Claims for Patent: 8,598,227

Summary for Patent: 8,598,227

Title:	Epoprostenol formulation and method of making thereof
Abstract:	This invention relates to a stable epoprostenol composition that can be combined with commercially available IV fluids and can be administered in its reconstituted and/or diluted form under ambient conditions of about 15-30.degree. C. for greater than 24 hours. The composition preferably contains (a) epoprostenol or a salt thereof; (b) a alkalinization agent; and (c) a base, such that when reconstituted or in solution, the solution has a pH>11. Methods for making the lyophilized composition are also disclosed.
Inventor(s):	Palepu; Nagesh R. (Southhampton, PA)
Assignee:	Actelion Pharmaceuticals Ltd. (Allschwil, CH)
Application Number:	13/621,489
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,598,227
Patent Claims:	1. A method for making an epoprostenol composition comprising the steps of: (a) providing a bulk solution comprising (i) epoprostenol or a salt thereof, and (ii) an alkalinizing agent; and (b) adjusting the pH of the bulk solution to greater than 13. 2. The method of claim 1, further comprising the step of: (c) lyophilizing the adjusted bulk solution. 3. The method of claim 2, wherein step (c) comprises: freezing the adjusted bulk solution in a freezing cycle; drying the frozen solution in a primary drying cycle; and drying the frozen solution in a secondary drying cycle. 4. The method of claim 3, wherein the freezing cycle comprises: (i) placing the bulk solution on a shelf in a lyophilization chamber; (ii) cooling the shelf to less than or about -30 degrees C. at the rate of approximately 0.5 to 0.7 C./min.; (iii) holding the shelf at about -30 degrees C. or below for about 30 min or until the adjusted bulk solution temperature reaches less than or about -25 degrees C.; (iv) lowering the shelf temperature to about -45.+-.2 degrees C. until the bulk adjusted solution temperature reaches approximately about -38.+-.2 degrees C.; (v) holding the bulk solution at about -38.+-.2 degrees C. for about six hours or more; (vi) applying vacuum until the lyophilization chamber pressure reaches about 50 milliTorr or less; and (vii) maintaining the shelf temperature at about -45.+-.2 degrees C. for about 45 minutes or more after vacuum application. 5. The method of claim 4, wherein the primary drying cycle comprises the steps of: (i) raising the shelf temperature to about 0.+-.2 degrees C. at the heating rate of about 20.+-.2 degrees C. per hour and continue drying under vacuum until the product temperature reaches about -3.+-.2 degrees C. or higher; and (ii) raising the shelf temperature to about 25.+-.2 degrees C. and continue drying until the product temperature reaches about 20 degrees C. or higher. 6. The method of claim 4, wherein the secondary drying cycle comprises the steps of: (i) raising the shelf temperature to about 45.+-.2 degrees C. at a rate of about 3 .+-.2 degrees C./hr and continue drying until the product temperature reaches about 38.+-.2 degrees C. or higher; (ii) turning off the vacuum while increasing the chamber pressure with nitrogen; and (iii) when the chamber pressure reaches atmospheric pressure, discontinuing the nitrogen and enclosing the composition under a nitrogen atmosphere. 7. The method of claim 1, wherein the ratio of epoprostenol or a salt thereof to alkalinizing agent is about 1:25 to about 1:200. 8. The method of claim 1, wherein the alkalinizing agent is selected from the group consisting of arginine, lysine, meglumine, N-methyl glucosomine, an amino acid with a pKa of 9.0 and above, trisodium phosphates, sodium carbonates, and tetrasodium-EDTA. 9. The method of claim 1, wherein the bulk solution further comprises (iii) a bulking agent. 10. The method in claim 9, wherein the bulking agent is selected from the group consisting of hydroxyl ethyl starch (HES), sorbitol, lactose, dextran, maltose, mannose, ribose, sucrose, mannitol, trehalose, lactose, dextran, cyclodextrin, glycine, and polyvinylpyrrolidine (PVP). 11. The method of claim 9, wherein the bulking agent is present at about 1-10%. 12. The method of claim 1, wherein the epoprostenol salt is epoprostenol sodium. 13. The method of claim 1, wherein step (b) comprises adding an organic or inorganic base. 14. The method of claim 13, wherein the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, and ammonium hydroxide. 15. The method of claim 13, where the organic base is selected from the group consisting of aromatic amines and aromatic alcohols. 16. A method for treating a patient suffering from a disease selected from the group consisting of cardiovascular disease, atherosclerosis, arteriosclerosis, congestive heart failure, angina pectoris, and hypertension, said method comprising the steps of (1) combining an intravenous fluid with an effective amount of a lyophilized pharmaceutical composition comprising: (a) a unit dose of 0.5 mg or 1.5 mg of epoprostenol or a salt thereof; (b) arginine; and (c) sodium hydroxide, wherein said lyophilized pharmaceutical composition is formed from a bulk solution having a pH of 13 or higher; and (2) administering the resulting intravenous fluid of step (1) to a patient in need thereof. 17. The method of claim 16, wherein step (1) comprises the step of reconstituting the lyophilized pharmaceutical composition with a first diluent prior to the administrating step to form a reconstituted solution. 18. The method of claim 17, wherein the first diluent is one of water for injection, 0.9% sodium chloride solution, lactated Ringer's solution, Ringer's solution, sodium carbonate solution, or bicarbonate solution. 19. The method of claim 17, wherein step (1) further comprises the step of diluting the reconstituted solution with a second diluent to form a diluted solution. 20. The method of claim 19, wherein the diluted solution is hemocompatible. 21. The method of claim 17, wherein the reconstituted solution is self-preserved. 22. A method for treating a patient suffering from a disease selected from the group consisting of cardiovascular disease or disorder, atherosclerosis, arteriosclerosis, congestive heart failure, angina pectoris, and hypertension, said method comprising the steps of (1) combining an intravenous fluid with an effective amount of a lyophilized pharmaceutical composition comprising: (a) a unit dose of 0.5 mg or 1.5 mg of epoprostenol or a salt thereof; (b) 50 mg of arginine; (c) Mannitol or sucrose; and (d) sodium hydroxide. wherein said lyophilized pharmaceutical composition is formed from a bulk solution having a pH of 13 or higher; and (2) and (2) administering the resulting intravenous fluid of step (1) to a patient in need thereof. 23. The method of claim 22, wherein step (1) comprises the step of reconstituting the lyophilized pharmaceutical composition with a first diluent prior to the administrating step to form a reconstituted solution. 24. The method of claim 23, wherein the first diluent is one of water for injection, 0.9% sodium chloride solution, lactated Ringer's solution, Ringer's solution, sodium carbonate solution, or bicarbonate solution. 25. The method of claim 23, wherein step (1) further comprises the step of diluting the reconstituted solution with a second diluent to form a diluted solution. 26. The method of claim 25, wherein the diluted solution is hemocompatible. 27. The method of claim 23, wherein the reconstituted solution is self-preserved. 28. The method of claim 22, wherein the intravenous fluid of step (1) is water for injection. 29. The method of claim 22, wherein the intravenous fluid of step (1) is 0.9% sodium chloride solution. 30. The method of claim 22, wherein the intravenous fluid of step (1) is 5 mL of water for injection or 0.9% sodium chloride solution. 31. The method of claim 22, wherein the administration step (2) comprises administration by injection or infusion. 32. A method for treating a patient suffering from a disease selected from the group consisting of cardiovascular disease, atherosclerosis, arteriosclerosis, congestive heart failure, angina pectoris, and hypertension, said method comprising the steps of (1)(i) reconstituting an effective amount of a lyophilized pharmaceutical composition comprising: (a) a unit dose of 0.5 mg or 1.5 mg of epoprostenol or a salt thereof; (b) 50 mg of arginine; (c) Mannitol or sucrose; and (d) sodium hydroxide, in 5 mL of water for injection or 0.9% sodium chloride solution to form a reconstituted solution, wherein said lyophilized pharmaceutical composition is formed from a bulk solution having a pH of 13 or higher; (1)(ii) diluting the reconstituted solution of step (1)(i) with a second diluent to form a diluted solution; and (2) administering the resulting diluted solution of step (1)(ii) to a patient in need thereof. 33. The method of claim 32, wherein the epoprostenol or a salt thereof is epoprostenol sodium. 34. The method of claim 33, wherein the second diluent in step (1)(ii) is the same diluent as the first diluent used in step (1)(i) to reconstitute the lyophilized composition. 35. The method of claim 33, wherein the administration step (2) comprises administration by injection or infusion. 36. The method of claim 16, wherein the intravenous fluid of step (1) is water for injection. 37. The method of claim 16, wherein the intravenous fluid of step (1) is 0.9% sodium chloride solution. 38. The method of claim 16, wherein the intravenous fluid of step (1) is 5 mL of water for injection or 0.9% sodium chloride solution. 39. The method of claim 16, wherein the administration step (2) comprises administration by injection or infusion. 40. A method for treating a patient suffering from a disease selected from the group consisting of cardiovascular disease, atherosclerosis, arteriosclerosis, congestive heart failure, angina pectoris, and hypertension, said method comprising the steps of (1)(i) reconstituting an effective amount of a lyophilized pharmaceutical composition comprising: (a) a unit dose of 0.5 mg or 1.5 mg of epoprostenol or a salt thereof; (b) 50 mg of arginine; (c) Mannitol or sucrose; and (d) sodium hydroxide, in 5 mL of water for injection to form a reconstituted solution, wherein said lyophilized pharmaceutical composition is formed from a bulk solution having a pH of 13 or higher; (1)(ii) diluting the reconstituted solution of step (1)(i) with water for injection to form a diluted solution; and (2) administering the resulting diluted solution of step (1)(ii) to a patient in need thereof. 41. The method of claim 40, wherein the epoprostenol or a salt thereof is epoprostenol sodium. 42. The method of claim 41, wherein the administration step (2) comprises administration by injection or infusion.