Morphine formulations

1. A method of reducing pain in a subject, comprising: administering to the subject 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 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) disodium edetate dihydrate;

(e) calcium chloride dihydrate; and

(f) water for injection.

2. The method 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 method of claim 1 , wherein the buffering agent has anti-oxidative properties.

4. The method of claim 1 , wherein the buffering system comprises citric acid monohydrate and sodium citrate dihydrate.

5. The method of claim 1 , wherein the formulation is stable at 80° C. for at least 14 days.

6. The method of claim 1 , wherein the formulation is stable at 40° C. and 75% Relative Humidity for at least three months.

7. The method of claim 1 , wherein the formulation is stable at 25° C. and 60% Relative Humidity for at least 12 months.

8. A method of reducing pain in a subject, comprising: administering to the subject an injectable 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 method 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 method 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 method 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 method 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 method 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. A method of reducing pain in a subject, comprising: administering to the subject an injectable 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.

15. The method of claim 14 , wherein, the morphine, or a salt thereof, or a hydrate thereof, is selected from anhydrous morphine, morphine hydrochloride, morphine sulfate, morphine tartrate, morphine citrate, morphine acetate, morphine methobromide, morphine hydrobromide, morphine hydroiodide, morphine lactate and morphine bitartrate.

16. The method of claim 14 , wherein the morphine, or a salt thereof, or a hydrate thereof, is selected from morphine sulfate pentahydrate or morphine hydrochloride.

17. The method of claim 14 , 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.

18. The method of claim 14 , wherein the isotonic agent is sodium chloride.

19. The method of claim 14 , wherein the buffering agent is a di-carboxylic or tri-carboxylic acid.

20. The method of claim 14 , 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.

21. The method of claim 14 , wherein the chelating agent is selected from edetic acid, ethylene glycol tetraacetic acid, ethylenediamine, diethylene triamine pentaacetic acid, N-(hydroxyethyl) ethylenediaminetriacetic acid, aminotriacetic acid, 2,3-dimercapto-1-propanesulfonic acid, dimercaptosuccinic acid, dimercaprol, 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, salts and hydrates thereof.

22. The method of claim 14 , wherein the chelating agent is edetic acid.

23. The method of claim 14 , wherein the complement to chelating agent is a calcium salt.

24. The method of claim 14 , wherein the complement to chelating agent is calcium chloride dihydrate.

25. The method of claim 14 , 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.

26. A method of reducing adverse effects of a injectable morphine pharmaceutical formulation comprising disodium edetate dihydrate, the method comprising the addition of calcium chloride dihydrate to the injectable morphine pharmaceutical formulation wherein the formulation comprises per mL:

(a) from about 2 mg to about 10 mg of morphine sulfate or a hydrate thereof;

(b) sodium chloride;

(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) disodium edetate dihydrate;

(e) calcium chloride dihydrate; and

(f) water for injection.