Injectable dispersion of propofol

Details Injectable dispersion of propofol Injectable dispersion of propofol

2001-06-14

2004-04-27

Page, Thurman K. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S451000, C424S489000, C424S642000, C424S643000, C514S487000, C514S731000

Reexamination Certificate

active

06726919

ABSTRACT:

This invention relates to processes and compositions and methods of use of formulations containing propofol (2,6-diisopropylphenol) and one or more antimicrobial agent.
BACKGROUND
Formulations containing propofol for injection can be used in clinical settings for production and maintenance of ambulatory anesthesia, neurosurgical anesthesia, neuroanesthesia, pediatric anesthesia, monitored anesthesia care (MAC) sedation, intensive care (ICU) sedation, cardiac anesthesia, and in other clinical situations (see for example, Smith, I., White, P. F., Nathanson, M. and Gouldson, R. (1994) “Propofol—An update on its clinical use,” Anesthesiology, 81, 1005-1043).
U.S. Pat. Nos. 4,056,635 and 4,452,817 disclose compositions containing propofol suitable for parenteral administration to produce anesthesia in warm-blooded animals as mixtures of propofol with surfactants such as CREMOPHOR-RH40™, CREMOPHOR-EL™, and TWEEN-8 ™ in an aqueous medium that may also contain ethanol or other pharmaceutically acceptable ingredients.
U.S. Pat. No. 4,798,846 discloses sterile propofol compositions containing 1% to 2% propofol alone or dissolved in oil such as arachis oil or ethyl oleate. These formulations are stabilized with surfactants.
A propofol preparation for clinical use is commercially available as DIPRIVAN® 1% Injection. This contains propofol dissolved in soybean oil as an emulsion stabilized with egg lecithin in water. Each milliliter of this formulation consists of 10 mg/mL of propofol, 100 mg/mL of soybean oil, 22.5 mg/mL of glycerol, 12mg/mL of egg lecithin, and disodium edetate (0.005%). This product formulation requires strict aseptic technique during handling, and a vial of the product can be used only once because of the ease of microbial contamination in a clinical use setting.
Incidences of serious infection in human subjects have been linked to the use of DIPRIVAN. For example, see Nichols, R. L. and Smith, J. W. (1995) “Bacterial Contamination of an Anesthetic Agent,” New Eng. J. Med., 333(3), 184-185; Tessler, M., Dascal, A., Gioseffini, S., Miller, M. and Mendelson, J. (1992) “Growth curves of
Staphyloccoccus aureus, Candida albicans
and
Moraxella osloensis
in propofol and other media,” Can. J. Anaesth. 39(5), 509-511; Ardulno, M. J., Bland, L. A., McAllister, S. K., Aguero, S. M., Villarino, M. E., McNeil, M. M., Jarvis, W. R. and Favero, M. S. (1991) “Microbial Growth and Endotoxin Production in the Intravenous Anesthetic Propofol,” Inf. Control Hosp. Epidem., 12(9), 535-539; Sosis, M. B. and Braverman, B. (1993) “Growth of
Staphylococcus aureus
in Four Intravenous Anesthetics,” Anesth. Anal. 77, 766-768; Sosis, M. B., Braverman, B. and Villaflor, E. (1995) “Propofol, but not Thiopental, Supports the Growth of
Candida albicans
,” Anesth. Anal. 81, 132-134; Crowther, J., Hrazdil, J., Jolly, D. T., Galbraith, J. C., Greacen, M. and Grace, M. (1996) “Growth of Microorganisms in Propofol, Thiopental and a 1:1 Mixture of Propofol and Thiopental,” Anesth. Anal. 82, 475-478; and Center for Disease Control report, New England Journal of Medicine (1995) Vol. 333, No 3, pp 184-5 and the accompanying editorial in the same issue.
DIPRIVAN can exhibit a thrombogenic potential in clinical use. Symptoms span the range of thrombosis and phlebitis and include incidences of burning, stinging or sensations of pain (see Physicians Desk Reference 1999, page 3416).
U.S. Pat. Nos. 5,714,520, 5,731,355 and 5,731,356 disclose propofol formulations containing disodium edetate as a preservative in amounts sufficient to prevent no more microbial growth than a 10-fold increase over 24 hours after adventitious extrinsic contamination with the microorganisms
Staphylococcus aureus
ATCC 6538
, Escherichia coli
ATCC 8739
, Pseudomonas aeruginosa
ATCC 9027 and
Candida albicans
ATCC 10231. However, this formulation is not considered to be an antimicrobially preserved product under USP standards as exemplified in Sklar, G. E. (1997) “Propofol and postoperative infections,” Ann Pharmacother, 31, 1521-3. Edetate may not be effective as a preservative against growth of microorganisms in a DIPRIVAN formulation if challenged by organisms other than those cited above or by higher loads of organisms, i.e., exceeding 100 CFU/mL.
U.S. Pat. No. 6,140,374 discloses the use of a number of antimicrobial agents in propofol containing oil-in-water emulsions including combinations of edetate and benzyl alcohol.
U.S. Pat. No. 6,028,108 discloses a sterile oil-in-water emulsion of propofol and an amount of pentetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination.
U.S. Pat. No. 6,177,477 discloses a sterile oil-in-water emulsion of propofol and an amount of tromethamine (TRIS) sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination.
U.S. Pat. No. 6,147,122 discloses a sterile oil-in-water emulsion of propofol and an amount of sulfite sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious contamination.
Pain on injection of commercial formulations of propofol has been reported to occur in many patients; for example, see Mirakhur, R. K. (1988) “Induction characteristics of propofol in children: Comparison with thiopentone,” Anesthesia, 43, 593-598; Stark, R. D., Binks, S. M., Dukta, V. N., O'Connor, K. M., Arnstein, M. J. A., Glen, J. B. (1985) “A review of the safety and tolerance of propofol (‘Diprivan’),” Postgrad. Med. J., 61 S, 152-156; and Mangar, D. and Holak, E. J. (1992) “Tourniquet at 50 mm Hg followed by intravenous lidocain diminishes hand pain associated with propofol injection,” Anesth. Analg., 74, 250-252. Even with a low dose of propofol administered for sedation, the incidence of pain can be high; for example, see White, P. F. and Negus, J. B. (1991) “Sedative infusions during local and regional anesthesia: A comparison of midazolam and propofol,” J. Clin. Anesth., 3, 32-39; and Ghouri, A. F., Ramirez Ruiz, M. A., and White, P. F. (1994) “Effect of flumazenil on recovery after midazolam and propofol sedation,” Anesthesiology, 81, 333-339.
The mechanism or mechanisms responsible for venous pain on propofol administration are unknown. No measurable reduction in pain was detected clinically after a change from a CREMOPHOR-EL based propofol formulation to the currently marketed soybean oil and lecithin based formulation; for example, see Mirakhur, R. K. (1988), Stark et al. (1985), Mangar and Holak (1992), White and Negus (1991), and Ghouri et al. (1994) herein.
Pain at the site of injection of propofol may be related to the concentration of propofol; for example, see Smith, I., White, P. F., Nathanson, M. and Gouldson, R. (1994) “Propofol—An update on its clinical use.” Anesthesiology, 81, 1005-1043.
Compositions containing 1% and 2% propofol and a mixture of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) in a dispersed oil phase have produced lowered propofol concentrations in an aqueous phase; see for example Babl, J., Doenicke, A., and Monch, V. (1995) “New propofol LCT/MCT fat emulsions as solvent. Approach to reducing pain on injection of propofol,” Eur. Hosp. Pharmacy, 1, 15-21 and Doenicke, A. W., Babl, J., Kellermann, W., Rau, J., and Roizen, M. F. (1996) “Reducing pain during propofol injection: the role of the solvent,” Anesth. Analg., 82, 472-4.
While the use of medium chain triglycerides in a propofol formulation in human volunteers can lower the incidence of severe or moderate pain on injection relative to that seen after injection of a commercially available propofol formulation, significantly higher amounts of oil (up to 20% w/v MCT, LCT, and vegetable oil) were required to produce the result (see for example Doenicke, A. W., Babi, J., Klotz, U., Kugler, J., O'Connor, M., Rau, J., Roizen, M. F. (1997) “Pharmacokinetics and pharmacodynamics of propofol in a new solvent,” Anesth. Analg., 85, 1399-403; Babl et al. (1995); and Doenicke et al. (1996 and 1997).
In an experimental

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