Propofol formulation containing TRIS

Details Propofol formulation containing TRIS Propofol formulation containing TRIS

1999-03-24

2001-01-23

Harrison, Robert H. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

C-o-group doai

C514S975000

Reexamination Certificate

active

06177477

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel oil-in-water emulsion pharmaceutical composition containing 2,6-diisopropylphenol, i.e. propofol.
Propofol is an injectable anesthetic which can be used to induce and maintain general anesthesia and for sedation, for example in intensive care units. There are a number of known propofol formulations. See, for example, UK Patent 1472793, U.S. Pat. Nos. 4,452,817 and 5,714,520. One formulation of propofol is an oil-in-water emulsion.
Sterile propofol formulations, including oil-in-water emulsion formulations of propofol, have been taught to include preservatives to prevent extrinsic contamination. Ideally, the concentration of preservative is kept to a minimum, especially where propofol is administered for the maintenance of general anaesthesia and sedation where such treatment allows for the possibility of significant amounts of preservative being administered to a patient over the course of treatment. In addition, to be effective for the intended purpose, namely the prevention of extrinsic contamination, a preservative should be broad spectrum, i.e. effective against gram negative (such as
Pseudomonas aeruginosa
) and gram positive (such as
Staphylococcus aureus
) bacteria as well as yeast (such as
Candida albicans
) at useful concentrations. Edetate has been taught to be the only preservative which has broad spectrum antimicrobial effect and can be exerted in the aqueous phase without destabilizing the oil-in-water propofol formulation. See, U.S. Pat. No. 5,714,520.
Tromethamine (TRIS) is a known buffering agent and electrolyte. It has also been previously suggested that tromethamine may enhance the antimicrobial effects of EDTA and other agents. Tjoelker, et al.,
J. Dairy Science,
68, Suppl. 1, 196 (1985); Angus Chemical Company,
Technology Review,
p. 10-13. Tromethamine has not been taught to be effective alone as an antimicrobial agent. Furthermore, due to its ionic nature, tromethamine would not be expected to be compatible with an oil-in-water emulsion because ionic compounds and electrolytes are known to destabilize oil-in-water emulsions. See, U.S. Pat. No. 5,714,520.
Despite these and other teachings, it has surprisingly been found that tromethamine is useful as a preservative in an oil-in-water emulsion. Thus, compositions of the present invention are excellent broad spectrum preservatives useful in an oil-in-water emulsion containing propofol.
DESCRIPTION OF THE INVENTION
The invention is a sterile pharmaceutical composition of propofol for parenteral administration comprising an oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent and is emulsified with water containing tromethamine as a preservative. Preservative is included in an amount sufficient to prevent any significant growth of microorganism for at least 24 hours in the event of extrinsic contamination.
By an oil-in-water emulsion is meant a two-phase system that is in equilibrium and in effect, as a whole, is kinetically stable and thermodynamically unstable.
Prevention of significant growth of microorganisms is meant growth of microorganism which is preferably no more than a 10 fold increase following extrinsic contamination. For purposes of this definition, the contamination is generally about 10 to about 200 colony forming units/ml, at temperatures in the range of about 20° to about 25° C.
Tromethamine as used herein, refers to 2-amino-2-hydroxymethyl-1,3-propanediol, also known as TRIS. Typically tromethamine is present in compositions of the present invention in amounts of no more than about 0.25% by weight. Preferably, tromethamine is present in the range of about 0.15% to about 0.25% by weight. In some embodiments of the present invention tromethamine is present in amounts of about 0.2% by weight. In other embodiments of the present invention, tromethamine is present in amount of about 0.24% by weight.
Compositions of the present invention typically comprise from 0.1 to 5% by weight of propofol and more preferably from 1 to 2% by weight of propofol. In particular, compositions of the present invention comprise 1% or 2% by weight of propofol.
The oil-in-water emulsion may be prepared by dissolving propofol and other oil-soluble ingredients in a water-immiscible solvent, providing an aqueous phase comprising a surfactant and other water-soluble ingredients, and homogenizing the oil and aqueous phases to provide a concentrated emulsion. The concentrated emulsion is, brought to final volume with water and again homogenized. The emulsion may be filtered. Finally, tromethamine is added. Alternatively, tromethamine may be added initially in the aqueous phase. The formulation is sterilized.
The water-inmmiscible solvent is suitably present in an amount that is up to 30% by weight of the composition, more suitably 5-25%, preferably 10-20% and in particular about 10%.
A wide range of water-immiscible solvents can be used in the compositions of the present invention. Typically the water-immiscible solvent is a vegetable oil, for example, soy bean, safflower, cottonseed, corn, sunflower, arachis, castor or olive oil. Preferably the vegetable oil is soy bean oil. Alternatively, the water-immiscible solvent is an ester of a medium or long-chain fatty acid for example a mono-, di-, or triglyceride; or is a chemically modified or manufactured palmitate, a glyceral ester or polyoxyl hydrogenated castor oil. In a further alternative the water-immiscible solvent may be a marine oil, for example cod liver or another fish-derived oil. Suitable solvents also include fractionated oils for example fractionated coconut oil or modified soy bean oil. Furthermore, the compositions of the present invention may comprise a mixture of two or more of the above water-immiscible solvents.
The oil phase, comprising propofol and a water immiscible solvent, is homogenized with an aqueous phase comprising a surfactant to provide a concentrated emulsion. The surfactant may be present in amounts of no more than about 2%, more suitably about 1% to about 2% by weight, and preferably about 1.2% by weight of the composition. Suitable surfactants include synthetic non-ionic surfactants, for example ethoxylated ethers and esters and polypropylene-polyethylene block co-polymers, and phosphatides for example naturally occurring phosphatides such as egg and soya phosphatides and modified or artificially manipulated phosphatides (for example prepared by physical fractionation and/or chromatography), or mixtures thereof. Preferred surfactants are egg and soya phosphatides. Most preferred is egg lecithin.
Tonicity modifiers are compounds which make the composition isotonic with blood. Tonicity modifiers are suitably present in amounts of no more than about 3% by weight, more preferably about 1% to about 2.5% and most suitably about 2.25% by weight of the total composition. Suitable tonicity modifiers include glycerin.
Compositions of the present invention are suitably formulated to be at alkaline pH. In some preferred embodiments the pH ranges from about 8.5 to about 10.0. In more preferred embodiments pH ranges from about 9.5 to about 10.0. If necessary pH may be adjusted by means of alkali such as sodium hydroxide or acid such as hydrochloric acid.
The composition of the present inventions are typically sterile aqueous formulations and are prepared according to conventional manufacturing techniques using, for example, aseptic manufacture or terminal sterilization by autoclaving.
Compositions of the present invention are useful as anaesthetics which includes sedation and induction and maintenance of general anaesthesia. Accordingly in another aspect the present invention provides a method of producing anaesthesia (including sedation and induction and maintenance of general anaesthesia) in warm-blooded animals, including humans, which comprises administering parenterally a sterile aqueous pharmaceutical composition which comprises an oil-in-water emulsion of propofol and tromethamine.
Dosage regimes will be appreciated by those skilled in the art an

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