Claims for Patent: 5,731,356

Summary for Patent: 5,731,356

Title:	Pharmaceutical compositions of propofol and edetate
Abstract:	Pharmaceutical compositions containing 2,6-diisopropylphenol (propofol) are described for use as anaesthetics. A method for their preparation is described, as their use in producing anaesthesia including induction and maintenance of general anaesthesia and sedation.
Inventor(s):	Jones; Christopher Buchan (Prestbury, GB), Platt; John Henry (Congleton, GB)
Assignee:	Zeneca Limited (London, GB)
Application Number:	08/802,447
Patent Claims:	1. A method for limiting the potential for microbial growth in a sterile pharmaceutical composition for parenteral administration comprising 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, which method comprises additionally providing edetate in said sterile pharmaceutical composition in an amount 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.degree.-25.degree. C., whereafter said aliquots are incubated at 20.degree.-25.degree. C. for 24 hours and thereafter tested for viable counts of said organism, said amount of edetate being no more than 0.1% by weight of said composition. 2. The method according to claim 1 wherein the edetate is disodium edetate. 3. The method according to claim 1 wherein said sterile pharmaceutical composition comprises up to about 30% by weight of water-immiscible solvent. 4. The method according to claim 3 wherein said sterile pharmaceutical composition comprises from about 10% to about 20% by weight of water-immiscible solvent. 5. The method according to claim 1 wherein the water-immiscible solvent is a vegetable oil or ester of a fatty acid. 6. The method according to claim 5 wherein the vegetable oil is soy bean oil. 7. The method according to claim 1 wherein the surfactant is a naturally occurring phosphatide. 8. The method according to claim 7 wherein the phosphatide is egg phosphatide or soya phosphatide. 9. The method according to claim 1 wherein the pH of said sterile pharmaceutical composition is between about 6.0 and about 8.5. 10. The method according to claim 9 wherein said sterile pharmaceutical composition additionally comprises sodium hydroxide. 11. The method according to claim 1 wherein said sterile pharmaceutical composition is isotonic with blood. 12. The method according to claim 11 wherein said sterile pharmaceutical composition is made isotonic with blood by incorporation of glycerol. 13. The method according to claim 1 wherein said sterile pharmaceutical composition comprises from about 1% to about 2% by weight of propofol. 14. The method according to claim 13 wherein said sterile pharmaceutical composition contains about 1% by weight of propofol. 15. The method according to claim 13 wherein said sterile pharmaceutical composition contains about 2% by weight of propofol. 16. A method for limiting the potential for microbial growth in a sterile pharmaceutical composition for parenteral administration comprising 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, which method comprises additionally providing edetate in said sterile pharmaceutical composition in a molar concentration in the range of from 3.times.10.sup.-5 to 9.times.10.sup.-4. 17. The method according to claim 16 wherein the molar concentration of edetate in said sterile pharmaceutical composition is within the range of from 3.times.10.sup.-5 to 7.5.times.10.sup.-4. 18. The method according to claim 17 wherein the molar concentration of edetate in said sterile pharmaceutical composition is within the range of from 1.5.times.10.sup.-4 to 3.0.times.10.sup.-4. 19. The method according to claim 18 wherein the molar concentration of edetate in said sterile pharmaceutical composition is about 1.5.times.10.sup.-4. 20. The method according to any one of claims 16 to 19 wherein the source of edetate is disodium edetate. 21. The method according to claim 16 wherein said sterile pharmaceutical composition comprises up to about 30% by weight of water-immiscible solvent. 22. The method according to claim 21 wherein said sterile pharmaceutical composition comprises from about 10% to about 20% by weight of water-immiscible solvent. 23. The method according to any one of claims 16 to 19 wherein the water-immiscible solvent is a vegetable oil or ester of a fatty acid. 24. The method according to claim 23 wherein the vegetable oil is soy bean oil. 25. The method according to any one of claims 16 to 19 wherein the surfactant is a naturally occurring phosphatide. 26. The method according to claim 25 wherein the phosphatide is egg phosphatide or soya phosphatide. 27. The method according to any one of claims 16 to 19 wherein the pH of said sterile pharmaceutical composition is between about 6.0 and about 8.5. 28. The method according to claim 27 wherein said sterile pharmaceutical composition additionally comprises sodium hydroxide. 29. The method according to any one of claims 16 to 19 wherein said sterile pharmaceutical composition is isotonic with blood. 30. The method according to claim 29 wherein said sterile pharmaceutical composition is made isotonic with blood by incorporation of glycerol. 31. The method according to any one of claims 16 to 19 wherein said sterile pharmaceutical composition comprises from about 1% to about 2% by weight of propofol. 32. The method according to claim 31 wherein said sterile pharmaceutical composition contains about 1% by weight of propofol. 33. The method according to claim 31 wherein said sterile pharmaceutical composition contains about 2% by weight of propofol. 34. The method according to any one of claims 1 and 16 wherein said sterile pharmaceutical composition 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%. 35. The method according to any one of claims 1 and 16 wherein said sterile pharmaceutical composition 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%. 36. A method for limiting the potential for microbial growth in a sterile pharmaceutical composition for parenteral administration comprising an oil-in-water emulsion in which propofol is emulsified with water and stabilised by means of a surfactant, which method comprises additionally providing edetate in said sterile pharmaceutical composition in an amount 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.degree.-25.degree. C. whereafter said aliquots are incubated at 20.degree.-25.degree. C. for 24 hours and thereafter tested for viable counts of said organism, said amount of edetate being no more than 0.1% by weight of said composition. 37. A method for limiting the potential for microbial growth in a sterile pharmaceutical composition for parenteral administration comprising an oil-in-water emulsion in which propofol is emulsified with water and stabilised by means of a surfactant, which method comprises additionally providing edetate in said sterile pharmaceutical composition in a molar concentration in the range of from 3.times.10.sup.-5 to 9.times.10.sup.-4.