Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-08-08
2002-09-03
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C514S722000, C514S816000
Reexamination Certificate
active
06444859
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to stable, anesthetic fluoroether compositions that do not degrade in the presence of a Lewis acid. The present invention also relates to a method of inhibiting the degradation of fluoroethers in the presence of Lewis acids.
BACKGROUND OF THE INVENTION
Fluoroether compounds are commonly employed as anesthetic agents. Examples of fluoroether compounds used as anesthetic agents include sevoflurane (fluoromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether), enflurane ((±)-2-chloro-1,1,2-trifluoroethyl difluoromethyl ether), isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether), methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether), and desflurane ((±)-2-difluoromethyl 1,2,2,2-tetrafluoroethyl ether).
Although fluoroethers are excellent anesthetic agents, it has been discovered that some fluoroethers experience stability problems. More specifically, it has been determined that certain fluoroethers, in the presence of one or more Lewis acids, degrade into several products including potentially toxic chemicals such as hydrofluoric acid. Hydrofluoric acid is toxic by ingestion and inhalation and is highly corrosive to skin and mucous membranes. Thereupon, the degradation of fluoroethers to chemicals such hydrofluoric acid is of great concern to the medical community.
Degradation of fluoroethers has been found to occur in glass containers. The degradation of fluoroethers in glass containers is believed to be activated by trace amounts of Lewis acids present in the container. The source of the Lewis acids can be aluminum oxides, which are a natural component of glass. When the glass wall becomes altered or etched in some manner, the aluminum oxide become exposed and come into contact with the contents of the container. The Lewis acids then attack the fluoroether and degrade it.
For example, when the fluoroether sevoflurane is contacted with one or more Lewis acids in a glass container under anhydrous conditions, the Lewis acid initiates the degradation of sevoflurane to hydrofluoric acid and several degradation products. The degradation products of sevoflurane are hexafluoroisopropyl alcohol, methyleneglycol bishexafluoroisopropyl ether, dimethyleneglycol bishexafluoroisopropyl ether and methyleneglycol fluoromethyl hexafluoroisopropyl ether. The hydrofluoric acid proceeds to further attack the glass surface and expose more of the Lewis acid on the glass surface. This results in further degradation of sevoflurane.
The degradation mechanism of sevoflurane in the presence of a Lewis acid can be illustrated as follows:
Abbv.
Compound Name
Structure
HFIP
hexafluoroisopropyl alcohol
(CF
3
)
2
CHOH
P1
methyleneglycol bishexafluoroisopropyl
(CF
3
)
2
CHOCH
2
OCH(CF
3
)
2
ether
P2
dimethyleneglycol bishexafluoroisopropyl
(CF
3
)
2
CHOCH
2
OCH(CF
3
)
2
ether
S1
methyleneglycol fluoromediyl
(CF
3
)
2
CHOCH
2
OCH
2
F
hexafluoroisopropyl ether
Therefore, a need exists in the art for a stable anesthetic composition containing fluoroether compounds that does not degrade in the presence of a Lewis acid.
SUMMARY OF THE INVENTION
The present invention involves a stable anesthetic composition that contains a fluoroether compound having an alpha fluoroether moiety having added thereto an effective stabilizing amount of a Lewis acid inhibitor. The preferred fluoroether compound is sevoflurane and the preferred Lewis acid inhibitor is water. The composition can be prepared by adding the Lewis acid inhibitor to the fluoroether compound, by adding the fluoroether compound to the Lewis acid inhibitor, or by washing a container with the Lewis acid inhibitor and then adding the fluoroether compound.
The present invention also involves a method for stabilizing a fluoroether compound having an alpha fluoroether moiety. The method involves adding an effective stabilizing amount of a Lewis acid inhibitor to the fluoroether compound to prevent the degradation of the fluoroether compound by a Lewis acid. The preferred fluoroether compound is sevoflurane and the preferred Lewis acid inhibitor is water.
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A. Carre, F. Roger, and C. Varinot, “Study of Acid/Base Properties of Oxide, Oxide Glass, and Glass-Ceramic Surfaces,”Journal of Colloid and Interface Science, vol. 154, No. 1, Nov. 1972.
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XP-002061443; “The Degradation, Absorption, and Solubility of Volatile Anesthetics in Soda Lime Depend on Water Content”; David P. Strum, MD, FRCP, and Edmond I. Eger II, MD; vol. 78, No. 2; Feb. 1994; Baltimore; pp. 340-348.
Smith, I. et al., Comparison of Induction, Maintenance, and Recovery Characteristics of Sevoflurane—N2O and Propofol-Sevoflurane-N2O with Propofol Isoflurane—N2O Anesthesia. Anes. Analg. vol. 74, pp. 253-259, 1992.
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Bieniarz Christopher
Chang Steve H.
Cromack Keith R.
Huang Shuyen L.
Kawai Toshikazu
Abbott Laboratories
Aulakh Charanjit S.
Woodsworth Brian R.
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