Pharmaceutical formulations comprising high purity cangrelor and methods for preparing and using the same

• US 9,295,687 B1
• Filed: 07/10/2015
• Issued: 03/29/2016
• Est. Priority Date: 01/14/2015
• Status: Active Grant

• Current Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Original Assignee: Medicines Company (Novartis Ag)
• Inventors: Rafai Far, Adel, Motheram, Rajeshwar, Dutta, Panna, Ding, Min
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US14/796,368
• Time in Patent Office: 263 Days
• Field of Search: 514/47
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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: 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: B65D 81/2069 in a special atmosphere

Abstract

The present invention relates to high purity cangrelor, pharmaceutical formulations comprising high purity cangrelor as an active ingredient, methods for preparing such compounds and formulations, and methods for using the pharmaceutical formulations in the inhibition of platelet activation and aggregation.

Claims

1. A pharmaceutical formulation comprising high purity cangrelor, or a salt thereof, as an active ingredient and one or more pharmaceutically acceptable excipients prepared by a method comprising:

(a) dissolving cangrelor or a salt thereof in a solvent to form a first solution;

(b) mixing a pH-adjusting agent with the first solution to form a second solution, wherein the pH of the second solution is between about 7.0 and 9.5; and

(c) removing the solvent from the second solution to produce high purity cangrelor or a salt thereof under conditions wherein a level of moisture of less than about 2.0% by weight is achieved,

wherein one or more pharmaceutically acceptable excipients is added to the first solution, or to the second solution, or to both,

wherein the high purity cangrelor or salt thereof has a combined total of selected hydrolysis and oxidation degradants of cangrelor not exceeding about 1.5% by weight of the high purity cangrelor, and

wherein the selected hydrolysis and oxidation degradants are one or more members selected from the group consisting of;

2. The pharmaceutical formulation of claim 1, wherein the combined total of selected hydrolysis and oxidation degradants of cangrelor does not exceed about 1.3% by weight of the high purity cangrelor.

3. The pharmaceutical formulation of claim 1, wherein the amount of impurity A is less than about 0.5% by weight, the amount of impurity B present is less than about 0.2% by weight, the amount of impurity C is less than about 0.3% by weight, the amount of impurity D is less than about 0.2% by weight, and the amount of impurity E is less than about 0.5% by weight of the high purity cangrelor.

4. The pharmaceutical formulation of claim 1, wherein the maximum impurity level of impurities A and D is each less than about 0.5% by weight of the high purity cangrelor.

5. The pharmaceutical formulation of claim 1, wherein removing the solvent of (c) is through lyophilization.

6. The pharmaceutical formulation of claim 1, wherein the mixing of (b) is performed in the absence of light, or performed under nitrogen, or both.

7. The pharmaceutical formulation of claim 1, further comprising sterilizing the second solution after the mixing of (b) and before removal of the solvent.

8. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable excipient is a polyol.

9. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable excipients are mannitol and sorbitol.

10. The pharmaceutical formulation of claim 1, wherein the solvent is water.

11. The pharmaceutical formulation of claim 1, wherein the pH-adjusting agent is selected from the group consisting of acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, monobasic potassium phosphate, sodium acetate, sodium citrate, sodium lactate solution, dibasic sodium phosphate and monobasic sodium phosphate, sodium hydroxide, hydrochloric acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium phosphate, dibasic potassium phosphate, sodium phosphate and sodium borate.

12. A sealed vessel containing the pharmaceutical formulation of claim 1 under a chemically inert dry gas.

13. The sealed vessel of claim 12, wherein the chemically inert dry gas is nitrogen or argon.

14. A pharmaceutical formulation consisting of high purity cangrelor, or a salt thereof, as an active ingredient and mannitol and/or sorbitol as a pharmaceutically acceptable excipient, prepared by a method comprising:

(a) dissolving cangrelor or a salt thereof in a solvent to form a first solution;

(b) mixing a pH-adjusting agent with the first solution to form a second solution, wherein the pH of the second solution is between about 7.0 and 9.5; and

(c) removing the solvent from the second solution to produce high purity cangrelor or a salt thereof under conditions wherein a level of moisture of less than about 2.0% by weight is achieved,

wherein the pharmaceutically acceptable excipient is added to the first solution, or to the second solution, or to both,

wherein the high purity cangrelor or salt thereof has a combined total of selected hydrolysis and oxidation degradants of cangrelor not exceeding about 1.5% by weight of the high purity cangrelor, and

wherein the selected hydrolysis and oxidation degradants are one or more members selected from the group consisting;

15. The pharmaceutical formulation of claim 14, wherein the combined total of selected hydrolysis and oxidation degradants of cangrelor does not exceed about 1.3% by weight of the high purity cangrelor.

16. The pharmaceutical formulation of claim 14, wherein the amount of impurity A is less than about 0.5% by weight, the amount of impurity B present is less than about 0.2% by weight, the amount of impurity C is less than about 0.3% by weight, the amount of impurity D is less than about 0.2% by weight, and the amount of impurity E is less than about 0.5% by weight of the high purity cangrelor.

17. The pharmaceutical formulation of claim 14, wherein the maximum impurity level of impurities A and D is each less than about 0.5% by weight of the high purity cangrelor.

18. The pharmaceutical formulation of claim 14, wherein removing the solvent of (c) is through lyophilization.

19. The pharmaceutical formulation of claim 14, wherein the mixing of (b) is performed in the absence of light, or performed under nitrogen, or both.

20. The pharmaceutical formulation of claim 14, further comprising sterilizing the second solution after the mixing of (b) and before removal of the solvent.

21. The pharmaceutical formulation of claim 14, wherein the solvent is water.

22. The pharmaceutical formulation of claim 14, wherein the pH-adjusting agent is selected from the group consisting of acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, monobasic potassium phosphate, sodium acetate, sodium citrate, sodium lactate solution, dibasic sodium phosphate and monobasic sodium phosphate, sodium hydroxide, hydrochloric acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium phosphate, dibasic potassium phosphate, sodium phosphate and sodium borate.

23. A sealed vessel containing the pharmaceutical formulation of claim 14 under a chemically inert dry gas.

24. The sealed vessel of claim 23, wherein the chemically inert dry gas is nitrogen or argon.

25. A pharmaceutical formulation consisting of high purity cangrelor, or a salt thereof, as an active ingredient and mannitol and/or sorbitol as a pharmaceutically acceptable excipient, prepared by a method consisting of:

(a) dissolving cangrelor or a salt thereof in methanol to form a first solution;

(b) mixing a pH-adjusting agent with the first solution to form a second solution, wherein the pH of the second solution is between about 7.0 and 9.5; and

(c) removing the methanol from the second solution to produce high purity cangrelor or a salt thereof under conditions wherein a level of moisture of less than about 2.0% by weight is achieved,

wherein the pharmaceutically acceptable excipient is added to the first solution, or to the second solution, or to both,

wherein the high purity cangrelor or salt thereof has a combined total of selected hydrolysis and oxidation degradants of cangrelor not exceeding about 1.5% by weight of the high purity cangrelor, and

wherein the selected hydrolysis and oxidation degradants are one or more members selected from the group consisting;

26. The pharmaceutical formulation of claim 25, wherein the combined total of selected hydrolysis and oxidation degradants of cangrelor does not exceed about 1.3% by weight of the high purity cangrelor.

27. The pharmaceutical formulation of claim 25, wherein the amount of impurity A is less than about 0.5% by weight, the amount of impurity B present is less than about 0.2% by weight, the amount of impurity C is less than about 0.3% by weight, the amount of impurity D is less than about 0.2% by weight, and the amount of impurity E is less than about 0.5% by weight of high purity the cangrelor.

28. The pharmaceutical formulation of claim 25, wherein removing the solvent of (c) is through lyophilization.

29. The pharmaceutical formulation of claim 25, wherein the mixing of (b) is performed in the absence of light, or performed under nitrogen, or both.

30. The pharmaceutical formulation of claim 25, wherein the pH-adjusting agent is selected from the group consisting of acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, monobasic potassium phosphate, sodium acetate, sodium citrate, sodium lactate solution, dibasic sodium phosphate and monobasic sodium phosphate, sodium hydroxide, hydrochloric acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium phosphate, dibasic potassium phosphate, sodium phosphate and sodium borate.