Propofol composition containing sulfite
AssigneeGensia Sincor Inc.
InventorsDorla Mirejovsky, Liananingsih Tanudarma, Dilip R. Ashtekar
Life of this patent
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Abstract
Sterile pharmaceutical compositions for parenteral administration containing 2,6-diisopropylphenol (propofol) are described for use as anesthetics. The compositions comprise an oil-in-water emulsion of propofol additionally comprising an amount of sulfite sufficient to prevent significant growth of microorganisms for at least 24 h after adventitious contamination.
Claims80
A sterile, pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent, is emulsified with water, and is stabilized by means of a surfactant, and which further comprises an amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-35.degree. C. and are tested for viable counts of said organisms after 24 h, and wherein said amount of sulfite is less than 0.1% weight of said composition.
A sterile, pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent, is emulsified with water, and is stabilized by means of a surfactant, and which further comprises an amount of sulfite wherein the amount of sulfite is in the range of about 0.0075% to less than 0.1% weight.
A sterile, pharmaceutical composition for parenteral administration which comprises by weight:
- a. about 1% propofol;
- b. about 10% soybean oil;
- c. about 2.25% glycerin;
- d. about 1.2% egg-yolk phospholipid;
- e. about 0.025% of any of sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, or potassium sulfite, or any combination thereof;
- f. sodium hydroxide;
- and
- g. water to 100%.
A sterile, pharmaceutical composition for parenteral administration which comprises by weight:
- a. about 2% propofol;
- b. about 10% soybean oil;
- c. about 2.25% glycerin;
- d. about 1.2% egg-yolk phospholipid;
- e. about 0.025% of any of sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, or potassium sulfite, or any combination thereof;
- f. sodium hydroxide;
- and
- g. water to 100%.
A sterile, pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol is emulsified with water, and is stabilized by means of a surfactant, and which further comprises an amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-35.degree. C. and are tested for viable counts of said organisms after 24 h and wherein said amount of sulfite is less than 0.1% weight of said composition.
A sterile, total-parenteral-nutrition composition for parenteral administration which comprises an oil-in-water emulsion in which a lipid is emulsified with water and which further comprises an amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-35.degree. C. and are tested for viable counts of said organisms after 24 h, wherein said amount of sulfite is less than 0.1% weight of said composition.
A sterile, pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which a lipophilic pharmaceutical or therapeutic agent is dissolved in a water-immiscible solvent, is emulsified with water, and is stabilized by means of a surfactant, and which further comprises an amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-35.degree. C. and are tested for viable counts of said organisms after 24 h, and wherein said amount of sulfite is less than 0.1% weight of said composition.
A sterile, pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which a lipophilic pharmaceutical or therapeutic agent is emulsified with water and is stabilized by means of a surfactant, and which further comprises an amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-35.degree. C. and are tested for viable counts of said organisms after 24 h, and wherein said amount of sulfite is less than 0.1% weight of said composition.
A method for inducing anesthesia comprising parenteral administration of a composition which comprises an oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent, is emulsified with water, and is stabilized by means of a surfactant, and which further comprises an amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-35.degree. C. and are tested for viable counts of said organisms after 24 h, and wherein said amount of sulfite less than 0.1% weight of said composition.
A method of maintaining anesthesia comprising parenteral administration of a composition which comprises an oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent, is emulsified with water, and is stabilized by means of a surfactant, and which further comprises an amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coil (ATCC 8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-35.degree. C. and are tested for viable counts of said organisms after 24 h, and wherein said amount of sulfite is less than 0.1% weight of said composition.
A method of sedation comprising parenteral administration of a composition which comprises an oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent, is emulsified with water, and is stabilized by means of a surfactant, and which further comprises an amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-35.degree. C. and are tested for viable counts of said organisms after 24 h, and wherein said amount of sulfite is lest than 0.1% weight of said composition.
A sterile, pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion of propofol and a pharmaceutically acceptable amount of sulfite sufficient to prevent a no more than 10-fold increase in the growth of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudomonas .ae butted.ruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 h as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony-forming units per mL and incubated at a temperature in the range 30-.+-..degree. C. and are tested for viable counts of said organisms after 24 h, prepared by
- a. Performing all steps under an inert atmosphere;
- b. Degassing the water for injection (WFI) by sparging with an inert gas;
- c. Preparing an aqueous phase by adding an isotonicity agent to WFI in a compounding tank while maintaining the temperature at approximately 40.degree. C.;
- d. Adding a surfactant to said aqueous phase;
- e. Homogenizing said aqueous phase;
- f. Filtering said aqueous phase through a 5.0 .mu.m filter;
- g. Preparing an oil phase selected from the group consiting of propofol, and propofol dissolved in a water immiscible solvent;
- h. Filtering said oil phase through a 0.45 .mu.m filter;
- i. Combining and homogenizing said aqueous and oil phases;
- j. Adding a solution of sulfite dissolved in WFI near the end of the homogenization step;
- k. Adding sodium hydroxide or hydrochloric acid solution to adjust the pH;
- l. Adjusting to volume with SWFI;
- m. Microfluidizing the crude emulsion to the target globule size and particle size distribution while maintaining the temperature at about 30.degree. C.;
- n. Filtering the propofol oil-in-water emulsion into a filling vessel;
- o. Filling and sealing containers under an inert gas;
- and
- p. Autoclaving said containers.
A method of inducing anesthesia comprising the parenteral administration of a sterile pharmaceutical composition which comprises by weight:
- a. about 1% propofol;
- b. about 10% soybean oil;
- c. about 2.25% glycerin;
- d. about 1.2% egg-yolk phospholipid;
- e. about 0.025% sodium metabisulfite;
- f. sodium hydroxide;
- g. water to 100%.
A method of inducing anesthesia comprising the parenteral administration of a sterile pharmaceutical composition which comprises by weight:
- a. about 2% propofol;
- b. about 10% soybean oil;
- c. about 2.25% glycerin;
- d. about 1.2% egg-yolk phospholipid;
- e. about 0.025% sodium metabisulfite;
- f. sodium hydroxide;
- g. water to 100%.
Dependencies are inferred from the claim text.