Anaesthetic mixtures containing enflurane or isoflurane in combi

Details Anaesthetic mixtures containing enflurane or isoflurane in combi Anaesthetic mixtures containing enflurane or isoflurane in combi

1997-03-07

1998-07-21

Kishore, Gollamudi S.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

424 40, 514816, A61K 900

Patent

active

057831998

DESCRIPTION:

BRIEF SUMMARY
This is 371 of International Patent Application PCT/GB95/02021, filed Aug. 25, 1995, and claiming priority based on British Patent Application No. 9418532.9, filed Sep. 14, 1994.
The present invention relates to anaesthetic gas mixtures and particularly to anaesthetic analgesic gas mixtures.
Entonox is a 50% admixture of oxygen and nitrous oxide and is used as a gaseous analgesic. Unfortunately nitrous oxide oxidizes the cobalt in Vitamin B.sub.12 so rendering it inactive. Prolonged administration of nitrous oxide either continuously or intermittently, can cause megaloblastic anaemia, degeneration of the spinal cord and depression of white cell formation. The dosage required to produce this effect with regard to intermittent exposures is not known. A large number of patients who require daily wound dressings, or who are subjected to other brief painful procedures, receive Entonox. This is not a problem for a limited number of uses, but for repeated use the problems for accumulated toxicity become real and there is a need for a gaseous analgesic gas of a similar potency and speed of onset to Entonox, but without the potential cumulative toxicity of nitrous oxide.
In our British Patent Application No. 9418532.9, we have described the addition of isoflurane and other ether based anaesthetic gases to Entonox to allow for more prolonged pain relief. We have now found that under suitable conditions, nitrous oxide may be replaced completely by an admixture of at least two anaesthetic analgesic gases having the correct relative properties.
The speed and onset of a gaseous agent is related to its solubility in the blood. For an agent of low solubility, a small mass of gas is removed from the lung-gas space by the blood. A high partial pressure is therefore maintained in the lung space (Alveoli) which ensures in turn a high partial pressure of the agent in the blood.
The pharmacological effect of such an agent is determined by arterial blood partial pressure. Nitrous oxide has a rapid onset to action since it has a blood/gas solubility co-efficient .lambda. of 0.4. Halothane has as much slower onset of action (.lambda.=2.4). Enflurane (.lambda.=1.9) and Isoflurane (.lambda.=1.4) are intermediate in onset while Sevoflurane (.lambda.=0.6-0.7) and Desflurane (.lambda.=0.42) have blood/gas solubility co-efficient close to that of nitrous oxide (0.46) and hence similar speeds of onset. The speed of onset is therefore predicated on an analgesic anaesthetic gas mixture incorporating agents with a fast onset and with a slower onset.
The time taken for the analgesic properties of a gaseous agent to wear off is determined again by blood/gas solubility but fast palinalgesia (offset of action) is not a desirable property for an analgesic since it is better if painful sensation returns gradually so that the patient can deal with it either by further self-administration or by mental readjustment. The ideal gaseous analgesic composition would therefore benefit from having a more soluble agent which delays analgesia and allows some accumulation of effect between inhalations. Inter alia, isoflurane has this effect when combined with Entonox as set out in our above-identified British Patent Application.
According therefore to the present invention, there is provided a high pressure pre-mixed analgesic anaesthetic gas composition comprising a life supporting gas and a volatile analgesic anaesthetic mixture, characterised in that the mixture comprises a first and second anaesthetic analgesic, said first analgesic having a blood/gas solubility co-efficient .lambda. significantly in excess of the .lambda. of the second analgesic. In one embodiment of the invention, the second analgesic may have a .lambda. value between about 25 to 50% of the first analgesic. Alternatively the first analgesic may have a blood/gas solubility co-efficient .lambda. above 1.0 and a second analgesic anaesthetic having a blood/gas solubility co-efficient below .lambda.1.0.
In a preferred embodiment, the .lambda. of the first analgesic may have a value above 1.3

REFERENCES:
patent: 4855511 (1989-08-01), Halpern et al.
patent: 4874901 (1989-10-01), Halpern et al.
patent: 5114714 (1992-05-01), Young et al.
patent: 5114715 (1992-05-01), Young et al.
Ornstein, E. et al. "Desflurane and Isoflurane Have Similar Effects on Cerebral Blood Flow in Patients with Intracranial Mass Lesions" Anesthesiology, vol. 79, No. 3, Sep. 1993.
Ornstein, E. et al. "Desflurane and isoflurane have similar effects . . . " Anesthesiology, vol. 79 No. 3, 1993, pp. 498-502.

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