Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-03-10
2001-03-06
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C514S816000, C514S937000
Reexamination Certificate
active
06197323
ABSTRACT:
The invention relates to a liquid preparation containing a lipophilic inert gas in a pharmacologically effective concentration.
Lipophilic inert gases are inert gases which have a degree of solubility in fat. This is expressed for example as an oil/gas partition coefficient of more than about 0.05 (krypton, 0.5; argon, 0.15; xenon, 1.9). Typically an oil such as n-octanol or olive oil is employed to measure such a coefficient. Alternatively lipophilicity of the inert gases may be defined with reference to the so-called Ostwald solubility (cf. Gerald L. Pollack et al. in J.Chem.Phys. 90 (11), 1989, “Solubility of xenon in 45 organic solvents including cycloalkanes, acids, and alkanals: experiment and theory”). The Ostwald solubility is the ratio of the concentration of dissolved gas molecules in a liquid solvent to their concentration in the gas phase at equilibrium. Thus the Ostwald solubility at 25° C. for xenon is about 4.8 in n-hexane. Accordingly the term lipophilic here defines a gas or a gas mixture (under standard conditions) having an Ostwald solubility of greater than about 0.2 in n-hexane at 25° C.
Pharmacologically or pharmaceutically effective is understood here as meaning a concentration in the liquid preparation which is capable of acting as a sedative, anaesthetic, analgesic, anti-inflammatory or muscle relaxant in a patient.
Xenon is being discussed inter alia as an inhalation anaesthetic because this inert gas has an anaesthetizing and analgesic action. As xenon is very expensive, its use as an inhalation anaesthetic involves a high consumption and treatment with a gas is also technically very expensive, anaesthesia with xenon has not been widely accepted. However, because of the obvious advantages of xenon gas compared with other gaseous anaesthetics, attempts are being made to facilitate the large-scale use of xenon, either by obtaining this gas in a simpler and less expensive way or by recovering it from the exhaled air.
Xenon is a colourless, odourless and tasteless monoatomic inert gas of atomic number 54. Xenon is five times denser than air. Naturally occurring xenon also contains isotopes, for example the isotopes 124, 126, 128, 129, 130, 131, 132, 134 and 136. Synthetic isotopes, like xenon 114, xenon 133 and xenon 142, are known as well. These isotopes disintegrate with half-lives of between 1.2 seconds and about 40 days. The present invention does not address such short living radioactive xenon isotopes.
When xenon is used as an inhalation anaesthetic, on the one hand very large amounts are required to achieve an anaesthetic action, and on the other hand the inspiratory concentration is limited to 70% or at most 79% in order to ensure that the patient is supplied with at least 21% of oxygen in the inhaled air. This allows a degree of anaesthesia and analgesia, although on its own this is not sufficient to ensure adequate general anaesthesia in a patient. It therefore has to be supplemented with additional sedatives or intravenous anaesthetics and analgesics. In the case of intra-abdominal or intrathoracic interventions, it also has to be supplemented with muscle relaxants.
It is not known whether an attempt has ever been made to use a liquid preparation containing lipophilic inert gases as an injectable anaesthetic. It is also not known to use such preparations for other medicinal purposes as well, for example for analgesia or sedation.
DE-A-39 40 389 describes a therapeutic agent containing a gas in a concentration which is above its natural degree of saturation with the gas. Among the gases mentioned are atmospheric oxygen, ozone and an inert gas. Said publication explains in detail that the therapeutic agent is to be used for the purposes of emergency medicine and shock treatment, especially when this agent is administered to a patient by infusion as a blood substitute and oxygen transporter. Isotonic saline solution containing up to 40 mg/l of oxygen is indicated in particular as an agent according to the invention. Said publication gives no information about the possible activity of inert gases or the fields of use of an agent containing inert gases.
DE-A-16 67 926 discloses a pharmacologically acceptable salt solution containing a radioactive gas. The present invention does not address radioactive gases.
DE-C-41 00 782 describes aqueous ozone preparations which can be administered to a patient as infusion solutions. However, said publication emphasizes that ozone has certain algicidal, bactericidal, fungicidal, sporicidal and virucidal actions. It further mentions that ozone reacts in fractions of a second with the unsaturated fatty acids in the blood. Because ozone rapidly disintegrates, it is recommended to prepare the infusion solutions at the site of use.
As well as inhalation anaesthetics, injectable anaesthetics are described in the state of the art.Injectable anaesthetics are used either on their own (TIVA) or together with gaseous anaesthetics. Although one of the remarkable features of the intravenous anaesthetics in current use is an immediate onset of action, they regularly exhibit a host of disadvantages. It should be stressed that they develop only a weak pain inhibiting (analgetic) action, if any, and are difficult to control. Thus the advantage of a psychic protection of the patient during the induction of anaesthesia, whereby the patient momentarily loses consciousness and is spared the face mask and the excitation stage, is offset by the disadvantage of the increased risk of anaesthesia. This risk principally derives from the fact that, once the anaesthetic has been injected, the anaesthetist can have effectively no further influence, so the course of the anaesthesia is determined only by the processes occurring in the organism—distribution, enzymatic degradation and inactivation, as well as elimination via the liver and kidney. Other disadvantages of the injectable anaesthetics in current use are side effects which are difficult to assess (for example drop in blood pressure, bradycardia, rigidity, allergic reaction) and in some cases serious contraindications. As known intravenous anaesthetics are frequently administered together with analgesics and muscle relaxants, the latter additionally modify the pharmacokinetics, particularly the half-life, to a considerable extent. Overall, this makes the controllability substantially more difficult.
Anaesthesia consists of hypnosis, analgesia and muscle relexation. However, there is no single intravenous substance, active as an anaesthetic, which can bring about these three components of anaesthesia effectively and safely. This aim is achieved by using active substance combinations. The currently known active substances have a mutually adverse effect as regards both the pharmacodynamics and the pharmacokinetics. In particular, there is an enhancement of side effects which can be not only undesirable but also dangerous in anaesthesia. In particular, these include pronounced effects on the heart and blood vessels and on the cardiovascular control mechanisms.
U.S. Pat. No. 4,622,219 has disclosed a local anaesthetic which can be administered intravenously. This injectable local anaesthetic contains microdroplets composed predominantly of vaporizable anaesthetics, for example methoxyflurane. However, this infusion solution is active exclusively as a local anaesthetic. General anaesthesia or the anaesthesia of a patient is neither described nor considered. It should be emphasized in this connection that methoxyflurane is about 440 times more active than gaseous inhalation anaesthetics like xenon (activity expressed as minimum alveolar concentration of anaesthetic at 1 atm (MAC); MAC values in % by volume: xenon, 71; methoxyflurane, 0.16).
There is consequently an appreciable need for an intravenous anaesthetic of high activity which does not exhibit said disadvantages.
Accordingly it is an object of the present invention to provide a liquid preparation which can be utilized for inducing anaesthesia, sedation, analgesia, and/or muscular relaxation.
A further object of the present invention
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