Medicinal preparation containing a lipophilic inert gas

Description

The invention relates to a liquid composition containing a lipophilic inert gas in a pharmaceutically effective concentration. Lipophilic inert gases are inert gases that are soluble in fat to some extent. The solubility is expressed, for example, as an oil / gas partition coefficient greater than about 0.05 (0.5 for krypton; 0.15 for argon; 1.9 for xenon). Typically, an oil such as octanol or olive oil is used to determine the coefficient. Alternatively, the lipophilicity of inert gases can be determined by the so-called Ostwald solubility (adapted by 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”). Ostwald solubility is the ratio of the concentration of gas molecules dissolved in a liquid solvent to the concentration of gas molecules in the gas phase at equilibrium. Thus, the Ostwald solubility of xenon in n-hexane is around 4.8 at 25 °C.Accordingly, the term lipophilic is defined herein as a gas or gas mixture having an Ostwald solubility greater than about 0.2 in n-hexane at 25°C. The term pharmacologically or therapeutically effective refers to a concentration in a liquid formulation that is capable of exerting a sedative, anesthetic, analgesic, anti-inflammatory, or muscle relaxant effect in patients. Xenon is also referred to as an inhalation anesthetic, as this inert gas has anesthetic and analgesic effects. Since xenon is very expensive, large quantities are needed for its use as an inhalation anesthetic, and the technical solution for treating with the gas is also very expensive, anesthesia with xenon is not widely accepted. However, due to the obvious advantages of xenon gas compared to other gaseous anesthetics, attempts are being made to promote the large-scale use of xenon, either by producing the gas in a simpler and less expensive way, or by recovering it from exhaust air. Xenon is a colorless, odorless, and tasteless inert gas with atomic number 54. Xenon is five times denser than air. It also includes naturally occurring xenon isotopes, such as 124, 126, 128, 129, 130, 131, 132, 134, and 136. Synthetic isotopes, such as xenon-114, xenon-133, and xenon-142, are also known. These isotopes decay with half-lives ranging from 1.2 seconds to about 40 days. The present invention does not address short-lived radioactive xenon isotopes. When xenon is used as an inhalation anesthetic, on the one hand, a very large amount is required to produce an anesthetic effect, on the other hand, the inhalation concentration can be a maximum of 70% or a maximum of 79%, because the patient must be provided with at least 21% oxygen in the inhaled air. This allows a certain degree of anesthesia and analgesia, although it is not sufficient in itself to provide adequate general anesthesia in patients. Therefore, this use must be supplemented with inhalation anesthetics, sedatives or intravenous anesthetics and analgesics. In the case of abdominal or thoracic interventions, muscle relaxants must also be administered as a supplement. It is not known whether any attempt has ever been made to use a liquid formulation comprising lipophilic inert gases as an injectable anesthetic. Nor is it known whether such formulations have been used for other medical purposes (such as anesthesia or sedation). DE-A-3940389 discloses a therapeutic agent containing a gas in a concentration higher than the natural gas saturation. Among the gases mentioned are atmospheric oxygen, ozone and an inert gas. The above document explains in detail that the therapeutic agent is to be used for emergency care and shock treatment, in particular when the agent is administered to the patient by infusion as a blood substitute and oxygen carrier. According to the invention, an isotonic saline solution containing up to 40 mg / l oxygen is a particularly preferred agent. The said document does not provide information on the possible effects of inert gases or on the possible uses of an agent containing inert gases. DE-A-1667926 discloses a pharmacologically acceptable saline solution containing a radioactive gas. The present invention does not concern radioactive gases. DE-C-4100782 discloses aqueous ozone preparations which can be administered to the patient as infusion solutions. However, the said document emphasizes that ozone has certain algaecidal, bactericidal, fungicidal, sporicidal and virucidal effects. The document further mentions that ozone reacts with unsaturated fatty acids in the blood within a fraction of a second. Since ozone decomposes quickly, it is recommended that the infusion solution be prepared at the site of application. In addition to inhalational anesthetics, injectable anesthetics are described in the prior art. Injectable anesthetics are used either alone (TIVA) or in combination with gaseous anesthetics. Although one of the important characteristics of currently used intravenous anesthetics is that they are immediate, their use regularly presents a number of disadvantages. It should be emphasized that they have only a weak analgesic (pain-relieving) effect, if any, and are difficult to control. Thus, the advantage of the patient's psychological protection during the induction of anesthesia - i.e. the patient can lose consciousness at any time, can do without the anesthesia mask and is not in a state of excitement - is offset by the disadvantage of the increased risk of anesthesia. This risk mainly stems from the fact that once the anesthetic has been injected, the anaesthetist has virtually no further control over the patient. HU 224 985 Β1 bi influence on the process, so the course of anesthesia is determined only by the processes occurring in the body, such as distribution, enzymatic degradation and inactivation, and excretion via the liver and / or kidneys. Other disadvantages of the widespread use of currently used injectable anesthetics are side effects that are difficult to control (e.g., drop in blood pressure, slowing of the heart rate, rigidity, allergic reactions), and in some cases serious contraindications. Since intravenous anesthetics are often used together with analgesics and muscle relaxants, the latter subsequently significantly modify the mechanism of action of the drug, especially its half-life. All in all, this makes control more difficult. Anesthesia consists of loss of consciousness, absence of pain sensation and muscle relaxation. However, there is no simple intravenous substance effective as an anesthetic that is capable of effectively and safely producing these three components of anesthesia. This goal is achieved by using combinations of active ingredients. The currently known active ingredients have a mutually unfavorable effect on both their pharmacodynamics and pharmacokinetics. In particular, side effects are emphasized that are not only undesirable but can be downright dangerous during anesthesia. These include, in particular, strong effects on the heart, blood vessels and cardiovascular control processes. US-A-4 622 219 describes a local anesthetic which can be administered intravenously. This injectable local anesthetic contains microdroplets which consist predominantly of a nebulizable anesthetic, such as methoxyflurane. However, this infusion solution is effective only as a local anesthetic. General anesthesia or anesthesia of a patient has not been described or investigated. In this connection, it should be emphasized that methoxyflurane is approximately 440 times more active than gaseous inhalation anesthetics such as xenon [activity is expressed as the minimum alveolar concentration of the anesthetic at 1 atm (MAC); MAC values ​​in volume %: xenon, 71; methoxyflurane, 0.16], Consequently, there is a great need for a highly active intravenous anesthetic that does not exhibit the aforementioned disadvantages. Thus, it is an object of the present invention to provide a liquid composition that can be used for anesthesia, sedation, analgesia and / or muscle relaxation. A further object of the invention is to provide a liquid composition for use in the therapy of inflammation. It is a further object of the invention to provide an infusion agent for inducing or maintaining anesthesia which overcomes all or part of the above-mentioned disadvantages of the prior art. In a broad sense, the invention provides a liquid composition containing a lipophilic inert gas in dissolved or dispersed form in the form of an emulsion. The present invention is particularly intended to utilize xenon and / or krypton gases or mixtures thereof. As will be described in more detail below, the compositions of the invention surprisingly exert a systemic effect on the central nervous system. In contrast to the physiological limitations of the use of inert gases as inhalation anesthetics, which we have described in connection with xenon, the anesthetic possibilities of intravenous administration of a lipophilic inert gas (e.g. xenon) are completely different. These allow for previously unknown developments, which are particularly beneficial for patient safety. Even preparations containing very small amounts of xenon produce strong anesthesia and analgesia. This is completely surprising. We have shown that xenon has no adverse effect on the myocardium. Xenon also has no effect on the cardiac conduction system. Thus, the inert gas has no adverse effect at all on the heart rhythm or the contractility of the heart muscle.The composition of the invention enables both complete anesthesia and analgesia in patients, which makes subsequent supplementation with other intravenous sedatives, anesthetics or analgesics unnecessary. It is also possible to use a dose that induces central muscle relaxation, thus making supplementation with a muscle relaxant unnecessary. In this way, the patient can already be subjected to anesthesia, analgesia and muscle relaxation during the induction of anesthesia by means of monointravenous anesthesia using a lipophilic inert gas, so that intubation can be performed without problems. Furthermore, problems have been reported when using xenon as an inhalation anesthetic in patients suffering from lung diseases (such as asthma and others) in which the air flow is obstructed for some reason (obstructive). The present invention also provides a solution for patients with such problems. It has been found that, in contrast to the use of xenon as an inhalation anesthetic, the dosage requirement is reduced and the anesthetic effect is more rapid to occur and to begin with. It appears that the liquid formulation of the present invention alters the disposition of xenon and, possibly, the uptake and distribution of xenon into the tissues. One possible explanation may be that liquid formulations (i.e., emulsions) restrict xenon within the vascular system and reduce the volume of distribution. Another explanation for the effect of xenon in the form of a liquid formulation may be that the emulsion vesicles of the liquid formulation of the present invention may reduce the volume of the first expiratory flow from the lungs, accelerate the pulmonary transport of xenon, and reduce the volume of the pulmonary circulation. HU 224 985 Β1 potency after intravenous administration, or both are possible. The invention also opens up new possibilities for supplementing intravenous therapy, for example when a patient requires additional sedation. This includes, among others, therapeutic forms of renal therapy such as hemofiltration, hemodiafiltration, hemodialysis, extracorporeal membrane oxygenation, extracorporeal CO2 removal and cardiopulmonary bypass. In such cases, xenon can be administered to patients as part of the appropriate therapeutic regimen. The composition of the invention can be administered as an infusion and / or the blood can be enriched with xenon. According to the invention, we provide liquid compositions which, based on a certain lipophilicity value, can easily absorb a fat-soluble gas, such as the aforementioned xenon or krypton. Examples of such fluids are blood substitutes, especially perfluorocarbon emulsions (e.g. perflubron). Perfluorocarbons can be administered intrapulmonarily, and when loaded with xenon, they can be used to treat acute lung injury, as well as to induce anesthesia, sedation, and / or analgesia, based on the pharmacological effects of xenon. Intrapulmonary administration of perfluorocarbons in combination with xenon is a novel approach to partial fluid gas exchange, anesthesia, or other pain relief in the treatment of severe respiratory crises. This reopens collapsed, atelectatic areas of the lung that are inaccessible to conventional therapy, thereby preparing these areas of the lung for renewed gas exchange. Perfluorocarbons can also be administered intravenously, so that the perfluorocarbon-based composition according to the invention can be used for intravenous anesthesia with the aid of xenon. However, perfluorocarbons also have a capacity for oxygen, thus offering the possibility of intravenous administration of perfluorocarbons saturated with oxygen at the same time. Thus, not only induction of anesthesia is possible, but also induction of anesthesia and (supplementary) oxygen supply. Consequently, any difficult intubations can be performed with a hitherto unknown degree of patient safety, namely avoiding hypoxia. It is generally known that many gases are well soluble in perfluorocarbon compounds. For example, the perfluorocarbon emulsion of the invention consists of up to 90% (w / v) perflubron (C8F17). Emulsifying agents, such as phospholipids derived from chicken egg yolk, are also required. These emulsions, which can be saturated with xenon according to the present invention, are described, for example, in the publication of JA Wahr et al. Anesth. Anal. 1996, 82, 103-7. Suitable fluorocarbon emulsions preferably contain from 20% w / v to 125% w / v of a highly fluorinated hydrocarbon compound, such as polyfluorobis(alkylethenes), cyclic fluorocarbon compounds such as fluorodecalin or perfluorodecalin, fluoroadamantane, or perfluoroamines such as fluorotripropylamine and fluorotributylamine. Monobromoperfluorocarbons such as 1-bromoheptadecafluorooctane (C8F17Br), 1-bromopentadecafluoroheptane (C7F15Br) and 1-bromotridecafluorohexane (C6F13Br) may also be used. Other compounds may also be used, including perfluoroalkyl ethers or polyethers, such as (CF3)2CFO(CF2CF2)2OCF(CF3)2, (CF3)2CFO(CF2CF2)3OCF(CF3), (CF3)2CFO(CF2CF2)2F, (CF3)2CFO(CF2CF2)3F and (θ6^ 13)2θ· Chlorinated derivatives of the aforementioned perfluorocarbons can also be used. The saturation capacity of the said perfluorocarbon composition is significant. Thus, for example, a xenon saturation of 1-10 ml / ml (at a temperature of about 20 °C under standard conditions) has been achieved using the simplest methods. These compositions can be saturated with the inert gas, for example, simply by flowing the gas through the compositions. The volume of gas contained in the liquid composition of the invention can be measured by simple methods known to those skilled in the art, such as gravimetry, other analytical methods, or, for example, by monitoring measurements with radioactive xenon (e.g., xenon-133) as described by Gerald L. Pollack (see above). The invention further provides (oily) emulsions containing the lipophilic inert gas in dissolved or dispersed form in a lipid phase. It has been found that xenon can be added to an (oil) emulsion in appreciable amounts. Thus, xenon can be dissolved or dispersed in concentrations of 0.2 to 10 ml or more / ml emulsion even by the simplest methods (the concentration values ​​refer to standard conditions, e.g. 20 °C and normal pressure). The concentration of xenon depends on a large number of factors, in particular the concentration of the oil or lipophilic compound. The compositions according to the invention can usually be "filled" with xenon up to the saturation limit. However, very low concentrations are also possible, provided, for example, that pharmacological activity can still be observed during intravenous treatment. With a 10% oil emulsion, it is easily possible to achieve concentrations of 0.3 to 2 ml xenon / ml emulsion. Of course, higher values ​​are also possible, e.g. 3, 4, 5, 6 or 7 ml xenon / ml emulsion.These oil emulsions are at least reasonably stable when stored in gas-tight containers, and do not release gas during the conventional storage period for xenon. It is quite surprising that these emulsions can be pressurized with high concentrations of xenon and still remain reasonably stable. The solubility of the inert gas in emulsions can be increased by the use of so-called solubility promoters, which are smaller lipophilic compounds that may or may not have therapeutic effects (molecular weight between about 30 and about 1000; n-octanol / water partition coefficient preferably HU 224 985 B1 greater than 500). We have found that aromatic compounds, such as 2,6-dialkylphenols (e.g. 2,6-diisopropylphenol) significantly improve the saturation capacity of emulsions for inert gases. A large number of prior art documents describe gas-containing contrast media, particularly in the context of ultrasound studies or in nuclear magnetic resonance spectrometry. An important feature of such contrast media is the formation of a distinct phase consisting of very small gas bubbles (or gas-filled spheres) (described, inter alia, in WO-A-96 / 39197, US-A-5088499, US-A-5334381, WO-A-96 / 41647). These documents propose a large number of gases, including in particular air, nitrogen, carbon dioxide, oxygen and inert gases in general (i.e. helium, argon, xenon and neon). Only EP-B-0357163 clearly states that xenon-containing media in particular can be used as X-ray contrast media. This document also highlights that the injectable solution must contain gas bubbles.Furthermore, WO-A-95 / 27438 describes the use of xenon in a noble gas nuclear magnetic resonance imaging method. However, there is no specific indication that xenon has an anesthetic or analgesic effect when used as a contrast agent or in spectrometry. In principle, such an effect may be undesirable. Furthermore, the gas concentration in the contrast agent is so low that it does not reach the concentration threshold required for a pharmacological effect. Consequently, the contrast agents as such or the preparations used in spectrometry do not fall within the scope of the present invention. The lipid phase of the composition, which absorbs the gas, i.e. which can dissolve and / or disperse the gas, is primarily formed by so-called fats, which are essentially esters of long-chain and medium-chain fatty acids. These are saturated or unsaturated fatty acids containing 8 to 20 carbon atoms. However, ω-3 or ω-6 fatty acids with up to 30 carbon atoms can also be used. Suitable esterified fatty acids are in particular vegetable oils, such as cottonseed oil, soybean oil, safflower oil, fish oil and the like. The most important components of these naturally occurring oils are fatty acid triglycerides. Preparations prepared in the form of so-called "oil-in-water" emulsions are of particular importance. The proportion of fat in the emulsion is usually 5 to 30% by weight, preferably 10 to 20% by weight. However, usually an emulsifier is present along with the fat, such emulsifiers are soy phosphatides, gelatin or egg phosphatides.Such emulsions can be prepared by emulsifying a water-immiscible oil with water in the presence of an emulsifier, which is usually a surfactant. Other polar solvents may also be present together with the water, such as ethanol and glycerol (propylene glycol, hexylene glycol, polyethylene glycol, glycol monoethers, a water-miscible ester, etc.). The inert gas can already be mixed into the lipid phase in an earlier process step. In the simplest case, however, the prepared emulsion is saturated with xenon. This can take place at various temperatures, for example between 1 °C and room temperature. In this case, it is occasionally useful to pressurize the vessel containing the emulsion, for example to 800 kPa or higher. Oil-containing emulsions can also be used according to the invention, such as those used in intravenous nutrition. These oil emulsions consist essentially of a suitable oil base (soybean oil or sunflower oil) and a well-tolerated emulsifier (phosphatides). Commonly used oil emulsions are Intralipid®, Intrafat®, Lipofundin®S and Liposyn®. More detailed information on such oil emulsions can be found in G. Kleinberger and H. Pmperl, Infusionstherapie, 108-117 (1983) 3. Oil emulsions generally also contain additives which make the osmolarity of the aqueous phase surrounding the oil phase present in the form of liposomes the same as that of blood (isotonicity). Glycerol and / or xylitol can be used for this purpose. Furthermore, it is often useful to add an antioxidant to the oil emulsion to prevent the oxidation of the unsaturated fatty acids. Vitamin E (DL-tocopherol) is particularly suitable for this purpose. Particularly preferred lipid phases are so-called liposomes, which can be formed from the aforementioned triglycerides or from so-called phospholipid molecules in general, especially in the case of "oil-in-water" emulsions. Phospholipid molecules generally consist of a water-soluble part, which is formed by at least one phosphate group, and a lipid part derived from a fatty acid or fatty acid ester. US-A-5 334 381 illustrates in detail how liposomes can be saturated with gas. In a very general form, a device is filled with liposomes, i.e. an emulsion of the oil-in-water type, and the device containing the gas is then pressurized. During the process, the temperature can be reduced to 1°C. The gas gradually dissolves under the pressure and enters the liposomes. When the pressure is released, small gas bubbles may form, but these are already enclosed by the liposomes. In practice, it is thus possible to keep xenon gas or other gases, for example, in an oily emulsion under pressurized conditions. Such preparations can also be used according to the invention, provided that no separate gas phase is formed outside the liposomes and that the desired therapeutic effect occurs. The lipids that make up liposomes can be of natural or synthetic origin. Examples of such substances are cholesterol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingomyelin, glycosphingolipids, glycolipids, glycolipids, etc. The surface of liposomes can also be modified with a polymer, for example polyethylene glycol. HU 224 985 B1 The compositions according to the invention thus have many advantages, (e.g. it was observed that after injection of the composition according to the invention, a practically immediate anesthetic effect occurred, which, in contrast to the injectable anesthetics known to date, was easily controlled. However, the composition according to the invention not only has an anesthetic effect, but also has a simultaneous analgesic effect and a well-being effect upon awakening. Its excretion from the body depends solely on breathing. In addition, with the use of intravenous anesthesia, the xenon concentration can be easily measured in the exhaled air. The control of anesthesia, which can be achieved in this way, has not been possible with conventional intravenous anesthesia until now. The invention thus provides a medicinal liquid composition comprising a lipophilic inert gas in a therapeutically effective amount, with the proviso that compositions used as contrast agents or for spectrometric purposes are excluded. In this case, therapeutically effective is understood to mean effective as an anesthetic (mild anesthetic), analgesic, muscle relaxant and / or anti-inflammatory. The therapeutic efficacy of the composition according to the invention may relate in particular to the systemic effect on the central nervous system. For example, to achieve a mild anesthetic effect, the xenon loading in the pharmaceutical preparation may be about 0.2-0.3 ml xenon / ml emulsion. This means that an anesthetic and / or sedative effect can be provided for preparations with a xenon concentration of at least 0.2 ml xenon / ml emulsion. The anti-inflammatory effect can be observed with an emulsion of as little as 0.1 ml / ml. It has been observed that after 30 seconds of continuous infusion, 20 ml of an emulsion with a xenon concentration of 0.3 ml / ml induces a mild anesthetic state in a patient weighing approximately 85 kg. When working with a high perfluorocarbon content, with an emulsion concentration of 1-4 ml xenon / ml, for example, 20 ml of this emulsion can be infused over 30 seconds to induce anesthesia. An infusion rate of at least 7.5 ml / min may be sufficient to maintain anesthesia. In this way, a total of 470 ml of emulsion can be used for a 1-hour surgery (starting: 20 ml; maintenance: 450 ml).A xenon content of 3 ml xenon / ml emulsion corresponds to a xenon volume of 1410 ml, i.e. a fraction of the amount of xenon consumed during inhalation anesthesia (calculated with a body weight of 85 kg, this would be a consumption of 16.6 ml / kg per hour). In any case, the skilled person can easily determine the effective xenon concentration by means of the stepwise approach. As indicated above, the presence of an emulsion or lipid phase in the liquid composition of the invention has an effect on the pharmacological effect. Thus, the concentration limits given above may be effective for compositions containing 10-40% (w / v) lipid or fluorocarbon emulsions. However, the present invention also relates to emulsions containing, for example, hydrocarbon compounds, such as their fluorine-containing and / or chlorine-containing derivatives, in an amount of more than 40% (w / v) and up to 125% (w / v). With such emulsions, the saturation capacity of the liquid composition can be much higher than the aforementioned limits. On the other hand, as described above, the emulsions thus affect the effectiveness of the xenon contained in the liquid composition.thus, there are some indications that the required xenon concentration may be drastically lower. In this way, the composition of the invention can be combined with any known inhalation anesthetic, i.e., intravenous administration can be accompanied by inhalation anesthesia. In combined use with nitrous oxide or xenon and / or other anesthetics (such as halothane, diethyl ether, sevoflurane, desflurane, isoflurane, Ethrane, etc.), the amount or concentration of the inhalation anesthetic used can be reduced. It is also possible - and in certain circumstances advantageous - for the preparation to contain a pharmacologically active agent other than the inert gas. This could be, for example, an intravenous sedative or anesthetic. Depending on whether this agent is water-soluble or fat-soluble, it is present in the aqueous phase or in the lipid phase together with the xenon. 2,6-diisopropylphenol, which is an effective anesthetic (in amounts of 1.5-20 mg / ml), has been found to be particularly suitable for this purpose. Etomidate is also a suitable anesthetic in concentrations of 0.1-2 mg / ml (Hypnomidate®, an imidazole-5-carboxylic acid derivative). If dissolved xenon is used in addition to other anesthetics, this makes it possible to reduce, for example, the concentration of diisopropylphenol or etomidate required for anesthesia. For example, 1 ml of the oily emulsion of the invention (containing approximately 0.1 g of fat per ml of emulsion) contains 2.5-20 mg It may contain 2,6-diisopropylphenol, i.e., for example, 2.5, 5.0, 7.5, 10, 15 or 20 mg in addition to xenon. We have found that the presence of 2,6-diisopropylphenol encompasses several surprising effects: 1. the saturation capacity is increased by the addition of 2,6-diisopropylphenol, for example, in the case of intralipid emulsions; 2. the concentration required to achieve an anesthetic effect is lower for both 2,6-diisopropylphenol and xenon (an inert gas), but the analgesic effect of xenon is still observed; 3. this route of administration allows for the first time the use of TIVA (total intravenous anesthesia) including analgesia, avoiding the obstacles of the prior art, including side effects and lack of regulation; 4. this is the first application in which a suitable analgesic agent (xenon) is administered intravenously. In general, the anesthetic, analgesic or sedative agent present with xenon may be another anesthetic, analgesic, muscle relaxant or sedative. Other suitable anesthetic agents are generally barbiturates (including barbital, phenobarbital, HU 224 985 Β1 pentobarbital, secobarbital, hexobarbital and thiopental) and opioids. Known analgesics include morphine-type compounds such as hydromorphone, oxymorphone, codeine, hydrocodone, thebacon and heroin. Synthetic derivatives of morphine can also be used, such as pethidine, levomethadone, dextromoramide, pentazocine, fentanyl and alfentanil. Less potent analgesics can also be used, such as anthranilic acid derivatives (flufenamic acid, mefenamic acid), acrylic acid derivatives (diclofenac, tolmetin, zomepirac), arylpropionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen) and indoleacetic acid or indeneacetic acid derivatives (indomethacin, sulindac). When using muscle relaxants, central muscle relaxants can be considered, such as baclofen, carisoprodol, chlordiazepoxide, chlormezanone, chloroxazone, dantrolene, diazepam, pheniramidol, meprobamate, fenprobamate and orphenadrine.Sedatives useful in the present invention include, but are not limited to, benzodiazepine derivatives such as triazolam, lormetazepam, clothiazepam, flurazepam, nitrazepam and flunitrazepam. The composition of the invention consequently serves several purposes: a) intravenous induction of anesthesia (optionally with 2,6-diisopropylphenol or etomidate as an adjuvant); b) supplementary intravenous administration of xenon or other gases (such as nitrous oxide or desflurane) in parallel with inhalation anesthesia allows a significant reduction in the total amount of gas used; c) maintenance of anesthesia over an extended period of time, the inert gas-containing preparation is optionally administered only as a supplement, for example together with 2,6-diisopropylphenol or etomidate; since, for example, in this case the concentration of diisopropylphenol can be significantly reduced, extended anesthesia with practically no side effects becomes possible; d) since xenon has an analgesic effect, it is possible to combine it with an inhalation anesthetic or intravenous anesthetic to reduce or completely avoid the need for additional analgesics; e) intravenous xenon preparations, regardless of whether they are combined with inhalational or intravenous anesthetics, reduce the need for muscle relaxants to the point where they can be completely dispensed with. As can be seen from the above, the invention is not limited to anesthesia as an application. The term "anesthesia" includes both the induction and maintenance of anesthesia. The compositions of the invention also have an analgesic effect, which may be essential in connection with anesthesia. However, in certain circumstances, pain relief is also of importance, for example in the treatment of acute and chronic pain, and a certain degree of additional mild anesthesia or sedation is often desirable. Intravenous administration of a mild anesthetic dose over a long period of time (from 1 hour to several days) results in an increased analgesic effect. One particular application of the composition of the invention as an anesthetic is in emergency medicine. This often requires particularly short periods of wakefulness after deep painless anesthesia.Another example is the emergency treatment of myocardial infarction. In this case, the composition according to the invention serves to reduce sympathetic tone and relieve pain. Thus, the active ingredient according to the invention can also be used in general in anti-inflammatory and anti-pain therapy. A further possibility is, among others, the topical application of the active ingredient according to the invention. The use of ointments, creams (oil emulsion or liposome) and the like, which can be used, for example, to treat damaged tissues, can be considered. These preparations can also be sprayed into body cavities or joints to induce a pharmacological effect. The ointments and creams according to the invention are particularly suitable for local pain relief. The ointment is then applied to the area to be treated and, if desired, the wound is sealed airtight. The invention can accordingly also be used by means of a patch which carries the composition according to the invention on the side to be applied to the wound and is prepared in the form of a conventional patch which, if desired, provides an airtight seal on the other side. In the broadest sense, the invention is a liquid or gel-like preparation containing an inert gas in dissolved or dispersed form. As has been shown by way of example in connection with the use of an oily emulsion, the liquid or gel-like preparation according to the invention is characterized in that the gas having a therapeutic effect is finely divided and dissolved in a separate phase. Typically, this separate phase is the dispersed phase of a dispersion or emulsion. However, the separate phase containing the gas may also be the continuous phase. The preparations according to the invention are generally prepared in such a way that the dispersed phase itself has the property of dissolving the gas. One possibility for the use of a lipophilic inert gas is therefore to have an oily emulsion with separate very small oil (fat) droplets or liposomes containing the inert gas in dissolved form.However, in general, we can state that the compositions according to the invention are preferably emulsions in which the dispersed phase contains the active gas. A further embodiment of the present invention is a method for inducing anesthesia, sedation, analgesia, muscle relaxation and anti-inflammatory treatment. In such treatment, the liquid composition is usually administered to patients parenterally. The present invention also provides a method for maintaining anesthesia by administering the liquid composition described above. In such a method, administration of the liquid composition according to the invention provides a rapid onset of the described effects. The methods according to the invention have a particular advantage in that they are HU 224 985 Β1 lies in the fact that the liquid preparation can be administered for long periods of time (several minutes and hours) without causing, for example, inflammatory side effects. Experimental part Oil emulsions In the following examples, commercially available Intralipid preparations (Pharmacia & Upjohn GmbH, Erlangen) were used as oil emulsions. These emulsions consist essentially of soybean oil, 3-sn-phosphatidylcholine (derived from chicken egg yolk) and glycerol. The oil emulsion lntralipid®10, for example, consists of the following ingredients: soybean oil 100 g 3-sn-phosphatidylcholine from chicken egg yolk 6 g glycerol 22.0 g water for injections to 1000 ml The pH value of 8.0 is adjusted with sodium hydroxide. Energy content / I: 4600 kJ (1100 kcal) Osmolarity: 260 mOsm / l For example, Intralipid®20 oil emulsion consists of the following ingredients: soybean oil 200 g 3-sn-phosphatidylcholine from chicken egg yolk 12 g glycerol 22.0 g water for injections to 1000 ml The pH value of 8.0 is adjusted with sodium hydroxide. Energy content / I: 8400 kJ (2000 kcal) Osmolarity: 270 mOsm / l Saturating perfluorocarbon emulsions with xenon The perfluorocarbon emulsion series were prepared or purchased and then saturated with xenon. The activity of the preparations was tested in an animal (rabbit) model. The emulsions were applied in the same way as the Intralipid preparations described above, i.e. the experimental animal was rapidly anesthetized by an injection (approximately 1 ml) into the ear. Each emulsion was placed in a beaker and saturated by flowing xenon gas. The following perfluorocarbon compounds were used: perfluorohexyloctane (1), perfluorodecalin (2), perflubron (C8F17) (3). To prepare the emulsions, we used emulsifying agents such as egg yolk lecithin (Lipoid E100, Lipoid GmbH, Ludwigshafen), Pluronic PE6800 and Pluronic F68. For all emulsions, we found that only 40% perfluorocarbon emulsion (weight / volume, i.e. the weight of the perfluorocarbon compound relative to the volume of the emulsion) was able to absorb 1-4 ml of xenon per 1 ml of emulsion. Studies on experimental animals To demonstrate the effectiveness of the compositions according to the invention, an experiment was conducted on 24 piglets, 14-16 weeks old and weighing 36.4-43.6 kg. The animals were randomly divided into 6 groups and anesthetized either conventionally or using the emulsions of the invention. Anesthesia was performed by intravenous injection of one capsule of pentobarbitone (8 mg / kg body weight) and buprenorphine (0.01 mg / kg body weight) in each group. Anesthesia was continued by conventional inhalation anesthetics (nitrogen gas or xenon / oxygen mixture) or by intravenous administration of pentobarbitone and buprenorphine. In one group (comparison group), anesthesia was maintained by intravenous administration of 2,6-diisopropylphenol (10 mg / l ml emulsion).To maintain anesthesia, two groups of piglets (according to the invention), containing 4 animals per group, received an intravenous infusion of 1 ml / kg per hour of a 10% w / w oil emulsion according to the invention, previously saturated with xenon [approximately 0.6 ml xenon / ml emulsion; determined by gravimetric measurement; the higher proportion of xenon was obtained in the aforementioned lntralipid®10 emulsions. It was obtained by saturating the oil emulsion in a xenon atmosphere between 5-7 bar (up to approximately 2.0 ml). In the second group, 7.5 mg / kg body weight / h of 2,6-diisopropylphenol was additionally administered with the oil emulsion. The piglets were subjected to surgical intervention (standard surgery: incision of the left femoral artery in the same way for each group and for all experimental animals), and adrenaline levels, heart rate, arterial blood pressure and oxygen uptake were recorded. In addition, it was determined how much additional pentobarbitone was needed to achieve the required level of analgesia and depth of anesthesia in each group. Table Group Adrenaline (pg / ml) Heart rate (min-1) Arterial blood pressure (mmHg) VO2 (ml / min) Pentobarbitone requirement (mg / kg / min) Comparison group 60 115 110 410 0.25 134 120 105 391 0.36 112 105 115 427 0.31 85 98 101 386 0.42 HU 224 985 B1 Table (continued) Group Adrenaline (pg / ml) Pulse rate (min*1) Arterial blood pressure (mmHg) VO2 (ml / min) Pentobarbitone requirement (mg / kg / min) Group 1 38 112 112 341 0.09 21 106 100 367 0.04 16 95 104 348 0.11 30 112 118 334 0.15 Group 2 10 88 100 325 - 23 100 85 346 - 14 94 93 331 - 8 104 87 354 - Evaluation of the results for the conventionally anesthetized groups (not shown in the table) shows that anesthesia with a xenon / oxygen mixture is clearly more favorable than other methods. Surprisingly, the two groups that received intravenous treatment with the oil emulsion of the invention (groups 1 and 2) showed similarly favorable results, with Combined treatment with 2,6-diisopropylphenol results in further significant improvement (group 2), as shown by lower adrenaline levels (less stress) and no need for pentobarbitone at all. The data in the table show that the composition according to the invention is more advantageous than all currently available intravenous anesthetics, especially due to the additional analgesic effect. Thus, comparing the data of the piglets in group 1 (10% by weight, xenon-saturated oil emulsion) (compared to the comparison group), there is a strikingly lower stress (adrenaline level), lower oxygen uptake (VO2) and lower pentobarbitone requirement (i.e. better anesthesia). The difference compared to the prior art intravenous anesthesia is even more pronounced when the The results of group 2 (10% oil emulsion containing 2,6-diisopropylphenol and enriched with xenon) are compared with the control group. They not only show a significantly reduced stress (adrenaline level). The significantly reduced heart rate and arterial blood pressure, combined with a lower oxygen requirement, make it possible to dispense with further pentobarbitone. The use of perfluorocarbon preparations was studied in another group (4 piglets weighing between 31.4 and 39.8 kg). In this experimental group, a 40% perfluorocarbon emulsion with a xenon content of 2.1 ml xenon / ml emulsion was used. For induction of anesthesia and intubation, the piglets received 20 ml of the emulsion intravenously over 20 seconds (corresponding to 1.34 ml xenon / kg body weight). After intubation and inhalation, xenon was continuously administered intravenously over 30 minutes, so that the experimental animals received a total of 75 ml of emulsion (corresponding to 10 ml xenon kg_1h_1). The following table shows the experimental results obtained for adrenaline levels, heart rate, arterial blood pressure and oxygen uptake. The results show that by increasing the xenon load and the infusion rate (more than 5 ml / kg / h) complete anesthesia can be achieved using the active ingredient of the invention alone. Overall, it was also found that oxygen consumption (VO2) is lower and anesthesia (adrenaline levels and heart rate) is less stressful. Adrenaline (pg / ml) Heart rate (min*1) Arterial blood pressure (mmHg) VO2 (ml / min) 8 90 101 301 6 87 96 320 10 94 98 308 5 100 106 316 Experiment on own body The inventor of the present invention conducted an experiment with the composition according to the invention to determine the effectiveness of the composition. In the experiment, Intralipid®10 oily emulsion was saturated with xenon as described above. According to determinations made by gravimetric methods, the said composition contained 0.7 ml of xenon in 1 ml of emulsion. Anesthesia was induced by administering 30 ml of said emulsion over 20 seconds. Anesthesia was observed to begin immediately. Anesthesia was then maintained by administering the said emulsion at a rate of 120 ml / hour. After about 20 minutes, the administration of the liquid composition was stopped. About 30 seconds later, the inventor regained consciousness and shortly after the experiment was conducted, he called his colleagues together for a detailed discussion. The experiment HU 224 985 Β1 observed complete anesthesia followed by maintenance of anesthesia with spontaneous breathing and very good analgesia (see table below). The inventor reported that he did not experience dizziness or other side effects that are usually observed after anesthesia with a well-known anesthetic agent according to the prior art, such as 2,6-diisopropylphenol (propofol). Time (min-1) Blood pressure Movements Abdominal response to ice cube Sensations 0 115 / 65 - Yes - +20 seconds 110 / 70 - No Numbness 5 110 / 75 No No Numbness 10 115 / 75 No No Numbness 15 115 / 80 No No Numbness 20 120 / 75 No No Numbness +30 seconds 120 / 75 Yes No Awakening 25 120 / 80 Yes Yes Awakening The experiment was repeated three times, and practically identical results were observed. No acute or visible toxic effects were observed in the above experiments. Further embodiments of the invention After further studies with xenon-containing emulsions, we found that the invention far surpasses the applicability of noble gases such as xenon and krypton. There is a constant debate in the field of anesthesia as to whether inhalational or intravenous anesthesia should be used (J. Clin. Anesth., vol. 8, May 1996). Notably, some experts still believe that inhalational anesthesia is immeasurably more favorable than intravenous anesthesia. The problem with the latter is that side effects, depth of anesthesia, and exhalation and inhalation concentrations are not fully controllable. In any case, to date, no one has proposed the use of inhalational anesthetics as active ingredients in intravenous anesthesia. In this context, the term anesthesia refers to loss of consciousness and not just a local effect. For inhalation anesthesia, certain volatile liquids, such as halothane (CF3-CHBr), as well as ethers and halogenated ethers, such as methoxyflurane, enflurane and isoflurane, are used in the prior art. These compounds are liquid at ambient temperature (20 °C, standard pressure) but volatile. Such inhalation anesthetics are often used in combination with other gases, such as nitrous oxide. US-A-4622219 discloses that microdroplets of the general anesthetic methoxyflurane coated with a monomolecular layer of dimyristoylphosphatidylcholine can be administered intradermally or intravenously to patients to produce local anesthesia. However, this reference emphasizes that this is only a local effect. The problem of the reference was to solve the local injury caused by the injection of an organic phase into the skin or other tissues. The reference suggests that it should be provided with a layer of certain compounds to avoid mixing with the organic phase. As shown in the examples, the amount of said compound never exceeds about 1% w / v of the finished microdroplet composition. In a broader sense, the present invention aims to provide a liquid formulation that can be used during general anesthesia. This object is achieved by a liquid composition consisting of at least 5% by weight of an emulsion / dispersion and containing an anesthetically effective amount of the compounds of the general formula I, II, III or IV: R4 II R2-CXC-Rs(i) II R3 Re Ri I R2-C-R4 (II) I R3 R3\ / C=c / \ R2R4 R1-C=C-R2(IV) HU 224 985 Β1 where Ri-R6 independently represent a hydrogen atom, an alkyl group having 1-3 carbon atoms or a halogen atom and X represents a single bond, an oxygen or a sulfur atom, with the proviso that said compound (I-IV) is liquid or gaseous at room temperature (20 °C) and has an oil / water partition coefficient of about 20 (in n-octanol at 20 °C). Compounds effective as anesthetics include, for example, ethers such as diethyl ether, divinyl ether, desflurane, sevoflurane, methoxyflurane, enflurane and isoflurane. Halogenated hydrocarbons include chloroform, ethyl chloride, trichloroethylene and halothane. Organic gases effective as anesthetics include, for example, ethylene, cyclopropane and acetylene. 15 The substituents R^Rg independently represent a hydrogen atom, a C1-3 alkyl group and a halogen atom. Among the halogen atoms, fluorine, bromine and iodine are particularly preferred. The C1-3 alkyl groups may be substituted, in particular with the aforementioned halogen atoms. Furthermore, two groups, for example R^ and R4, may be linked together to form a 5- or 6-membered ring (which may also contain a heteroatom, such as an oxygen atom or, less preferably, a sulfur atom). 25 Compounds with an oil / water partition coefficient of 50-1000 are preferably used. For example, enflurane has an oil / water partition coefficient of 120 and methoxyflurane has an oil / water partition coefficient of 400. It is surprising that such preparations can be administered intravenously 30 and have a general anesthetic and sedative effect, not just a local one. This effect is particularly surprising in light of the disclosure of US-A-4,622,219, which, for example, recommends particularly high concentrations of methoxyflurane. 35 A high lipid content is particularly important in the composition according to the invention. It has been found that the lipid content of the composition is critical and thus according to the invention the lipid content of the composition should be at least 5% by weight. According to the invention, it is preferred to use oil emulsions containing about 10-40% by weight of lipid. According to the invention, it is advantageous to use known volatile liquids which are used as inhalation anesthetics in the prior art. These compounds are purely water-soluble compounds which are transported in the bloodstream bound to blood cells and proteins. It has not been reported so far that such compounds have any effect on the central nervous system when administered in liquid formulations. The compositions of the invention can be readily prepared by mixing the preferred liquid compounds with a pre-prepared emulsion, such as Intralipid® 10 or Intralipid® 20 oil emulsion. A preferred method of preparing the composition involves subjecting the mixed ingredients to ultrasonic treatment. Saturating emulsions with various suitable anesthetics The following suitable anesthetics are mixed in quantities of 1-5 ml with 50 ml of Intralipid®20 or Intralipid®10 emulsion: halothane, chloroform, diethyl ether, methoxyflurane, enflurane, isoflurane, desflurane, sevoflurane, divinyl ether. These compounds dissolve readily in emulsions without forming a separate phase or precipitate. Occasionally, the blended mixtures must be heated and stirred or briefly sonicated. The efficacy of the preparations was tested on laboratory rats. The anesthetic preparation was injected intravenously (0.5 ml). In particular, an immediate anesthetic effect was observed in the case of halothane, enflurane and methoxyflurane. All laboratory rats survived the test. In addition, the inventor conducted an experiment on himself. He received an intravenous infusion of 5 ml (40 ml of Intralipid®10 emulsion containing 1 ml of halothane). After injection of the preparation, an immediate onset of the anesthetic effect was observed.

Claims

1. A liquid composition in the form of an emulsion for inducing and / or maintaining anesthesia, characterized in that it contains a lipophilic inert gas in an anesthetically effective concentration.

2. A liquid preparation in the form of an emulsion for inducing sedation, characterized in that it contains a lipophilic inert gas in a concentration effective as a sedation.

3. A liquid preparation in the form of an emulsion for providing analgesia, characterized in that it contains a lipophilic inert gas in an analgesically effective concentration. 55 4. A liquid preparation in the form of an emulsion for inducing muscle spasm relief, characterized in that it contains a lipophilic inert gas in a concentration effective as a muscle spasm reliever.

5. A liquid preparation in the form of an emulsion for the treatment of inflammation, characterized in that it contains a lipophilic HU 224 985 Β1 inert gas in an effective concentration as an anti-inflammatory agent.

6. A composition according to any one of claims 1-5, characterized in that it contains xenon in dissolved or dispersed form. 5 7. A composition according to any one of claims 1-6, characterized in that it is in the form of a perfluorocarbon emulsion.

8. The composition according to any one of claims 1-6, characterized in that it is an oily emulsion comprising an oil-in-water emulsion or a liposomal emulsion.

9. The composition according to any one of claims 1-8, characterized in that an additional pharmacologically active agent is present in dissolved form. 15 10. The composition according to claim 9, characterized in that the additional pharmacologically active agent is an anesthetic, analgesic, sedative or muscle relaxant, which is to be administered intravenously.

11. The composition according to claim 10, characterized in that the additional pharmacologically active agent is 2,6-diisopropylphenol, etomidate or a derivative thereof.

12. The composition of claim 10, wherein the additional pharmacologically active agent is fentanyl or alfentanil.

13. An infusion agent for anesthesia, characterized in that it contains a composition according to any one of claims 1-12.

14. Use of a xenon-containing liquid emulsion according to any one of claims 1-13 for the preparation of a composition suitable for inducing and / or maintaining anesthesia.