thereof.
23. The composition of claim 22 , wherein the buffering agent is acetate.
24. The composition of claim 19 , wherein the buffering agent has a pKa of about 3.5 to about 5.
25. The composition of claim 24 , wherein the buffering agent has a pKa of about 4.2 to about 4.5.
26. The composition of claim 19 , wherein the pH is obtained by a pH-adjusting agent.
27. The composition of claim 26 , wherein the pH-adjusting agent comprises an acid or base.
28. The composition of claim 27 , wherein the pH-adjusting agent comprises acetic acid or sodium hydroxide.
29. The composition of claim 19 , wherein the pH is about 4.2 to about 4.5.
30. The composition of claim 19 , wherein the total impurities are less than about 10% AUC as determined by HPLC after storage at about 2° C. to about 8° C. for 12 months.
31. The composition of claim 19 , comprising at least one preservative.
32. The composition of claim 31 , wherein the preservative is methyl-paraben.
33. The composition of claim 19 , comprising at least one antioxidant.
34. The composition of claim 33 , wherein the antioxidant is selected from a group consisting of histidine, methionine, and any combination thereof.
35. The composition of claim 19 , comprising at least one inorganic salt.
36. The composition of claim 35 , wherein the inorganic salt is sodium chloride.
37. An aqueous, injectable composition that has not been reconstituted from a lyophilizate, comprising:
(i) bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;
(ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is selected from a group consisting of (a) polymers, and (b) sugars or polyols;
(iii) a pH of about 4 to less than 5 as obtained by a pH-adjusting agent; and
(iv) total impurities present in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 215 nm after storage at 25° C. for 1 month.
38. The composition of claim 37 , wherein the bivalirudin is at a concentration of about 5 mg/mL.
39. The composition of claim 37 , wherein the bivalirudin is at a concentration of about 10 mg/mL.
40. The composition of claim 37 , wherein the polymers are selected from a group consisting of polyethylene glycol, poloxamer, polysorbates, hydroxyethyl starch, polyvinylpyrrolidone, and any combination thereof.
41. The composition of claim 37 , wherein the sugars or polyols are selected from a group consisting of sucrose, dextrose, dextrin, propylene glycol, sorbitol, glycerol, and any combination thereof.
42. The composition of claim 37 , wherein the pH-adjusting agent is selected from a group consisting of an acid, base, and buffering agent.
43. The composition of claim 42 , wherein the pH-adjusting agent comprises acetic acid or sodium hydroxide.
44. The composition of claim 37 , wherein the pH is about 4.2 to about 4.5.
45. The composition of claim 37 , wherein the total impurities are less than about 10% AUC as determined by HPLC after storage at 25° C. for 1 month.
46. The composition of claim 37 , comprising at least one preservative.
47. The composition of claim 46 , wherein the preservative is methyl-paraben.
48. The composition of claim 37 , comprising at least one antioxidant.
49. The composition of claim 48 , wherein the antioxidant is selected from a group consisting of histidine, methionine, and any combination thereof.
50. The composition of claim 37 , comprising at least one inorganic salt.
51. The composition of claim 50 , wherein the inorganic salt is sodium chloride.
52. An aqueous, injectable composition that has not been reconstituted from a lyophilizate, comprising:
(i) bivalirudin in an amount of about 5 mg/mL;
(ii) a buffering agent having a pKa of about 2.5 to about 6.5, wherein the buffering agent is acetate;
(iii) a pH of about 4.2; and
(iv) total impurities in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 215 nm after storage at 25° C. for 1 month.
53. An aqueous, injectable composition that has not been reconstituted from a lyophilizate, comprising:
(v) bivalirudin, or salts thereof, in an amount of about 5 mg/mL;
(vi) a buffering agent having a pKa of about 2.5 to about 6.5, wherein the buffering agent is acetate;
(vii) sodium chloride;
(viii) a pH of about 4.2; and
(ix) total impurities in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 215 nm after storage at 25° C. for 1 month.