Pharmaceutical formulations of bivalirudin and processes of making the same

• US 7,598,343 B1
• Filed: 07/27/2008
• Issued: 10/06/2009
• Est. Priority Date: 07/27/2008
• Status: Active Grant

• Current Assignee: Sandoz Inc. (Novartis Ag)
• Original Assignee: Medicines Company (Novartis Ag)
• Inventors: Musso, Gary, Krishna, Gopal
• Primary Examiner(s): Tsang; Cecilia
• Assistant Examiner(s): Ha; Julie
• Application Number:
  US12/180,551
• Time in Patent Office: 436 Days
• Field of Search: None
• US Class Current: 530/325
• CPC Class Codes: A61K 38/58 from leeches, e.g. hirudin, eglin
• 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: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

Pharmaceutical batch(es) or pharmaceutical formulation(s) comprising bivalirudin as the active ingredient, and a method of preparing the pharmaceutical batch(es) or pharmaceutical formulation(s). The pharmaceutical batch(es) or pharmaceutical formulation(s) may have a maximum impurity level of Asp⁹-bivalirudin that does not exceed about 0.6%. Also, the pharmaceutical batch(es) or pharmaceutical formulation(s) may have a reconstitution time that does not exceed about 42 seconds. The method of preparing the pharmaceutical batch(es) or pharmaceutical formulation(s) may comprise dissolving bivalirudin in a solvent to form a first solution, efficiently mixing a pH-adjusting solution with the first solution to form a second solution in which the pH-adjusting solution may comprise a pH-adjusting solution solvent, and removing the solvent and the pH-adjusting solution solvent from the second solution.

Claims

1. Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO:

1) and a pharmaceutically acceptable carrier, for use as an anticoagulant in a subject in need thereof, said batches prepared by a compounding process comprising;

(i) dissolving bivalirudin in a solvent to form a first solution;

(ii) efficiently mixing a pH-adjusting solution with the first solution to form a second solution, wherein the pH-adjusting solution comprises a pH-adjusting solution solvent; and

(iii) removing the solvent and pH-adjusting solution solvent from the second solution;

wherein the batches have a pH adjusted by a base, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum impurity level of Asp⁹-bivalirudin that does not exceed about 0.6% as measured by HPLC.

2. The pharmaceutical batches of claim 1, wherein the maximum impurity level of Asp⁹-bivalirudin does not exceed about 0.4% as measured by HPLC.

3. The pharmaceutical batches of claim 2, wherein the maximum impurity level of Asp⁹-bivalirudin does not exceed about 0.3% as measured by HPLC.

4. The pharmaceutical batches of claim 1, wherein the batches have a maximum total impurity level that does not exceed about 2% as measured by HPLC.

5. The pharmaceutical batches of claim 4, wherein the maximum total impurity level does not exceed about 1% as measured by HPLC.

6. The pharmaceutical batches of claim 5, wherein the maximum total impurity level does not exceed about 0.5% as measured by HPLC.

7. The pharmaceutical batches of claim 1, wherein the batches have a maximum level of D-Phe¹²-bivalirudin that does not exceed about 2.5% as measured by HPLC.

8. The pharmaceutical batches of claim 1, wherein the pharmaceutically acceptable carrier comprises one or more of a bulking agent or a stabilizing agent.

9. The pharmaceutical batches of claim 8, wherein the bulking agent is a sugar.

10. The pharmaceutical batches of claim 9, wherein the sugar is mannitol.

11. The pharmaceutical batches of claim 1, wherein the base is sodium hydroxide.

12. Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO:

1) and a pharmaceutically acceptable carrier, for use as an anticoagulant in a subject in need thereof, said batches prepared by a compounding process comprising;

(i) dissolving bivalirudin in a solvent to form a first solution;

(ii) efficiently mixing a pH-adjusting solution with the first solution to form a second solution, wherein the pH-adjusting solution comprises a pH-adjusting solution solvent; and

(iii) removing the solvent and pH-adjusting solution solvent from the second solution;

wherein the batches have a pH adjusted by a base, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum reconstitution time that does not exceed about 42 seconds and a maximum total impurity level that does not exceed about 2% as measured by HPLC.

13. The pharmaceutical batches of claim 12, wherein the maximum reconstitution time does not exceed about 30 seconds.

14. The pharmaceutical batches of claim 13, wherein the maximum reconstitution time does not exceed about 21 seconds.

15. The pharmaceutical batches of claim 12, wherein the pharmaceutically acceptable carrier comprises one or more of a bulking agent or a stabilizing agent.

16. The pharmaceutical batches of claim 15, wherein the bulking agent is a sugar.

17. The pharmaceutical batches of claim 16, wherein the sugar is mannitol.

18. The pharmaceutical batches of claim 12, wherein the base is sodium hydroxide.

19. Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO:

1) and mannitol for use as an anticoagulant in a subject in need thereof, said batches prepared by a compounding process comprising;

(i) dissolving bivalirudin in a solvent to form a first solution;

(ii) efficiently mixing a pH-adjusting solution with the first solution to form a second solution, wherein the pH-adjusting solution comprises a pH-adjusting solution solvent; and

(iii) removing the solvent and pH-adjusting solution solvent from the second solution;

wherein the batches have a pH adjusted by a sodium hydroxide, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum reconstitution time that does not exceed about 42 seconds and a maximum total impurity level that does not exceed about 2% as measured by HPLC.

20. The pharmaceutical batches of claim 19, wherein the batches have a maximum impurity level of Asp⁹-bivalirudin that does not exceed about 0.6% as measured by HPLC.