Propofol formulation with enhanced microbial inhibition

Details Propofol formulation with enhanced microbial inhibition Propofol formulation with enhanced microbial inhibition

2000-12-20

2002-06-04

Tate, Christopher R. (Department: 1651)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Biocides; animal or insect repellents or attractants

C424S757000, C514S731000, C514S816000, C514S938000

Reexamination Certificate

active

06399087

ABSTRACT:

TECHNICAL FIELD
The invention generally pertains to optimized pharmaceutical formulations of a drug known as Propofol, which is an intravenous anesthetic with enhanced micorbial inhibition. More particularly, the invention pertains to an optimized Propofol emulsion formulation that is shown to be bacteriostatic or fungistatic and in some formulations bactericidal and fungicidal without using a preservative or other antimicrobial agents.
BACKGROUND ART
Propofol (2,6-Diisopropylphenol) is a well-known and widely used intravenous anesthetic agent. For example, in intensive care units (ICU) where the duration of treatment may be lengthy, Propofol has the advantage of a rapid onset after infusion or bolus injection plus a very short recovery period of several minutes, instead of hours.
Propofol is a hydrophobic, water-insoluble oil. To overcome the solubility problem, it must be incorporated with solubilizing agents, surfactants, solvents, or an oil in water emulsion. There are a number of known Propofol formulations, such as disclosed in U.S. Pat. Nos. 4,056,635, 4,452,817 and 4,798,846 all of which are issued to Glen and James.
There are two major problems associated with the formulations described in the above patents: (1) the risk of microbial contamination due to the high nutrient content and lack of antimicrobial preservatives. Studies by Arduino, et al., 1991; Sosis & Braverman, 1993; and PDR, 1995, have shown that a Propofol emulsion formulated without preservatives will grow bacteria and present a risk of bacterial contamination. (2) Hyperlipidemia in patients undergoing long-term ICU sedation due to a large amount of fat content. Studies have shown that triglyceride overload can become a significant problem when a 1% Propofol/10% soybean oil emulsion is used as the sole sedative for a long period of ICU sedation by Gottardis, et al., 1989; DeSoreruer, et al., 1990; Lindholm, 1992; and Eddieston, et al, 1991.
To solve the problem of bacterial contamination of Propofol emulsion, the following patented formulations of Propofol have been developed:
PATENT NO.
INVENTOR
ISSUED
5,637,625
Duncan H. Haynes
10 June 1997
5,714,520
Christopher B. J., et al
 3 February 1998
6,028,108
Mary M. G.
22 February 2000
6,100,302
Satish K. P., et al
 8 August 2000
PCT W.O. 99/396,96
Mirejovsky D., et al
12 August 1999
PCT W.O. 00/24376
Mary T., et al
 4 May 2000
The formulations described in U.S. Pat. No. 5,714,520 is sold as DIPRIVAN
(R)
and comprises a sterile, pyrogen-free emulsion containing 1% (W/v) Propofol in 10% (w/v) soybean oil. The formulation also contains 1.2(w/v) egg lecithin as a surfactant, 2.25% (w/v) glycerol to make the formulation isotonic, sodium hydroxide to adjust the pH, and EDTA 0.0055% (w/v) as a preservative. This formulation prevents no more than a 10-fold increase against gram negative (such as
Pseudomonas aeruginosa
and
Escherichia coli
) and gram positive (
Staphylococcus aureus
) bacteria, as well as yeast (such as
Candida albicans
) over a twenty-four hour period. However, EDTA, which is a metal ion chelator, remove cations like calcium magnesium and zinc. This can be potentially dangerous to some patients with low calcium or other low cation levels, and especially critical for ICU patients.
In U.S. Pat. No. 6,028,108 the Propofol formulation contains pentetate 0.0005% (w/v) as a preservative to prevent microbial contamination. Pentetate is a metal ion chelator similar to EDTA and therefore represents the same potential danger.
The formulation described in W.O. Patent No. 99/39696, is generic Propofol containing 0.25 mg/mL sodium metabisulfite as a preservative to prevent microbial growth. At 24 hours there is no more than a one log increase. Recently, P. Langevin, 1999, has expressed concern that generic Propofol containing 0.25 mg/mL sodium metabisulfite, infused at a rate of 50 ug/kg/min, will result in sulfite administration approaching the toxic level (i.e., near the LD50 for rats) in about 25 hours. Particularly, the addition of sulfites to this drug is worrisome for the potential effects to the pediatric population.
The formulation described in PCT W.O. Patent No. 00/24376 is a formulation having an antimicrobial agent, which is a member selected from the group consisting of benzyl alcohol and sodium ethylenediamine tetraacetate, benzethonium chloride; and benzyl alcohol and sodium benzoate. The formulation contains EDTA, which was mentioned as related to the side effect above. Benzyl alcohol is linked to adverse reactions reported by Evens and Lopez-Herce, et al. The formulation may be unsafe upon administration, particularly to those patients who need an extended period of ICU sedation.
The formulation described in U.S. Pat. No. 5,637,625 is of phospholipid-coated microdroplets of Propofol, containing 6.8% Propofol with no soybean oil. However, it is believed that this formulation may increase injection site pain to an unacceptable level during administration.
The formulation described in U.S. Pat. No. 6,100,302 is an emulsion of Propofol that contains 1-3% of soybean oil to prevent against accidental microbial contamination during long-term IV infusions due to an increased availability of Propofol. However, the formulation containing 2% of soybean oil can not prevent a less than one log increase for
E. coli
at 48 hours.
Particularly, the formulation comprising 3% of soybean oil has more than a 10-fold increase for E. coli at 24 hours, which fails to meet current industry standards to prevent no more than one log increase in microbial growth at 24 hours. It appears that upon administration this formulation may also increase the problem of pain on injection due to a higher partition of Propofol in the aqueous phase. This has been studied by M. Eriksson, et al 1997.
The problems described above are addressed by developing an optimized Propofol formulation provided in the present invention. Propofol is a hindered phenol. Phenol shows substantial antimicrobial activity in low pH solutions (Arthur H. Kibbe, 2000). It has been found in this invention that a Propofol formulation with a low pH is more effective in inhibiting microbial growth as shown in
FIGS. 2 and 3
. Also, the lower pH in the formulation reduces the concentration of Propofol anions. As Propofol is a weak acid with a pKa of 11, such an effect would result in reduced pain on injection, which has been studied by W. Klement, et al., 1991 and J. Babl 1995.
Egg lecithin is mainly used in pharmaceutical products as a dispersing, emulsifying, and stabilizing agent. The lecithin is also used as component of enteral and paranteral nutrition formulations, Arthur H. Kibbe, 2000.
It has been also found that in this invention a Propofol formulation containing a reduced amount of egg lecithin results in a significant increase in the ability to be antimicrobial as shown in FIG.
4
. The soybean oil is also source of nutrition to support the microbial growth. As shown in
FIG. 2
, this invention shows that the high amount of soybean oil in the formulation increases microbial growth.
Thus, it has been found that the preservative-free, optimized Propofol formulation of this invention addresses the prior art problems to the point where the problems are eliminated or at the least are substantially reduced.
DISCLOSURE OF THE INVENTION
Accordingly, the present invention provides an optimized, sterile formulation of Propofol for parenteral administration containing a reduced amount of egg lecithin and soybean oil triglycerides. The formulation is preferably comprised of an oil in water emulsion with a particle range of about 200 to 400 nonometers in diameter, in which the Propofol is dissolved in a water-immiscible solvent such as soybean oil, and stabilized by a surfactant such as egg lecithin. The low amount of lecithin and soybean oil, with a pH 5.0-7.5 range for the Propofol formulation, has a number of advantages:
(1) eliminating of preservatives,
(2) providing formulations with excellent exhibition of antimicrobial activity compared to formulations with higher amount of lecithin and oi

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