Claims for Patent: 9,072,781

Summary for Patent: 9,072,781

Title:	Morphine formulations
Abstract:	Provided herein, generally, are pharmaceutical formulations, e.g., injectable pharmaceutical formulations with improved stability, comprising morphine sulfate or a hydrate thereof, and methods of producing and using the same. Also provided herein are kits comprising the formulations, e.g., injectable morphine formulations.
Inventor(s):	Cuine; Alain (St. Fargeau-Ponthierry, FR), Hoarau; Didier (Claix, FR), Romain; Pauline (Saint Egreve, FR)
Assignee:	Becton, Dickinson France S.A.S. (La Pont de Claix, FR)
Application Number:	14/207,245
Patent Claims:	1. An injectable pharmaceutical formulation comprising per mL: (a) from about 2 mg to about 10 mg of morphine sulfate or a hydrate thereof; (b) sodium chloride; (c) a buffering system comprised of a buffering agent in an amount which provides a molar ratio of morphine sulfate to the buffering agent from about 0.4 to about 1.3 and is in an amount sufficient to provide a pH of about 5 to the formulation and a conjugate base to the buffering agent; (d) disodium edetate or a hydrate thereof; (e) calcium chloride or a hydrate thereof; and (f) water for injection. 2. The formulation of claim 1, comprising (a) from about 4 mg and 10 mg of morphine sulfate or a hydrate thereof; and (c) a buffering agent in an amount which provides a molar ratio of morphine sulfate to the buffering agent from about 0.4 to 0.8 and is in an amount sufficient to provide a pH of about 5 to the formulation. 3. The formulation of claim 1, wherein the buffering agent has anti-oxidative properties. 4. The formulation of claim 1, wherein the buffering system comprises citric acid monohydrate and sodium citrate dihydrate. 5. The formulation of claim 1, wherein the formulation is stable at 80.degree. C. for at least 14 days. 6. The formulation of claim 1, wherein the formulation is stable at 40.degree. C. and 75% Relative Humidity for at least three months. 7. The formulation of claim 1, wherein the formulation is stable at 25.degree. C. and 60% Relative Humidity for at least 12 months. 8. A pharmaceutical formulation comprising per mL: (a) from about 2 mg to about 10 mg of morphine sulfate pentahydrate; (b) from about 7 mg to about 9 mg of sodium chloride; (c) from about 2 mg to about 4 mg of sodium citrate dihydrate; (d) from about 0.7 to about 1.2 mg of citric acid monohydrate; (e) from about 0.1 to about 0.15 mg of disodium edetate dihydrate; (f) from about 0.04 to about 0.06 mg calcium chloride dihydrate; and (g) water for injection. 9. The formulation of claim 8, wherein the formulation comprises (a) about 2 mg morphine sulfate pentahydrate; (b) about 8.4 mg of sodium chloride; (c) about 2.3 mg of sodium citrate dihydrate; (d) about 0.74 mg of citric acid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f) about 0.053 mg calcium chloride dihydrate; and (g) water for injection. 10. The formulation of claim 8, wherein the formulation comprises (a) about 4 mg morphine sulfate pentahydrate; (b) about 8.4 mg of sodium chloride; (c) about 2.3 mg of sodium citrate dihydrate; (d) about 0.74 mg of citric acid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f) about 0.053 mg calcium chloride dihydrate; and (g) water for injection. 11. The formulation of claim 8, wherein the formulation comprises (a) about 5 mg morphine sulfate pentahydrate; (b) about 7.5 mg of sodium chloride; (c) about 3.45 mg of sodium citrate dihydrate; (d) about 1.11 mg of citric acid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f) about 0.053 mg calcium chloride dihydrate; and (g) water for injection. 12. The formulation of claim 8, wherein the formulation comprises (a) about 8 mg morphine sulfate pentahydrate; (b) about 7.5 mg of sodium chloride; (c) about 3.45 mg of sodium citrate dihydrate; (d) about 1.11 mg of citric acid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f) about 0.053 mg calcium chloride dihydrate; and (g) water for injection. 13. The formulation of claim 8, wherein the formulation comprises (a) about 10 mg morphine sulfate pentahydrate; (b) about 7.5 mg of sodium chloride; (c) about 3.45 mg of sodium citrate dihydrate; (d) about 1.11 mg of citric acid monohydrate; (e) about 0.111 mg of disodium edetate dihydrate; (f) about 0.053 mg calcium chloride dihydrate; and (g) water for injection. 14. The formulation of claim 1, wherein the formulation is stored in a glass or plastic container. 15. The formulation of claim 14, wherein the glass or plastic container is a prefilled syringe or a vial. 16. The formulation of claim 1, wherein the formulation is stored in a glass container which is stored in a secondary container having reduced permeability to oxygen and further comprising an oxygen scavenger. 17. The formulation of claim 16, wherein the formulation is stable at 40.degree. C. and 75% Relative Humidity for at least six months. 18. The formulation of claim 16, wherein the formulation is stable at 25.degree. C. and 60% Relative Humidity for at least 24 months. 19. A kit comprising (a) a pre-filled syringe comprising a morphine formulation of claim 8; and (b) a secondary container having reduced permeability to oxygen and further comprising an oxygen scavenger. 20. A pharmaceutical formulation comprising: a) morphine, or a salt thereof, or a hydrate thereof; b) an isotonic agent; c) a buffering agent with anti-oxidative properties; d) a chelating agent; e) a complement to a chelating agent; and (f) water; wherein the isotonic agent is selected from sodium chloride, calcium chloride, potassium chloride, sodium bicarbonate, sodium lactate, Ringer's solution, dextrose, lactose, mannitol, glucose, glycerine, dextran, Normosol R, saline, Hartmann's solution, and mixtures and combinations thereof. 21. The formulation of claim 20, wherein the isotonic agent is sodium chloride. 22. The formulation of claim 20, wherein the buffering agent is a di-carboxylic or tri-carboxylic acid. 23. The formulation of claim 20, wherein the buffering agent is citric acid, iso citric acid, aconitic acid, trimesic acid, propane-1,2,3-tricarboxylic acid, fumaric acid, oxalic acid, maleic acid, malonic acid, glutaric acid, succinic acid or tartaric acid, or hydrates thereof. 24. The formulation of claim 20, wherein the buffering agent is citric acid. 25. The formulation of claim 20, wherein the formulation further comprises a conjugate base to the buffering agent. 26. The formulation of claim 20, wherein the buffering agent is in an amount which provides a molar ratio of morphine to the buffering agent from about 0.4 to about 1.3. 27. The formulation of claim 20, wherein the buffering agent is in an amount which provides a molar ratio of morphine to the buffering agent from about 0.4 to about 0.8. 28. The formulation of claim 20, wherein the buffering agent forms a buffer comprised of anhydrous citric acid and hydrates thereof and anhydrous sodium citrate and hydrates thereof. 29. The formulation of claim 20, wherein the buffering agent is in an amount sufficient to provide a pH of from about 2.5 to about 6.5 to the formulation. 30. The formulation of claim 20, wherein the buffering agent is in an amount sufficient to provide a pH of from about 4.5 to about 5.5 to the formulation. 31. The formulation of claim 20, wherein the buffering agent is in an amount sufficient to provide a pH of about 5 to the formulation. 32. The formulation of claim 20, wherein the complement to chelating agent is a calcium salt. 33. The formulation of claim 20, wherein the complement to chelating agent is calcium chloride dihydrate. 34. The formulation of claim 20, wherein, the formulation provides a unit dose of morphine, or a salt thereof, or a hydrate thereof, in a concentration from about 2 mg/mL to about 15 mg/mL. 35. The formulation of claim 20 comprising per mL: (a) from about 2 mg to about 15 mg of morphine sulfate pentahydrate; (b) an isotonic agent; (c) a buffering agent in an amount which provides a molar ratio of morphine sulfate to the buffering agent from about 0.4 to about 1.3 and is in an amount sufficient to provide a pH of 5 to the formulation; (d) a chelating agent; (e) a complement to a chelating agent; and (f) water. 36. The formulation of claim 20, wherein the formulation is stable at 80.degree. C. for at least 14 days. 37. The formulation of claim 20, wherein the formulation is stable at 40.degree. C. and 75% Relative Humidity for at least three months. 38. The formulation of claim 20, wherein the formulation is stable at 25.degree. C. and 60% Relative Humidity for at least 12 months. 39. The formulation of claim 20, wherein the formulation is stored in a glass or plastic container which is stored in a secondary container having reduced permeability to oxygen and further comprising an oxygen scavenger. 40. The formulation of claim 39, wherein the formulation is stable at 40.degree. C. and 75% Relative Humidity for at least six months. 41. The formulation of claim 39, wherein the formulation is stable at 25.degree. C. and 60% Relative Humidity for at least 24 months. 42. A kit comprising (a) a pre-filled syringe comprising a formulation of claim 20; and (b) a secondary container having reduced permeability to oxygen and further comprising an oxygen scavenger.