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.

What is claimed is: 
     
         1 . A prefilled syringe comprising 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 formulation has a pH of from about 4.5 to about 6.5, and wherein following storage at 25° C./60% Relative Humidity for at least 12 months, the formulation comprises not more than about 0.2% pseudomorphine and not more than about 1.5% total impurities. 
     
     
         2 . The prefilled syringe of  claim 1 , wherein, the morphine, or a salt thereof, or a hydrate thereof, is selected from morphine sulfate pentahydrate, morphine hydrochloride, anhydrous morphine, morphine hydrochloride, morphine sulfate, morphine tartrate, morphine citrate, morphine acetate, morphine methobromide, morphine hydrobromide, morphine hydroiodide, morphine lactate and morphine bitartrate. 
     
     
         3 . The prefilled syringe 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 prefilled syringe of  claim 1 , wherein the buffering agent is a di-carboxylic or tri-carboxylic acid. 
     
     
         5 . The prefilled syringe of  claim 1 , 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. 
     
     
         6 . The prefilled syringe of  claim 1 , comprising a conjugate base to the buffering agent. 
     
     
         7 . The prefilled syringe of  claim 1 , wherein the pH is about 5. 
     
     
         8 . The prefilled syringe 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 prefilled syringe of  claim 1 , wherein the buffering agent forms a buffer comprising citric acid and sodium citrate. 
     
     
         10 . The prefilled syringe 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 prefilled syringe of  claim 1 , wherein the complement to chelating agent is a calcium salt. 
     
     
         12 . The prefilled syringe of  claim 1 , wherein, the prefilled syringe 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. 
     
     
         13 . The prefilled syringe 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 24 months. 
     
     
         14 . The prefilled syringe 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 24 months. 
     
     
         15 . The prefilled syringe of  claim 1 , wherein the syringe barrel is made of glass and the stopper and tip cap comprise a thermoplastic elastomer. 
     
     
         16 . 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 formulation. 
     
     
         17 . The method according to  claim 16 , wherein the formulation is prepared under inert conditions and packaged into a glass syringe. 
     
     
         18 . The method according to  claim 17 , wherein following storage at 25° C./60% Relative Humidity for at least 12 months, the formulation comprises not more than about 0.2% pseudomorphine and not more than about 1.5% total impurities. 
     
     
         19 . The method according to  claim 16 , wherein the formulation comprises a buffering agent with anti-oxidative properties. 
     
     
         20 . The method according to  claim 19 , wherein the formulation has a pH of from about 4.5 to about 6.5.