Pharmaceuticals compositions

Abstract

Pharmaceutical compositions containing 2,6-diisopropylphenol (propofol) are described for use as anesthetics. A method for their preparation is described, as their use in producing anesthesia including induction and maintenance of general anesthesia and sedation.

1 . A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises an amount of edetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious, extrinsic contamination.  
     
     
         2 . A sterile pharmaceutical composition according to  claim 1  wherein the amount of edetate is sufficient to prevent a no more than 10-fold increase in growth of clinically relevant microorganisms for at least 24 hours after contamination by up to 10 colony forming units (at a temperature in the range 20-25° C.).  
     
     
         3 . A sterile pharmaceutical composition according to  claim 2  wherein the clinically relevant microorganisms are selected from strains of  Staphylococcus aureus, Escherichia coli, Candida albicans  and  Pseudomonas aeruginosa.    
     
     
         4 . A sterile pharmaceutical composition according to  claim 1  which comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises an amount of edetate sufficient to prevent a no more than 10-fold increase in growth of each of  Staphylococcus aureus  ATCC 6538,  Escherichia coli  ATCC 8739,  Pseudomonas aeruginosa  ATCC 9027 and  Candida albicans  ATCC 10231 for at least 24 hours as measured by a test wherein a washed suspension of each said organism is added to a separate aliquot of said composition at approximately 50 colony forming units per ml, at a temperature in the range 20-25° C., said aliquots are incubated at 20-25° C. and are tested for viable counts after 24 hours.  
     
     
         5 . A sterile pharmaceutical composition according to any one of  claims 1  to  4  wherein the edetate is disodium edetate.  
     
     
         6 . A sterile pharmaceutical composition according to  claim 1  which comprises up to about 30% by weight of water-immiscible solvent.  
     
     
         7 . A sterile pharmaceutical composition according to  claim 4  which comprises up to about 30% by weight of water-immiscible solvent.  
     
     
         8 . A sterile pharmaceutical composition according to  claim 6  which comprises from about 10% to about 20% by weight of water-immiscible solvent.  
     
     
         9 . A sterile pharmaceutical composition according to  claim 7  which comprises from about 10% to about 20% by weight of water-immiscible solvent.  
     
     
         10 . A sterile pharmaceutical composition according to any one of  claims 1  to  4  wherein the water-immiscible solvent is a vegetable oil or ester of a fatty acid.  
     
     
         11 . A sterile pharmaceutical composition according to  claim 10  wherein the vegetable oil is soy bean oil.  
     
     
         12 . A sterile pharmaceutical composition according to any one of  claims 1  to  4  wherein the surfactant is a naturally occurring phosphatide.  
     
     
         13 . A sterile pharmaceutical composition according to  claim 12  wherein the phosphatide is egg phosphatide or soya phosphatide.  
     
     
         14 . A sterile pharmaceutical composition according to any one of  claims 1  to  4  wherein the pH is between about 6.0 and about 8.5.  
     
     
         15 . A sterile pharmaceutical composition according to  claim 14  wherein sodium hydroxide is present.  
     
     
         16 . A sterile pharmaceutical composition according to any one of  claims 1  to  4  which is isotonic with blood.  
     
     
         17 . A sterile pharmaceutical composition according to  claim 16  which is made isotonic with blood by incorporation of glycerol.  
     
     
         18 . A sterile pharmaceutical composition according to any one of claims  1 - 4  which comprises from about 1% to about 2% by weight of propofol.  
     
     
         19 . A sterile pharmaceutical composition according to  claim 18  which contains about 1% by weight of propofol.  
     
     
         20 . A sterile pharmaceutical composition according to  claim 18  which contains about 2% by weight of propofol.  
     
     
         21 . A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises an amount of edetate wherein the amount of edetate is a molar concentration in the range 3×10 −5  to 9×10 −4 .  
     
     
         22 . A sterile pharmaceutical composition according to  claim 21  wherein the amount of edetate is a molar concentration in the range 3×10 5  to 7.5×10 −4 .  
     
     
         23 . A sterile pharmaceutical composition according to  claim 22  wherein the amount of edetate is a molar concentration in the range 1.5×10 −4  to 3.0×10 −4 .  
     
     
         24 . A sterile pharmaceutical composition according to  claim 23  wherein the amount of edetate is a molar concentration of about 1.5×10 −4 .  
     
     
         25 . A sterile pharmaceutical composition according to any one of  claims 21  to  24  wherein the source of edetate is disodium edetate.  
     
     
         26 . A sterile pharmaceutical composition according to  claim 21  which comprises up to about 30% by weight of water-immiscible solvent.  
     
     
         27 . A sterile pharmaceutical composition according to  claim 26  which comprises from about 10% to about 20% by weight of water-immiscible solvent.  
     
     
         28 . A sterile pharmaceutical composition according to any one of  claims 21  to  24  wherein the water-immiscible solvent is a vegetable oil or ester of a fatty acid.  
     
     
         29 . A sterile pharmaceutical composition according to  claim 28  wherein the vegetable oil is soy bean oil.  
     
     
         30 . A sterile pharmaceutical composition according to any one of claims to  21  to  24  wherein the surfactant is a naturally occurring phosphatide.  
     
     
         31 . A sterile pharmaceutical composition according to  claim 30  wherein the phosphatide is egg phosphatide or soya phosphatide.  
     
     
         32 . A sterile pharmaceutical composition according to any one of  claims 21  to  24  wherein the pH is between about 6.0 and about 8.5.  
     
     
         33 . A sterile pharmaceutical composition according to  claim 32  wherein sodium hydroxide is present.  
     
     
         34 . A sterile pharmaceutical composition according to any one of  claims 21  to  24  which is isotonic with blood.  
     
     
         35 . A sterile pharmaceutical composition according to  claim 34  which is made isotonic with blood by incorporation of glycerol.  
     
     
         36 . A sterile pharmaceutical composition according to any one of  claims 21  to  24  which comprises from about 1% to about 2% by weight of propofol.  
     
     
         37 . A sterile pharmaceutical composition according to  claim 36  which contains about 1% by weight of propofol.  
     
     
         38 . A sterile pharmaceutical composition according to  claim 36  which contains about 2% by weight of propofol.  
     
     
         39 . A sterile pharmaceutical composition for parenteral administration in the form of an oil-in-water emulsion which comprises: 
 a) about 1% by weight of propofol,    b) about 10% by weight of soy bean oil,    c) about 1.2% by weight of egg phosphatide,    d) about 2.25% by weight of glycerol,    e) about 0.005% by weight of disodium edetate,    f) sodium hydroxide    g) water to 100%.    
     
     
         40 . A sterile pharmaceutical composition for parenteral administration in the form of an oil-in-water emulsion which comprises: 
 a) about 2% by weight of propofol,    b) about 10% by weight of soy bean oil,    c) about 1.2% by weight of egg phosphatide,    d) about 2.25% by weight of glycerol,    e) about 0.005% by weight of disodium edetate,    f) sodium hydroxide    g) water up to 100%.    
     
     
         41 . A method for limiting the potential for microbial growth in a sterile pharmaceutical composition for parenteral administration which comprises the use of edetate in an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, wherein the amount of edetate is sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious, extrinsic contamination.  
     
     
         42 . A method for limiting the potential for microbial growth in a sterile pharmaceutical composition for parenteral administration which comprises the use of edetate in an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, wherein the amount of edetate is a molar concentration in the range 3×10 −5  to 9×10 −4 .  
     
     
         43 . A method of producing anaesthesia in a warm-blooded animal which comprises administering an effective amount of a sterile pharmaceutical composition according to any one of  claims 1  to  4 .  
     
     
         44 . A method of producing anaesthesia in a warm-blooded animal which comprises administering an effective amount of a sterile pharmaceutical composition according to any one of  claims 21  to  24 .  
     
     
         45 . A method of producing anaesthesia in a warm-blooded animal which comprises administering an effective amount of a sterile pharmaceutical composition according to either  claim 39  or  claim 40 .  
     
     
         46 . A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol is emulsified with water and stabilised by means of a surfactant, and which further comprises an amount of edetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious, extrinsic contamination.  
     
     
         47 . A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol is emulsified with water and stabilised by means of a surfactant, and which further comprises an amount of edetate wherein the amount of edetate is a molar concentration in the range 3×10 −5  to 9×10 −4 .  
     
     
         48 . A method for limiting the potential for microbial growth in a sterile pharmaceutical composition for parenteral administration which comprises the use of edetate in an oil-in-water emulsion in which propofol is emulsified with water and stabilised by means of a surfactant, wherein the amount of edetate is sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious, extrinsic contamination.  
     
     
         49 . A method for limiting the potential for microbial growth in a sterile pharmaceutical composition for parenteral administration which comprises the use of edetate in an oil-in-water emulsion in which propofol is emulsified with water and stabilised by means of a surfactant, wherein the amount of edetate is a molar concentration in the range 3×10 −5  to 9×10 −4 .  
     
     
         50 . A method of improving the time for administration, and/or the time between the changes of giving sets, for an oil-in-water emulsion of propofol by including in said emulsion an amount of edetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious, extrinsic contamination.  
     
     
         51 . A method of improving the time for administration, and/or the time between the changes of giving sets, for an oil-in-water emulsion of propofol by including in said emulsion edetate in a molar concentration in the range 3×10 −5  to 9×10 −4 .  
     
     
         52 . A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent is emulsified with water and stabilised by means of a surfactant, and which further comprises an amount of edetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious, extrinsic contamination wherein the edetate does not physically destabilise said composition.  
     
     
         53 . A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent is emulsified with water and stabilised by means of a surfactant, and which further comprises an amount of edetate wherein the amount of edetate is a molar concentration in the range 3×10 −5  to 9×10 −4  and does not physically destabilise said composition.  
     
     
         54 . A sterile, aqueous composition for parenteral administration which comprises an oil-in-water emulsion which is emulsified with water and stabilised by means of a surfactant and which further comprises an amount of edetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious, extrinsic contamination.  
     
     
         55 . A sterile, aqueous composition for parenteral administration which comprises an oil-in-water emulsion which is emulsified with water and stabilised by means of a surfactant, and which further comprises an amount of edetate wherein the amount of edetate is a molar concentration in the range 3×10 −5  to 9×10 −4 .  
     
     
         56 . A sterile pharmaceutical composition which comprises an oil-in-water emulsion containing a therapeutic or pharmaceutical agent, in which the agent, either alone or dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant and which further comprises an amount of edetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious, extrinsic contamination.  
     
     
         57 . A sterile pharmaceutical composition which comprises an oil-in-water emulsion containing a therapeutic or pharmaceutical agent, in which the agent, either alone or dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant and which further comprises an amount of edetate wherein the amount of edetate is a molar concentration in the range 3×10 −5  to 9×10 −4 .  
     
     
         58 . A composition according to  claim 56  comprising an antifungal agent, anaesthetic, antibacterial agent, anti-cancer agent, anti-emetic, agent acting on the central nervous system, steroid, barbiturate or a vitamin preparation.  
     
     
         59 . A composition according to  claim 56  comprising an antifungal agent, anaesthetic, antibacterial agent, anti-cancer agent, anti-emetic, agent acting on the central nervous system, steroid, barbiturate or a vitamin preparation.