MORPHINE FORMULATIONS
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.
1 . A pharmaceutical formulation for injectable administration comprising:
(a) morphine sulfate 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 formulation has a pH of from about 2.5 to about 6.5.
2 . The formulation of claim 1 , wherein, the morphine sulfate is provided as morphine sulfate pentahydrate.
3 . The formulation of claim 1 , 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.
4 . The formulation of claim 1 , wherein the buffering agent is a di-carboxylic or tricarboxylic acid.
5 . The formulation of claim 1 , wherein the buffering agent is citric acid, isocitric 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.
6 . The formulation of claim 1 , comprising a conjugate base to the buffering agent.
7 . The formulation of claim 1 , wherein the pH is from about 4.5 to about 5.5.
8 . The formulation of claim 1 , 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.
9 . The formulation of claim 1 , wherein the buffering agent forms a buffer comprising citric acid and sodium citrate.
10 . The formulation of claim 1 , 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.
11 . The formulation of claim 1 , wherein the complement to chelating agent is a calcium salt.
12 . The formulation of claim 1 , wherein, the formulation provides a unit dose of morphine sulfate in a concentration from about 2 mg/mL to about 15 mg/mL.
13 . The formulation of claim 1 , wherein the formulation comprises not more than about 1.5% total impurities following storage at 25° C./60% Relative Humidity for at least 12 months.
14 . The formulation of claim 1 , wherein the formulation comprises not more than about 0.2% pseudomorphine following storage at 25° C./60% Relative Humidity for at least 12 months.
15 . A pharmaceutical product comprising the formulation of claim 1 packaged in a vial, syringe, ampoule, bottle, cartridge, carpule, bag, or pouch made of glass or plastic.
16 . A method of reducing pain in a subject comprising administering to the subject an injectable pharmaceutical formulation comprising:
(a) morphine sulfate 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 formulation comprises not more than about 0.2% pseudomorphine and not more than about 1.5% total impurities following storage at 25° C./60% Relative Humidity for at least 12 months.
17 . The method of claim 16 , wherein the formulation has a pH of about 2.5 to about 6.5.
18 . The method of claim 16 , wherein the buffering agent is a di-carboxylic acid or a tri-carboxylic acid and comprises a conjugate base to the buffering agent, and 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.
19 . A method of reducing adverse effects of an injectable morphine pharmaceutical formulation comprising a chelating agent, the method comprising the addition of a complement to the chelating agent to the injectable morphine pharmaceutical formulation.
20 . The method of claim 19 , 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, and the complement is a calcium salt.