HK1028335B - Medicinal preparation containing a lipophilic inert gas - Google Patents

Description

Pharmaceutical formulations containing lipophilic inert gases

The present invention relates to liquid formulations containing a lipophilic inert gas in a pharmacologically effective concentration.

Lipophilic inert gases are inert gases that have some degree of solubility in fats. This is expressed in terms of an oil/gas distribution coefficient greater than about 0.05 (krypton, 0.5; argon, 0.15; xenon, 1.9). The coefficient is usually measured with an oil such as n-octanol or olive oil. Alternatively, the lipophilicity of inert gases can be defined by reference to the so-called Ostwald solubility (see Gerald L. Pollack et al. J. chem. Phys.90(11), 1989. "solubility of xenon in 45 organic solvents including cycloalkanes, acids and alkanals: experimental and theoretical"). The ostwald solubility is the ratio of the concentration of dissolved gas molecules in a liquid solvent to the concentration of dissolved gas molecules in the gas phase at equilibrium. The solubility in n-hexane of xenon is therefore approximately 4.8 in terms of the Mohr's solubility at 25 ℃. Accordingly, the term lipophilic is defined herein to mean that the gas or gas mixture (under standard conditions) has an Ostwald solubility greater than 0.2 in n-hexane at 25 ℃.

Pharmacologically or pharmaceutically effective is herein understood to be the concentration in a liquid formulation which exerts sedative, anaesthetic, analgesic, anti-inflammatory or muscle relaxant effects on a patient.

Xenon is particularly discussed as an inhalation anesthetic because of its anesthetic and analgesic effects. Since xenon is very expensive, its use as an inhalation anesthetic involves high consumption, and gas treatment is also technically very expensive, so that anesthetics with xenon are not widely accepted. However, due to the significant advantages of xenon over other gaseous anesthetics, efforts are being made to facilitate the large-scale use of xenon, either to obtain the gas in a simple and inexpensive manner, or to recover it in vaporized air.

Xenon is a single-atom, inert gas with an atomic weight of 54 that is colorless, odorless, and tasteless. Xenon is 5 times more dense than air. Naturally occurring xenon also contains isotopes, such as isotopes 124, 126, 128, 129, 130, 131, 132, 134 and 136. Synthetic isotopes like xenon 114, xenon 133 and xenon 142 are well known. The half-life of these isotopes transmutation is between 12 seconds and about 40 days. The present invention does not mention such short-lived radioactive xenon isotopes.

When xenon is used as an inhalation anesthetic, on the one hand a large amount is required to obtain anesthetic effect, and on the other hand the inhalation concentration is limited to 70% or at most 79% in order to ensure that the patient gets at least 21% oxygen when inhaling air. This allows for a degree of anesthesia and analgesia, although not sufficient by itself to ensure that the patient has adequate general anesthesia. Inhalation anesthetics, sedatives, or intravenous anesthetics and analgesics have to be replenished. Muscle relaxants also have to be supplemented in the case of intra-abdominal or intra-thoracic surgery.

It is not known whether the use of liquid formulations containing lipophilic inert gases as injectable anesthetics has been attempted. It is also not known to use such formulations for other medical purposes, for example for analgesia or sedation.

DE-A-3940389 describes a therapeutic agent containing a gas at a concentration above its natural saturation level. Among the gases mentioned are atmospheric oxygen, ozone and inert gases. Said publication explains in detail the use of the therapeutic drug for the purpose of emergency medicine and shock therapy, in particular when the therapeutic drug is administered to a patient as a blood substitute and oxygen transporter infusion. It is particularly pointed out according to the invention that isotonic saline solutions containing up to 40mg/l of oxygen can be used as medicaments. Said publication gives no information about the possible activity of the inert gas or the field of use of the inert gas-containing medicament.

DE-A-1667926 discloses pharmaceutically acceptable salt solutions containing radioactive gases. The invention does not mention radioactive gases.

DE-C-4100782 describes water-soluble ozone preparations which can be administered to patients as infusion solutions. However, this publication emphasizes that ozone has a certain algicidal, bactericidal, fungicidal, sporicidal and virucidal effect. It further suggests that ozone can react with unsaturated fatty acids in parts within 1 second in blood. Since ozone is rapidly decomposed, it is recommended to prepare the infusion liquid at the site of use.

Like inhalation anesthetics, injectable anesthetics are described in the state of the art. Injectable anesthetics can be used by Themselves (TIVA) or in combination with gaseous anesthetics. Although one of the notable features of currently used intravenous anesthetics is their rapid onset of action, they often exhibit a number of deficiencies. It should be emphasized that they exhibit only a weak pain-suppressing (analgesic) effect, if any, and are difficult to control. The psychological protective advantages of the patient during induction of anesthesia (the patient losing consciousness instantaneously and omitting the mask and excitement phase) are therefore offset by the disadvantage of the risk of the anesthetic rising. This risk is derived in principle from the fact that once the anesthetic is injected, the anaesthetist cannot effectively exert any further influence, so that the anaesthesia process is only determined by the processes occurring in the human body-distribution, enzymatic degradation and inactivation and elimination by means of the liver and/or kidneys. Other disadvantages of the injectable anesthetics used today are the difficult to control side effects (e.g. blood pressure drop, bradycardia, rigidity, allergies) and in some cases serious contraindications. As is well known, intravenous anesthetics are often co-administered with analgesics and muscle relaxants, which alter the pharmacokinetic properties, particularly the half-life, to a considerable extent. Overall, this makes controllability practically more difficult.

Anesthesia includes loss of consciousness, analgesia, and muscle relaxation. However, there is no single intravenous substance that can be used as an active anesthetic to produce the three components of effective and safe anesthesia. This object is achieved by using a combination of active substances. The active substances known to date have mutually disadvantageous effects both in the pharmacogenomics and in the pharmacokinetics. Particularly in anaesthesia, not only is not undesirable, but also the side effects, which are harmful, are enhanced. In particular, these adverse effects include the published effects on the heart and blood vessels and on cardiovascular control mechanisms.

US-A-4622219 has disclosed local anaesthetics which can be administered intravenously. The local anesthetic for injection consists essentially of tiny droplets of an evaporable anesthetic, such as methoxyflurane. However, the infusion solution is specifically active as a local anaesthetic. General anesthesia or anesthesia of a patient is neither described nor considered. In this respect it should be emphasized that methoxyflurane is about 440 times more active than a gas inhalation anesthetic like xenon (activity expressed as the lowest alveolar concentration (MAC) of the anesthetic at one atmosphere; MAC values expressed in% by volume: xenon, 71; methoxyflurane, 0.16).

There is therefore a clear need for intravenous anaesthetics which do not exhibit the said disadvantages and which are highly active.

Accordingly, it is an object of the present invention to provide liquid formulations that can be used to induce anesthesia, sedation, analgesia and/or muscle relaxation.

It is a further object of the invention to provide a liquid formulation for the treatment of inflammation.

It is another object of the present invention to provide an infusion agent that induces or maintains anesthesia that overcomes all or some of the deficiencies in the prior art described above.

Still another object of the invention relates to a method of treatment of the formulation by parenteral administration to induce anesthesia, sedation, analgesia and/or muscle relaxation. Accordingly, it is a general object of the present invention to provide novel methods of inducing anesthesia, sedation, analgesia, and/or muscle relaxation, as well as inflammatory therapies.

In summary, the present invention provides liquid formulations containing a lipophilic inert gas in dissolved or dispersed form.

In particular, the present invention contemplates the use of gases or mixtures thereof, such as xenon and/or krypton.

As will be discussed in detail below, surprisingly, the formulations of the present invention appear to have a systemic effect on the central nervous system.

In contrast to the physiological limitations of using noble gases as inhalation anesthetics, as described with respect to xenon, the anesthesiologic possibilities of intravenous administration of lipophilic noble gases such as xenon are quite different. They allow hitherto unrecognized improvements and, in particular, safety for the patient. Even formulations containing very small amounts of xenon produce significant anesthetic and analgesic effects. This is entirely surprising. Further, it was established that xenon does not adversely affect the myocardial system. Xenon also has no effect on the cardiac conduction system. Therefore, the inert gas has no adverse reaction at all in the aspects of heart rhythm and myocardial contraction. The formulation of the present invention makes it possible for the patient to obtain complete anesthesia and analgesia, making it superfluous to further supplement the vein with other sedatives, anesthetics or analgesics. It is also possible to use dosages which achieve central muscle relaxation, so that supplementation with muscle relaxants becomes superfluous. It has therefore been possible to achieve anesthesia, analgesia and muscle relaxation in patients with lipophilic inert gases by a single intravenous injection of anesthesia during induction of anesthesia. The intubation method can then be carried out without problems. In addition, problems with xenon as an inhalation anesthetic have been reported for patients with obstructive pulmonary diseases such as asthma and the like. The present invention also overcomes such problems with patients.

It has been found that administration of the formulations of the invention, as opposed to xenon as an inhalation anesthetic, reduces dosage requirements and produces a rapid onset and recovery of anesthetic action. It appears that the liquid formulation of the present invention alters the distribution of xenon (displacement) and possibly the in vivo uptake and distribution of xenon to the tissue. One possible explanation is that liquid formulations (such as emulsions) confine the xenon to the intravascular space and reduce the volume of distribution. One explanation that xenon may also have an effect in providing a liquid formulation is that emulsion vesicles of the liquid formulation of the present invention, when administered intravenously, may reduce the extent of first-pass lung elimination, accelerate pulmonary delivery, or both.

The invention opens up new possibilities for intravenous drug supplementation, for example if patients additionally need to be sedated. As mentioned above, this includes forms of renal replacement therapy such as hemofiltration, hemodiafiltration and hemodialysis, extracorporeal membrane oxidation or extracorporeal CO2 elimination and heart-lung machines. In such cases, xenon is administered to the patient as part of these treatments. The formulations of the present invention can also be infused and/or enriched with xenon.

According to the present invention, liquid formulations are provided which readily dissolve lipid-soluble gases such as xenon or krypton as mentioned above by virtue of certain lipophilicities.

Blood substitutes, in particular perfluorocarbon emulsions (e.g. perflutron), can be considered as examples of such liquids.

In particular, perfluorocarbons can be administered intrapulmonary, so that when loaded with xenon, they can be used on the one hand to treat acute lung injury, but on the other hand also to induce anesthesia, sedation and/or analgesia on the basis of the pharmacological effect of xenon. The combined pulmonary administration of perfluorocarbons and xenon is a new approach to the treatment of severe respiratory crisis for incomplete liquid ventilation and additional anesthesia or additional pain relief. It can reopen collapsed, atelectasis areas that cannot be reached by conventional treatments, thus restoring gas exchange to these areas of the lung.

Perfluorocarbons can also be administered intravenously, so that the perfluorocarbon-based formulation of the present invention can be used for intravenous anesthesia with the aid of xenon. However, perfluorocarbons also have a loading capacity for oxygen, suggesting the possibility of intravenous administration of perfluorocarbons, which are simultaneously loaded with oxygen. It can induce not only anesthesia but also anesthesia and supply (replenish) oxygen. Any kind of difficult intubation to avoid hypoxia, for which no patient safety was known so far, can be performed.

It is well known that a large amount of gas has a high solubility in perfluorocarbons. The perfluorocarbon emulsions of the present invention contain, for example, up to 90% (w/v) perflutron (C)₈F₁₇). MilkAn agent such as phospholipids from egg yolk is additionally required. These emulsions of the invention that can be loaded with xenon have been reported, for example, by J.A. Wahr et al in Anesth.Analg.1996, 82, 103-7.

Suitable fluorocarbon emulsions preferably contain 20% w/v to 125% w/v of a highly fluorinated hydrocarbon such as polyfluorinated dialkylethylene, cyclic fluorocarbons like fluorodecalin, perfluorodecalin. Fluoroadamantamines, or perfluoroamines such as fluorotripropylamine and fluorotributylamine. It is also possible to use monobromoperfluorocarbons such as 1-bromoheptadecafluorooctane (C)₈F₁₇Br), 1-bromopentadecafluoroheptane (C)₇F₁₅Br) and 1-bromotridecafluorohexane (C)₆F₁₃Br). Other compounds may also be used including perfluoroalkylated ethers or polyethers, such as (CF)₃)₂CFO(CF₂CF₂)₂OCF(CF₃)₂、(CF₃)₂CFO(CF₂CF₂)₃OCF(CF₃)、(CF₃)₂CFO(CF₂CF₂)₂F、(CF₃)₂CFO(CF₂CF₂)₃F and (C)₆F₁₃)₂O。

The chlorinated derivatives of perfluorocarbons mentioned above may also be used.

The loading capacity of the above-mentioned perfluorocarbon formulations is very large. For example, a xenon load of 1 to 10ml/ml (at about 20 ℃ C. under standard conditions) can be achieved by the simplest means. For example, they can be loaded with inert gas simply by passing inert gas through the formulation. The volume of gas contained in the liquid formulation of the invention can be determined by simple methods well known to those skilled in the art, such as gravimetric or other analytical means or assays controlled, for example, by radioactive xenon (such as xenon 133) as described by Gerald l.pollack (see above).

The invention also provides (fat) emulsions comprising a lipophilic inert gas dissolved or dispersed in a lipid phase.

It has been found that an appreciable amount of xenon can be added to the (fat) emulsion. Thus, even with the simplest means, xenon can be dissolved or dispersed in an emulsion at a concentration of 0.2 to 10ml or more per ml of emulsion (the concentration being related to the standard state, i.e. 20 ℃ and normal atmospheric pressure). The concentration of xenon depends on a number of factors, especially the concentration of fatty or lipophilic substances. In general, the formulations of the present invention will be "loaded" with xenon to the saturation limit. However, even if a small concentration is provided, for example, a pharmacological activity is observed as long as it is administered intravenously. Even in the case of a 10% fat emulsion, it is easy to achieve a concentration of xenon of 0.3ml to 2ml per ml of emulsion. Higher values such as 3, 4, 5, 6, or 7ml xenon per ml of emulsion are of course likely to be achieved. These emulsions are sufficiently stable, at least in gas-tight containers, that xenon is not released as a gas during normal storage. Quite surprisingly, these emulsions were able to be loaded with high concentrations of xenon at high pressures and were still sufficiently stable.

The solubility properties of inert gases in emulsions are increased by means of so-called solubility promoters, for example less lipophilic compounds which may or may not be pharmacologically active (molecular weights of about 30 to 1000; n-octanol/water partition coefficients preferably greater than 500). Aromatic compounds such as 2, 6-dialkylphenols (e.g., 2, 6-diisopropylphenol) have been found to significantly improve the loading capacity of the emulsion for inert gases.

A large number of documents in the state of the art describe gas-containing contrast agents, in particular for ultrasound studies or nuclear magnetic resonance spectroscopy. The essential feature of such contrast agents is the formation of A separate phase consisting of very small gas bubbles (or even gas-filled balloons) (see in particular WO-A-96/39197, US-A-5088499, US-A-5334381, WO-A-96/41647). Various gases have been proposed including, inter alia, air, nitrogen, carbon dioxide, oxygen and also generally inert gases such as helium, argon, xenon and neon. Only EP-B-0357163 discloses in explicit terms that in particular xenon-containing contrast agents can be used as X-ray contrast agents. Here again, it is emphasized that the injection liquid must contain air bubbles. WO-A-95/27438 further discloses the use of xenon in A method of rare gas imaging by nuclear magnetic resonance. However, nothing is suggested about the analgesic or anesthetic effect of xenon as a contrast agent or spectral. In fact, such an effect is also undesirable. Furthermore, the concentration of gas in the contrast agent is too small to achieve a limited concentration of pharmacological activity. Thus, such contrast agents or formulations for spectrometry are not claimed in the present patent application.

The lipid phase in the formulation, which absorbs, i.e. dissolves and/or disperses, gas, is formed mainly by so-called fats, which are essentially esters of long-and medium-chain fatty acids. Such fatty acids, whether saturated or unsaturated, contain from 8 to 20 carbon atoms. However, it is also possible to use omega-3 or omega-6 fatty acids containing up to 30 carbon atoms. Suitable esterified fatty acids are, in particular, vegetable oils such as cottonseed oil, soybean oil and thistle oil, fish oil and the like. The main component of these natural source oils is fatty acid triglycerides. Formulations in the form of so-called oil-in-water emulsions are of particular importance, the proportion of fat in the emulsion generally being from 5 to 30% by weight, preferably from 10 to 20% by weight. However, emulsifiers are usually present together with the fat, and have been found to be soy-, gelatin-or egg-phospholipids. Such emulsions can be prepared by emulsifying a water-immiscible oil, which is normally a surfactant, with water in the presence of an emulsifier. Other polar solvents may also be present with water, such as ethanol, glycerol (propylene glycol, hexylene glycol, polyethylene glycol, ethylene glycol monoethyl ether, water-miscible esters, etc.). The inert gas has been mixed and incorporated into the lipid phase in the previous process step. In the simplest case, the emulsion prepared is loaded with xenon. This may occur at different temperatures, for example from 1 ℃ to room temperature. Occasionally pressure is also used, for example applying up to 8 atmospheres or more to the container containing the emulsion.

The present invention is applicable to fat emulsions, as are those used for intravenous administration. Fat emulsions essentially contain a suitable fat base (soybean oil or sunflower oil) and well tolerated emulsifiers (phospholipids). A commonly used fat emulsion is Intralipid^*、Intrafat^*、Lipofundin^*S and Liposon^*. More detailed information on fat emulsions can be found in G.kleinberger and H.Pamperl.Infusanstherapiee, 108-117(1983) 3. Fat emulsions also typically contain additives to make the aqueous phase, which is present in liposome form around the fat phase, isotonic with blood. Glycerol and/or xylitol may be used for this purpose. In addition to this, it is often useful to add antioxidants to the fat emulsion in order to prevent oxidation of unsaturated fatty acids. Vitamin E (DL-tocopherol) is particularly suitable for this purpose.

So-called liposomes, which can be formed from the triglycerides mentioned above but also usually from molecules known as phospholipids, are particularly advantageous as lipid phase, especially in oil-in-water emulsions. These phospholipid molecules typically contain a water-soluble moiety formed by at least one phosphate group and a lipid moiety derived from a fatty acid or fatty acid ester.

US-A-5334381 illustrates in detail how liposomes are loaded with gas. In very popular terms, a device is filled with liposomes, such as an oil-in-water emulsion, and the device is then pressurized with gas. During which the temperature dropped to 1 ℃. The gas gradually dissolves under pressure and enters the liposomes. Small bubbles form when pressure is released, but these are encapsulated by liposomes (encapsulated). It is practically feasible to keep xenon or other gases in the fat emulsion at high pressure. Formulations such as these may also be used in accordance with the invention if the isolated gas phase is formed without exceeding the extent of the liposomes and under conditions where the desired pharmacological effect occurs.

The lipids forming the liposomes may be of natural or synthetic origin. Examples of such materials are cholesterol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingomyelin, glycosphingolipids, glucolipids, glycolipids, and the like. Furthermore the surface of the liposomes may be modified by polymers such as polyethylene glycol.

The formulations of the present invention possess a number of advantages. Thus a virtually rapid onset of anaesthetic effect can be observed after injection with the formulation of the invention, which is easy to control compared to all known injection anaesthetics. However, the drug of the present invention not only has an anesthetic effect, but also simultaneously has an analgesic effect, a wakening effect and a euphoric effect. Elimination from the body is dependent only on respiration. In addition, for intravenous anesthetics, xenon concentrations are readily measured in exhaled air. The anesthesia control achieved in this manner is not achievable with conventional intravenous administration heretofore.

The invention accordingly provides a pharmaceutical liquid formulation comprising a lipophilic inert gas in a pharmacologically effective concentration with the proviso that the formulation is not included for use as a contrast agent or in spectrometry. Pharmacologically effective is understood here to mean anesthetic (including sub-anesthetic), analgesic, muscle relaxant, sedative and/or anti-inflammatory effects. In particular, the pharmacological effectiveness of the present invention may be related to systemic effects of the central nervous system.

For achieving the linolenic effect, the xenon loaded on the pharmaceutical preparation may be, for example, about 0.2 to 0.3ml xenon per ml of emulsion. This means that a xenon content of the preparation of at least 0.2ml xenon per ml of emulsion ensures an analgesic and/or sedative effect. Anti-inflammatory activity has been observed at 0.1ml/ml emulsion. It was observed that a continuous infusion of 20ml of a cream containing 0.3ml xenon per ml of cream for 30 seconds produced a sub-anesthetic state in a patient weighing 85 kg. When working with high loads of perfluorocarbon emulsions containing l to 4ml of xenon per ml of emulsion, for example for inducing anaesthesia, 20ml of this emulsion can be infused over 30 seconds. An infusion rate of at least 7.5ml/min is effective to maintain anesthesia. Thus a total of 470ml of emulsion was available for 1 hour of surgery (induction: 20 ml; maintenance: 450 ml). The xenon capacity containing 3ml of xenon per ml of emulsion corresponds to a xenon volume of 1410ml, i.e. a part of the xenon is consumed in inhalation anaesthesia (consumption of 16.6ml per kg for 1 hour based on 85kg body weight).

In any event, the skilled artisan can readily determine the effective xenon concentration by trial and error. As indicated previously, the presence of the emulsion or lipid phase of the liquid formulations of the present invention has an effect on the pharmacological effect. Thus, the concentration limits given above are performable for formulations containing 10 to 40% (weight/volume) lipid or fluorocarbon emulsion. However, emulsions containing more than 40% w/v and up to 125% w/v of, for example, a hydrocarbon, e.g., a fluorinated and/or chlorinated derivative thereof, are also contemplated by the present invention. For such emulsions, the loading capacity of the liquid formulation is higher than the limits given above. On the other hand, as mentioned above, such emulsions affect the effectiveness of xenon in liquid formulations. Thus, the concentration of xenon required for a particular indication is greatly reduced.

The formulations of the invention may thus be used in combination with any of the well-known inhalation anesthetics, i.e. administration of the inhalation anesthetic intravenously. The concentration or amount of inhalation anesthetic used may be reduced when used in combination with laughing gas or xenon and/or other anesthetics such as halothane (halothane), ethyl ether, sevoflurane, desflurane, isoflurane, enflurane (Ethrane), and the like.

Furthermore, it is possible and advantageous in certain circumstances to include additional pharmacologically active ingredients in the formulation in addition to the inert gas. It may be, for example, an intravenous sedative or anesthetic. Depending on whether the drug is water-soluble or fat-soluble, it may then be present with xenon in the aqueous or lipid phase. An effective anesthetic, 2, 6-diisopropylphenol (e.g., 1.5-2.0mg/ml), was found to be particularly suitable for this purpose. Etomidate (Hypnomidate) at a concentration of 0.1-2mg/ml^*A derivative of imidazole-5-carboxylic acid) is also suitable. The concentration necessary for anesthesia, for example, with diisopropylphenol or etomidate, can be reduced by adding dissolved xenon to the other anesthetic. Thus, 1ml of fat emulsion according to the invention (containing about 0.1g of fat per 1ml of emulsion) can contain 2.5-20mg of 2, 6-diisopropylphenol, i.e. for example 2.5, 5.0, 7.5, 10, 15 or 20mg thereof in addition to xenon.

It has now been found that the presence of 2, 6-diisopropylphenol involves several exciting effects: 1. by adding 2, 6-diisopropylphenol, the loading capacity of the lactone emulsion will increase; 2.2, 6-diisopropylphenol and xenon (inert gas) are both present in lower concentrations necessary to obtain an anaesthetic effect, but the analgesic effect of xenon is still observed; 3. the route of administration allows for the first time the administration of TIVA (general intravenous anesthesia) including analgesia, avoiding the drawbacks of the prior art, in particular side effects and lack of control. 4. This is the first use of a volatile analgesic (xenon) administered intravenously.

Under very common conditions, the substance with anaesthetic, analgesic or sedative effect in the presence of xenon may be another anaesthetic, analgesic, muscle relaxant or sedative. Other examples of suitable anesthetics are barbiturates in general (barbiturates, phenobarbital, pentobarbital, secobarbital, hexobarbital and in particular thiobarbital) and opioids. Known analgesics are in particular morphine-type compounds such as hydromorphone, oxymorphone, codeine, dihydrocodeinone, acetyldihydrocodeinone and heroin. Synthetic derivatives of morphine such as meperidine, levomethadone, molindomethacin, pentazocine, fentanyl, and alfentanil may also be used. It is also possible to use low-potency analgesics like anthranilic acid derivatives (flufenamic acid, mefenamic acid), acrylic acid derivatives (diclofenac sodium, tolmetin, zomepirac), levulinic acid derivatives (ibuprofen, naproxen, fenbufen, ketoprofen) and indoleacetic acid or indeneacetic acid derivatives (indomethacin, sulindac). The muscle relaxant used may be a central muscle relaxant such as baclofen, carisoprodol, chlormeprazole, chlorzoxazone, dantrolene, diazepam, phenylalaninol, meprobamate, phencyclamate and diphenhydramine. Sedatives useful in the present invention are in particular benzodiazepine * derivatives such as triazolam, lorazepam, chlorthiazazole, fluzepam, nitrazepam and flunitrazepam.

The formulations of the invention can therefore be used for several purposes: a) intravenous anesthesia induction (optionally with 2, 6-diisopropylphenol or etomidate as a supporting ingredient); b) supplemental intravenous administration in parallel with inhalation anesthesia with xenon or other gases (e.g., laughing gas or desflurane) can greatly reduce the amount of gas used overall. c) For extended periods of maintenance anesthesia, the inert gas containing formulation is administered alone as a supplement, along with, for example, 2, 6-diisopropylphenol or etomidate; since, for example, the concentration of 2, 6-diisopropylphenol can be greatly reduced here, prolonged anesthesia without adverse effects is made possible; d) because of its analgesic effect, the use of xenon in combination with inhalation or intravenous anesthetics can significantly reduce or entirely eliminate supplemental anesthesia; e) the intravenous xenon preparation, whether used in combination with an inhalation anesthetic or an intravenous anesthetic, reduces the need for muscle relaxants until it can be completely dispensed with.

From the above comments it is clear that the invention is not limited to anaesthesia as a field of use. The term anesthesia herein includes both induction and maintenance of anesthesia. In addition, the preparation of the invention also has a pain-relieving effect, which becomes evident in conjunction with anesthesia. However, in certain circumstances, such as for acute and chronic pain therapy, additional levels of flaccid or sedation are often desirable. Intravenous administration at sub-anesthetic doses over a longer period of time (1 hour or even several days) produced enhanced pain suppression. One particular field of application of the formulations of the invention as anesthetics is emergency medicine. This often requires a particularly short wake-up period after deep painless anesthesia. Another example is the emergency treatment of myocardial infarction. In this case the formulation of the invention is used to reduce sympathetic tone and relieve pain. Therefore, the medicine of the present invention can be widely used for treating inflammation and pain. A further possibility here is the topical use of the medicament of the invention.

It is also possible to consider ointments and creams (fat emulsions and liposomes), etc., which can be applied, for example, to already damaged tissues. These agents can also be sprayed into the cavity and joints in order to produce pharmacological effects.

The ointments and creams according to the invention are particularly suitable for local pain relief. Where the ointment is applied to the treated site, optionally providing hermetic wound healing. The invention therefore also produces an effect by means of a plaster, which on the one hand carries the preparation according to the invention to the wound to be applied and on the other hand takes the form of a suitable plaster sleeve of any airtight design.

In its broadest sense, the present invention is therefore understood to be a liquid or gel-like formulation containing an inert gas in dissolved or dispersed form. As demonstrated herein by way of example with a fat emulsion, the liquid or gel-like formulation of the invention is characterized in that it contains a pharmacologically active gas dissolved in a well-distributed separate phase. Generally, the separate phase is the dispersed phase of a dispersion or emulsion. However, the separated phase containing the gas is also the continuous phase. The formulations of the present invention are generally composed in such a way that the dispersed phase has the properties of dissolving gas. With regard to the lipophilic inert gas used, one possibility is therefore to have a fat emulsion with isolated, very small fat droplets or liposomes which contain the inert gas in dissolved form. However, in general, it is preferred that the formulations of the present invention are emulsions, the dispersed phase of which normally contains the activated gas.

Another embodiment of the invention is a method of inducing anesthesia, sedation, analgesia, muscle relaxation, and inflammatory therapy. During such treatment, the liquid formulation is typically administered to the patient parenterally. In addition, the present invention relates to a method of maintaining anesthesia by administering the above liquid formulation. Administration of the liquid formulation of the present invention in this manner ensures that the above-described effects occur rapidly. A particular advantage of any of the above-described methods of the present invention is based on the fact that liquid formulations can be administered over a longer time interval, e.g. several minutes or hours, and do not cause e.g. inflammatory side effects.

Experimental part fat emulsion

Commercially available lactone preparations (from Pharmacia)&Upjohn GmbH, Erlangen) was used as a fat emulsion in the following examples. These emulsions consist essentially of soybean oil, 3-sn-phosphatidylcholine (from egg yolk) and glycerol. For example, Intralipid^*The fat emulsion 10 contains the following components: soybean oil 100g 3-sn-phosphatidylcholine 6g glycerol from egg yolk22.0g of water for injection 1000ml are adjusted to pH 8.0 energy value/l with sodium hydroxide: 4600KJ (1100kcal) osmolarity: 260mOsm/l, e.g. Intralipid^*20 the fat emulsion contains the following components: soybean oil 200g 3-sn-phosphatidylcholine from egg yolk 12g glycerol 22.0g water for injection 1000ml adjusted pH to 8.0 energy value/liter with sodium hydroxide: 8400KJ (2000kcal) osmolarity: 270mOsm/l loading of xenon-containing perfluorocarbon emulsions

A series of perfluorocarbon emulsions were prepared or purchased and loaded with xenon. The activity of the preparation was verified in animal models (rats). All emulsions were used in the same manner as the above-described lactone formulations, i.e. all experimental animals were rapidly anesthetized by otic injection (about 1 ml).

Each emulsion was placed in a beaker and loaded with xenon gas through it.

The following perfluorocarbon compounds used were: perfluorohexyloctane (1), perfluorodecalin (2), perflubron (C)₈F₁₇)(3)。

Emulsifiers such as egg yolk lecithin (lipid E100 from Lipoid GmbH, Ludwigshafen), pluronic PE6800 and pluronic F68 are also used to prepare the emulsion.

For all emulsions it was established that only 40% (weight/volume, i.e. weight of perfluorocarbon compound to volume of emulsion) of perfluorocarbon emulsions would dissolve 1 to 4ml xenon per ml of emulsion.

Research on laboratory animals

To confirm the effectiveness of the formulation of the invention, the experiment was carried out on 24 pigs aged 14 to 16 weeks and weighing 36.4-43.6 kg. They were randomly divided into 6 groups, which were either anesthetized by conventional methods orAnaesthesia was performed with the emulsion of the invention. In all groups, anesthesia was induced by intravenous injection of pentobarbitone (8mg/kg body weight) with buprenorphine hydrochloride (0.01mg/kg body weight) in large doses (bolus). Anesthesia is then continued with either conventional inhalation anesthetics (laughing gas or xenon/oxygen mixtures) or intravenous administration of pentobarbitone and buprenorphine hydrochloride. Anesthesia was maintained in one group (control) by intravenous administration of 2, 6-diisopropylphenol (10mg/lml emulsion). For the maintenance of anaesthesia, two groups of pigs (according to the invention) each containing 4 pigs (each group) received an intravenous infusion of 1ml/kg/h of a 10% by weight fat emulsion according to the invention, which had been previously saturated with xenon (approximately 0.6ml of xenon per ml of emulsion; determined by a pycnometer; filled with said Intralipid at a pressure of 5 to 7 bar xenon by filling it with^*A higher proportion of xenon (up to about 2.0ml) was obtained with the 10 emulsion). In group 2, 7.5mg/kg body weight/h of 2, 6-diisopropylphenol was additionally administered together with the fat emulsion.

The pigs underwent a surgical operation (standard operation: left femoral artery dissection) (identical in each group and for each experimental animal) and were recorded for epinephrine levels, heart rate, arterial blood pressure and oxygen consumption. To achieve the desired level of analgesia and depth of anesthesia in each group, it was also established how much additional pentobarbitone was administered.

Watch (A)

Group adrenalin heart rate arterial blood pressure VO₂Pentobarbital requirements

pg/ml [min^-1] [mmHg] [ml/min]Requirement amount

mg/kg/min

Control group 601151104100.25

134 120 105 391 0.36

112 105 115 427 0.31

85 98 101 386 0.42

Group 1381121123410.09

21 106 100 367 0.04

16 95 104 348 0.11

30 112 118 334 0.15

Group 21088100325-

23 100 85 346 -

14 94 93 331 -

8 104 87 354 -

Evaluation of the results of experiments on the group of animals anesthetized in the conventional manner (not tabulated herein) showed that anesthesia with the xenon/oxygen mixture was significantly superior to the other methods. Surprisingly, the two groups (group 1 and group 2) that have received intravenous administration of the fat emulsion of the present invention show similar good results. It was possible to achieve even a significant improvement in the combined use with 2, 6-diisopropylphenol (group 2), as evidenced by lower adrenaline levels (less stress) and the lack of need for pentobarbitone at all.

The values indicated in the table show that the formulations of the invention are superior to the currently available veinsAnesthetics, especially because of their additional analgesic potency. Thus pigs in group 1 (10% by weight fat emulsion saturated with xenon) showed significantly less stress (epinephrine levels), lower oxygen consumption (VO) by comparison (reference control group)₂) And lower pentobarbitone requirements (i.e., better anesthesia). The difference associated with the state of the art intravenous anesthetic was even more pronounced when the results of group 2 (10% fat emulsion containing 2, 6-diisopropylphenol and enriched in xenon) were compared to the control group. This shows that not only the stress response (adrenaline levels) is significantly reduced. With a significantly reduced heart rate and lower arterial blood pressure, accompanied by a lower oxygen demand, administration of additional amounts of pentobarbitone may be dispensed with.

In another group the use of perfluorocarbon formulations was studied (4 pigs weighing 31.4 to 39.8 kg). 40% perfluorocarbon emulsions with a xenon content of 2.1ml xenon per 1ml of emulsion were used in this experimental group. For induction and intubation, these pigs received 20ml of emulsion intravenously over a 20 second period (equivalent to 1.34ml xenon/kg body weight). After intubation and breathing, the experimental animals thus received a total of 75ml of emulsion (equivalent to 10ml of xenon kg) by continuous intravenous infusion of xenon for 30 minutes^-1h^-1)。

The following table indicates the results of the experiments with epinephrine levels, heart rate, arterial blood pressure and oxygen consumption. The results show that by increasing the xenon loading and infusion rate (above 5 ml/kg/h) a complete anaesthetic effect is produced using the formulation of the invention alone. Overall, oxygen consumption (VO) is consistently established₂) Lower and less stress for anesthesia (adrenaline levels and heart rate).

Adrenaline heart rate arterial blood pressure VO₂

[pg/ml] [min^-1] [mmHg] [ml/min]

8 90 101 301

6 87 96 320

10 94 98 308

5100106316 human body experiment

The inventors of the present invention conducted an experiment to determine the effectiveness of the formulation using the formulation of the present invention. Intralipid in this experiment^*The 10 fat emulsion was filled with xenon as described above. The formulation contained about 0.7ml xenon per 1ml of emulsion as determined gravimetrically. Anesthesia was induced by injection of 30ml of the emulsion over a period of approximately 20 seconds. Anesthesia was observed to occur immediately. Anesthesia was later maintained by infusion of the formulation at a rate of 120 ml/h. After about 20 minutes, the liquid formulation administration was stopped. After about 30 seconds the inventor regained consciousness and summoned his colleagues and conducted experiments in detail shortly thereafter. During the experiment a complete induction of anaesthesia followed by maintenance of anaesthesia with spontaneous breathing and a good analgesic effect was observed (see table below). The inventors reported that there was no dizziness or other side effects often observed after anesthesia with other anesthetics known in the prior art, such as 2, 6-diisopropylphenol (propofol).

Temporal blood pressure exercise ice cube (cube) pair perception [ min ]^-1]Abdominal reaction

0115/65-is-

+20 seconds 110/70-no anesthesia

5110/75 whether or not to anaesthetize

10115/75 whether or not to anaesthetize

15115/80 whether or not to anaesthetize

20120/75 whether or not to anaesthetize

+30 seconds 120/75 is awake

25120/80 is waking up

This experiment was repeated three times and practically identical results were observed.

In none of the above experiments acute or significant toxicity was observed. Further embodiments of the invention

After further investigation with xenon-containing emulsions, the utility of the above-described invention is expected to far exceed the use of inert gases such as xenon or krypton. There is a constant debate in the field of anesthesia as to whether inhalation anesthetics or intravenous anesthetics should be used (j.clin.anasth., vol 8, 5 months 1996). In particular, many experts still believe that inhalation anesthetics are greatly superior to intravenous anesthetics. The latter has the problem that side effects, depth of anaesthesia and end-stage rebound concentrations are not easily controlled. However, to date, no suggestion has been made to use inhalation anesthetics as the active drug in intravenous anesthesia. In this context, the term anesthesia is related to loss of consciousness and is not merely a local effect.

For the purpose of inhalation anesthesia, the prior art uses certain volatile liquids such as halothane (CH)₃-CHBr). Further, diethyl ether or halogenated ether such as methoxyflurane, enflurane and isoflurane is used. These compounds are at ambient temperature (20 ℃ C.; standard pressure)Liquid but volatile. Inhalation anesthetics like this are often used in combination with other gases such as laughing gas.

US-A-4622219 entitled "method of inducing local anesthesiA using microdroplets of A general anesthetic" describes the coating of microdroplets of the general anesthetic methoxyflurane with A monolayer of dimyristoylphosphatidylcholine, which can be administered subcutaneously or intravenously to A patient to induce local anesthesiA. However, in this document it is emphasized that the effect is only local. The problem with this document is to overcome the disadvantages of local damage caused by injection of organic phase into the skin or other tissue. Accordingly, this document suggests that molecular layers made of certain compounds should be provided in order to avoid coalescence of the organic phase. As shown in this example, the amount of the compound never exceeds about 1% m/v of a complete droplet containing the formulation.

According to the broader concept of the present invention, the object is to provide a liquid formulation that can be used for general anesthesia.

This object is solved by a liquid formulation comprising at least 5% by weight (m/v) of an emulsion/dispersion and which contains an effective anaesthetic amount of compound I, II, III or IV.

R₁-C＝C-R₂ IV

Wherein R is₁To R₆Each independently of the other being hydrogen, C₁-C₃-alkyl or halogen and X is a single bond or oxygen or sulphur.

With the proviso that the compounds (I-IV) are liquid or gaseous at room temperature (20 ℃) and have an oil-water partition coefficient (in n-octanol, 20 ℃) of about 20.

The anaesthetically effective compounds may be, for example, ethers such as diethyl ether, butadiene ether, desflurane, sevoflurane, methoxyflurane, enflurane and isoflurane. Halogenated hydrocarbons (halohydrocarbons) may be chloroform, ethyl chloride, trichloroethylene and halothane. Further, anaesthetically effective organic gases such as ethylene, cyclopropane and acetylene may be mentioned.

Substituent R₁To R₆Can be independently hydrogen or C₁-C₃-alkyl or halogen. Particularly desirable from the halogen are fluorine, bromine and iodine. C₁-C₃Alkyl groups may be substituted, in particular with the halogens mentioned above. Further, two residues such as R₁And R₄May combine to form a five-or six-membered ring (which may further contain heteroatoms such as oxygen, followed by sulfur atoms).

It is preferable to use a compound having an oil-water distribution coefficient of 50 to 1000. For example, enflurane has a water-oil partition coefficient of 120 and methoxyflurane has a water-oil partition coefficient of 400.

It is exciting that such formulations are applied for intravenous administration and have analgesic or sedative effects systemically rather than only locally. This effect is particularly exciting in the view disclosed in US-A-4622219, which expects particularly high concentrations of, for example, methoxyflurane.

Of particular importance is the high lipid content of the formulations of the present invention. It has been found that the lipid fraction of the formulation is critical and therefore the lipid fraction of the formulation, in the broader aspect of the invention, must be at least 5% by weight (m/v). Accordingly, the present invention preferably uses a fat emulsion containing about 10 to 40% (m/v) fat.

The present invention preferably employs volatile liquids well known in the art for use as inhalation anesthetics. These compounds are purely water-soluble compounds that are carried by the bloodstream through binding to blood cells and proteins. There has never been reported that these compounds may have an effect on the central nervous system when administered in a liquid formulation.

The preparation of the invention is prepared byPreferred liquid compounds are those which react with already prepared emulsions, such as Intralipid^*10 or Intralipid^*The 20 fat emulsion can be conveniently prepared. In a preferred method of preparing the formulation, the mixed ingredients are sonicated.

Loading of emulsions of different volatizable anesthetics

The following volatile anesthetics were used in amounts of 1 to 5ml each with 50ml of Intralipid^*20 or Intralipid^*10, mixing emulsion:

fluoroalkane

Chloroform

Ether (A)

Methoxyflurane

Enflurane

Isofluorane

Desflurane

Sevoflurane

Butadiene ethers

These compounds readily dissolve in emulsions without forming a separate phase or precipitate. The mixed compositions occasionally have to be heated and shaken, or they are subjected to a brief sonication.

The efficacy of the formulation was tested in laboratory rats. The anesthetic formulation was injected intravenously (0.5 ml). In particular, immediate effects of anesthesia were observed with halothane, enflurane and methoxyflurane. All laboratory rats were enrolled in this experiment.

Further, the inventors performed an experiment in themselves. It received 5ml of intravenous infusion (at 40ml of intralipid)^*10 emulsion containing 1ml halothane). An immediate effect of anesthesia was observed during injection of this formulation.

Claims (13)

1. A liquid formulation for inducing and/or maintaining anaesthesia in the form of an emulsion comprising xenon gas in an effective concentration as an anaesthetic.

2. A liquid formulation for inducing sedation in the form of an emulsion comprising a concentration of xenon gas effective as a sedative.

3. A liquid formulation for inducing analgesia in the form of an emulsion, the formulation containing xenon gas in an effective concentration as an analgesic.

4. A liquid formulation for inducing muscle relaxation in the form of an emulsion comprising xenon gas in a concentration effective as a muscle relaxant.

5. A liquid formulation for the treatment of inflammation in the form of an emulsion comprising xenon gas in an effective concentration as an anti-inflammatory agent.

6. The formulation according to any one of the preceding claims 1 to 5, which is in the form of a perfluorocarbon emulsion.

7. The formulation of any one of claims 1-5 in the form of a fat emulsion comprising an oil-in-water emulsion or a liposome emulsion.

8. A formulation according to any one of the preceding claims 1 to 5, wherein the further drug is additionally present in dissolved form.

9. The formulation of claim 8 wherein the additional pharmacologically active agent is an intravenously administered anesthetic, analgesic, sedative, or muscle relaxant.

10. A formulation as claimed in claim 9 wherein the additional pharmacologically active agent is 2, 6-diisopropylphenol, etomidate or a derivative thereof.

11. The formulation of claim 9 wherein the additional pharmacologically active agent is fentanyl or alfentanil.

12. An infusion drug for anaesthesia comprising a formulation according to any of the preceding claims 1-5.

13. Use of xenon in the manufacture of a liquid emulsion for use as an induction and/or maintenance anaesthetic.