sign in sign up
<<
Home , Butanilicaine, Oxetacaine, Procaine, Vinylbital

US 2005O255169A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0255169 A1 Pilger et al. (43) Pub. Date: Nov. 17, 2005

(54) ADJUVANT CONTAINING XENON Aug. 10, 2002 (DE)...... 102 36 761.2 Aug. 10, 2002 (DE)...... 102 36 760.4 (75) Inventors: Carsten Pilger, Rheurdt (DE); Peter Neu, Duisburg (DE); Matthias Publication Classification Reyle-Hahn, Berlin (DE) (51) Int. Cl." ...... A61K 33/00; A61K 31/46; Correspondence Address: A61K 31/24 CONNOLLY BOVE LODGE & HUTZ, LLP (52) U.S. Cl...... 424/600; 514/304; 514/537 PO BOX 22O7 WILMINGTON, DE 19899 (US) (57) ABSTRACT (73) Assignee: MESSER GRIESHEIM The invention relates to Xenon or Xenon-containing gases which is/are used for producing an adjuvant that is admin (21) Appl. No.: 10/518,067 istered together with another medicament, Such as an anti Viral, antibacterial, antimycotic, neuroprotective, or antican (22) PCT Fed: Jul. 4, 2003 cerogenic agent, parasympathomimetic, parasympatholytic, Spasmolytic, Symnpathomimetic, Sym (86) PCT No.: PCT/EP03/07186 patholytic, preceptor blocker, tranquilizer, neuroleptic, anti (30) Foreign Application Priority Data , analgesic, antipyretic, anticephalalgic, anti-Par kinson's drug, analeptic, antiepileptic, antiemetic, emetic, a Jul. 5, 2002 (DE)...... 10230544.7 Substance influencing coagulation, an amino acid, a Vitamin, Aug. 10, 2002 (DE)...... 102 36 762O or a hormone. US 2005/0255169 A1 Nov. 17, 2005

ADJUVANT CONTAINING XENON ally. The adjuvant or inhalable medicament comprises gas eous Xenon in pharmacologically or therapeutically effective 0001. The invention relates to a medicament comprising amount, in particular in an amount, concentration or dosage XCO. which has a Subsedative effect, effect, Subanalgesic 0002 WO 02/22141 A2 describes the use of xenon or activity, analgesic activity, Subhypnotic activity, Xenon-containing gases as medicaments, in particular car activity, Subanesthetic activity or activity. diovascular agents. 0014 Subanesthetic amounts of xenon mean the 0003) DE 19933704 A1 describes the use of a liquid amounts, concentrations or dosages of Xenon which are preparation which comprises a lipophilic gas Such as Xenon insufficient for general . Subsedative amounts of for neuroprotection and neuroregeneration. Xenon mean the amounts, concentrations or dosages of xenon which are insufficient for sedation. Subhypnotic 0004. Many pharmacological active ingredients reach the amounts of Xenon mean the amounts, concentrations or target site (site of action) in a patient's body via the dosages of Xenon which are insufficient for inducing and bloodstream. If the blood flow in a part of the body is maintaining Sleep. Subanalgesic or analegesically active restricted, the active ingredients cannot reach the Site of action in Sufficient quantity. Bloodlessness of individual amounts of Xenon mean the amounts, concentrations or parts of organs as a result of insufficient blood Supply is dosages of Xenon which are insufficient for an analgesic referred to as ischemia. Ischemia arises for example in effect. connection with thrombosis or embolism. Particularly seri 0015 The combination medicament is usually employed ous impairments of blood flow in the brain occur in con for humans or mammals. nection with Stroke. 0016. The medicaments which are combined with the 0005 For many medicaments an inadequate concentra adjuvant include besides the medicaments with pharmaco tion of active ingredient in the brain also derives from the logically active Substances (active ingredients) also diag blood-brain barrier. Medicaments are administered in higher nostic aids, X-ray contrast agents, radioactive isotopes. dose for this reason. 0017. The adjuvant is used for example in combination 0006 Means assisting the effect of a medicament are with an antiviral, antibacterial, antimycotic, neuroprotective, referred to in medicine as adjuvant. anticarcinogenic, Sedative, analgesically or anesthetically acting Substance, in particular with (e.g. Sufentanil, 0007. The invention is based on the object of improving remifentanil), , volatile anesthetics (e.g. meth the medicament Supply or active ingredient Supply to parts oxyflurane, , , , and of the body, in particular of the brain. ), C2-adrenoceptor agonists (e.g. , 0008. The invention relates to an adjuvant having the ) or catecholamines. The active ingredi features described in claim 1. ents of the assisted medicaments are usually organic Sub 0009 Xenon or xenon-containing gases (gas mixtures) StanceS. are used as adjuvant or as component of an adjuvant. 0018. The adjuvant is advantageously combined with 0.010 The adjuvant assists in particular medicaments parasympathomimetics, parasympatholytics, Spasmolytics, whose active ingredient or active ingredients are transported Sympathomimetics, , 3-receptor blockers, via the bloodstream. Medicaments with one or more active tranquilizers, neuroleptics, , (sedat ingredients which are transported via the bloodstream are ing agents), analgesics, antipyretics, migraine remedies, referred to herein as hemogenous medicaments. Medica antiparkinson agents, analeptics, antiepileptics, antiemetics, ments assisted by the adjuvant are preferably medicaments emetics, Substances influencing blood clotting, amino acids, intended to act in the brain (cerebral medicaments), espe Vitamins or hormones. cially hemogenous cerebral medicaments. 0019. The adjuvant is further employed with medica 0.011 The adjuvant is preferably administered by inhala ments for NOS inhibition, with medicaments for treating tion. The adjuvant is therefore preferably employed as migraine, with medicaments for treating Septic shock, mul inhalable medicament. tiple Sclerosis, inflammations or inflammatory pain. 0012. Adjuvant and supported medicament which are 0020. The adjuvant is used for example with medica employed together are regarded as combination product or ments for the treatment and/or prophylaxis of Stroke, rep combination medicament, the adjuvant and Supported medi erfusion damage, brain trauma, of impairments of the blood cament being administered together in one medicament (the flow in the brain, of impairment of cerebral perfusion, of adjuvant is present in the medicament) or as separate medi cognitive disorders or of post-ischemia Syndrome. CamentS. 0021. The adjuvant is further employed with a medica 0013 The combination medicament composed of a ment for neuroprotection, a medicament for the prophylaxis Xenon-containing medicament, the adjuvant and a further and/or therapy of impairments of cognitive performance, a medicament (the medicament assisted by the adjuvant) serve medicament for improving the oxygen Supply in the brain or for Simultaneous, Separate or Sequential use of the medica a medicament for promoting blood flow in the brain. ments (of the components of the combination medicament). 0022. The combination medicaments include in particu The combination medicament preferably consists of an lar the adjuvant and a medicament for the therapy of inhalable medicament which comprises xenon (e.g. Xenon or disorders associated with a loSS of cognitive and memory a xenon-containing gas), and of a hemogenous medicament, functions, e.g. in the course of pathological aging process e.g. a medicament which is administered orally or parenter Such as, for example, Parkinson's disease, Alzheimer's US 2005/0255169 A1 Nov. 17, 2005 disease, the organic brain Syndrome, AIDS dementia, 0029 Salicylic acid derivatives are acetylsalicylic acid, depressive pseudodementias, dementing Syndromes, deliria benorilate, diflunisal, ethenZamide gentisate Sodium, Salac as acute organic brain Syndromes, intoxications, withdrawal etamide, Salicylamide, Salicylic acid or Salsalate. Pyrazolone Syndromes or cytopathic influences. derivatives are metamizole (noramidopyrine), moraZone, phenaZone or propyphenaZone. An aminophenol derivative 0023 The adjuvant is advantageously employed in com is paracetamol. Further analgesics are quinine, flunixine, bination with medicaments for chronic neurodegenerative disorderS Such as Huntington's disease, amyotropically lat or benzyl phenylglycolate (mandelic acid benzyl eral Sclerosis, Parkinson's disease, AIDS dementia, Alzhe ester, benzyl mandelate). imer's disease or acute neurodegenerative disorderS Such as 0030 The adjuvant is further employed in combination ischemias of the brain and neurotraumata. with a agent (local anesthetic). Local anes thetic agents are, for example, , benzoVaine, bupi 0024. The adjuvant is advantageously used in combina vacaine, , butoxycaine, , , tion with Sedative Substances, in particular with centrally , fomocaine, , , , Sedative Substances. The Sedative Substances are usually Oxybuprocaine, , , , organic active ingredients having a Sedative effect. The , , tolycaine or . The Sedative Substances are usually contained in a medicament (sedative medicament, Sedating agent or sedative) which is assisted medicament may also be a mixture of two or more administered with the adjuvant, in particular as combination local esthetic agents. product or combination medicament. Such combination 0031. The adjuvant is preferably employed as a gas products or combination medicaments therefore generally mixture which Supports breathing and comprises Xenon and consist of a Xenon-containing medicament as adjuvant and OXygen. of a Sedative medicament for Simultaneous, Separate or Sequential use of the medicaments. Such a combination 0032. The provided adjuvant or the adjuvant produced medicament preferably consists of an inhalable medicament directly on use, in particular in the immediate vicinity of the with Xenon or a Xenon-containing gas and a Sedative medi patient, is for example a gas mixture which comprises from cament which is administered orally or parenterally. The 1 to 80% by volume (based on standard conditions, i.e. 20 adjuvant or inhalable medicament is administered for C., 1 bar absolute) Xenon (e.g. remainder oxygen). The example in an amount, concentration or dosage with a medicament which is administered to the patient advanta Subsedative or sedative effect. geously comprises Xenon in Subanesthetic amounts. Sub anesthetic amounts of Xenon mean amounts or concentra 0025 Sedative medicaments or active ingredients (seda tions of Xenon which are insufficient for anesthesia. These tives) are, for example, long-acting Such as are in general amounts of up to 70% by Volume Xenon, or , medium- and Short-acting barbi preferably up to 65% by volume, particularly preferably up turates Such as , , , bral to 60% by volume, in particular up to 50% by volume is lobarbital, , , proallylanol, Seco Xenon. Pure Xenon is accordingly metered in the Stated barbital and vinylbital, and aldehydes such as concentrations into the patient's respiratory gas. This means hydrate, and and ben that the respiratory gas Supplied to the patient comprises, for Zodiazepines Such as , , , example, from 5 to 60% by volume, 5 to 50% by volume, 5 , , , , to 40% by volume, 5 to 30% by volume or 5 to 20% by , , , , Volume Xenon. In Special cases, e.g. for prophylaxis, espe and . cially during prolonged ventilation, a dosage of Xenon in the respiratory gas with a low concentration, for example from 0026. The adjuvant effects a potentiation of known seda 1 to 35% by volume, 5 to 25% by volume or 5 to 20% by tives. Conventional Sedatives can thus be administered in Volume Xenon in the respiratory gas, may be advantageous. lower dose, whereby side effects can be considerably reduced or avoided. 0033. The gaseous adjuvant preferably comprises besides Xenon one or more gases or Substances which are gaseous at 0027. The adjuvant is further employed in combination body temperature under atmospheric pressure. Gas mixtures with an analgesic. The combination product or combination which can be used are, for example, Xenon-oxygen gas medicament generally consists of a Xenon-containing medi mixtures or gas mixtures of Xenon and one or more inert cament and an analgesic for Simultaneous, Separate or gases Such as or a rare gas (e.g. helium) or Sequential use, in particular for the treatment and prophy Xenon-oxygen-inert gas gas mixtures. Suitable gas mixtures laxis of pain. The combination medicament preferably con are described in WO 02/22141 A2, to which reference is Sists of an inhalable medicament with Xenon or a Xenon hereby made. containing gas and an analgesic which can be administered orally or parenterally. 0034 Gaseous xenon (pure xenon) is generally provided as compressed gas in compressed gas containerS Such as 0028 Analgesics or analgesic active ingredients are anal compressed gas cylinderS or pressurized cans. It is also gesics with -like effect Such as , possible to provide Xenon-containing gas mixtures in com cetobemidone, codeine, dextromoramide, dextropro poxyphene, fentanyl, hydromorphone, meptaZinol, metha pressed gas containers. The gaseous medicament can also be done, morphine, nalbuphine, , opium complete provided in a container as liquefied gas or gas mixture or in extract, oxycodone, pentazocine, (meperidine), cryogenically Solidified form. piritramide, tilidine, tramadol or naloxone. Further analge 0035. The adjuvant is usually administered using a ven Sics are Salicylic acid derivatives, pyrazolone derivatives tilation machine with a gas-measuring unit or with an and aminophenol derivatives. anesthesia machine. The adjuvant is advantageously pro US 2005/0255169 A1 Nov. 17, 2005 duced directly for use from the pure gases, for example by acaine, tolycaine or tetracaine, 2-adrenoceptor agonists, mixing Xenon, oxygen and, where appropriate, an inert gas clonidine, dexmedetomidine, catecholamines, parasym (e.g. with the aid of an anesthesia machine or a gas-metering pathomimetics, parasympatholytics, Spasmolytics, Sym device) in the immediate vicinity of the patient. pathomimetics, Sympatholytics, B-receptor blocks, tranquil izers, narcoleptics, antidepressants, Sedatives, centrally 0036) One, more than one or all of the gas components of Sedative Sedating agents, analgesics, antipyretics, migraine the gaseous adjuvant, in particular Xenon and oxygen or a remedies, antiparkinson agents, analeptics, antiepileptics, respiratory gas are advantageously mixed with the aid of a antiemetics, emetics, Substances influencing blood clotting, gas-metering device. The gas-metering device is used to amino acids, Vitamins or hormones, medicament S for NOS vary the concentrations of the gas components advanta inhibition, medicaments for treating migraine, medicaments geously during a ventilation. The device and the various for treating Septic Shock, medicaments for treating multiple methods for gas metering, in particular continuous and Sclerosis, medicaments for treating inflammations or inflam discontinuous gas metering with constant or variable gas matory pains, hemogenous cerebral medicaments, medica component concentration, are described in DE 19746 742 ments for the treatment and/or prophylaxis of Stroke, rep A1 and WO 98/31282, to which reference is hereby made. erfusion damage, brain trauma, of impairments of blood 0037. The adjuvant or combination medicament is also flow in the brain, of impairment of cerebral perfusion, of administered for example with a heart-lung machine. cognitive impairments or of postischemia Syndrome, barbi turates; barbital or phenobarbital, allobarbital, amobarbital, 0.038. The combination medicament is employed in the aprobarbital, bralobarbital, cyclobarbital, pentobarbital, following way, for example. Initially a Xenon-containing gas proallylanol, and Vinylbital, , is administered as adjuvant in a Subanesthetically and/or methylpentynol, paraldehyde; , alprazolam, Sedatively active amount. In a next phase of the Sequential bromazepam, brotizolam, diazepam, flunitrazepam, flu administration of the medicament, the hemogenous medi raZepam, loprazolam, lormetazepam, midazolam, cament is administered. nitrazepam, oxazepam, temazepam and triazolam; medica 0.039 The adjuvant is usually administered as dry, moist ments for neuroprotection, medicaments for the prophylaxis gas or water vapor-Saturated gas to the patient. and/or therapy of impairments of cognitive performance; medicaments for Parkinson's disease, Alzheimer's disease, 0040. The adjuvant is, for example, also a liquid prepa organic brain Syndrome, AIDS dementia, depressive ration comprising Xenon. Such a liquid preparation is pseudodementias, dementing Syndromes, deliria as acute described in DE 19933704 A1 to which reference is hereby organic brain Syndromes, intoxications, withdrawal Syn made. dromes or cytopathic influences, medicaments for chronic 1. An adjuvant comprising Xenon or a Xenon-containing neurodegenerative disorders, medicaments for Huntington's gaS. disease, amyotropically lateral Sclerosis, Parkinson's dis 2. The adjuvant as claimed in claim 1, characterized in ease, AIDS dementia, Alzheimer's disease or acute neuro that the adjuvant is an adjuvant for hemogenous medica degenerative disorders, medicaments for ischemias of the ments or active ingredients. brain or neurotraumata, diagnostic aids, X-ray contrast 3. The adjuvant as claimed in claim 2, characterized in agents or radioactive isotopes. that the adjuvant is gaseous. 8. The use of Xenon, of a Xenon-containing gas or of a 4. The adjuvant as claimed in claim 3, characterized in Xenon-containing preparation as adjuvant or to produce an that the adjuvant is administered by inhalation. adjuvant, in particular as adjuvant or to produce an adjuvant 5. The adjuvant as claimed in claim 4, characterized in for hemogenous medicaments or for brain-penetrating medi that Xenon is present in a pharmacologically effective caments or active ingredients. amount, in particular in an amount having a Subsedative 9. The use as claimed in claim 8, characterized in that the effect, Sedative effect, Subanalgesic activity, analgesic activ adjuvant is administered with at least one medicament for ity, Subhypnotic activity, hypnotic activity, Subanesthetic the treatment of acute and chronic cerebral disorders or activity or anesthetic activity. impairments or a medicament for the treatment and/or 6. A combination medicament which comprises Xenon or prophylaxis of ischemic brain disorders or the Sequelae of a a Xenon-containing gas as adjuvant and at least one addi cerebral ischemia or the adjuvant is administered with at tional medicament for Simultaneous, Separate or Sequential least one medicament for the treatment and/or prophylaxis use of adjuvant and medicament. of Stroke, reperfusion damage or brain trauma. 7. The combination medicament as claimed in claim 6, 10. The adjuvant as claimed in claim 1, characterized in characterized in that the additional medicament comprises at that the adjuvant is gaseous. least one medicament from the group consisting of medica 11. The adjuvant as claimed in claim 1, characterized in ments with an antiviral, antibacterial, antimycotic, neuro that the adjuvant is administered by inhalation. protective, anticarcinogenic, Sedative, analgesically or anes 12. The adjuvant as claimed in claim 1, characterized in thetically acting Substance, opioids, Sufentanil, remifentanil; that Xenon is present in a pharmacologically effective anesthetics, Volatile anesthetics, , halothane, amount, in particular in an amount having a Subsedative enflurane, isoflurane, Sevoflurane and desflurane, local anes effect, Sedative effect, Subanalgesic activity, analgesic activ thetics, articaine, benzoVaine, , butanilicaine, ity, Subhypnotic activity, hypnotic activity, Subanesthetic butoxycaine, cinchocaine, cocaine, etidocaine, fomocaine, activity or anesthetic activity. lidocaine, mepivacaine, OXetacaine, Oxybuprocaine, pramocaine, prilocaine, procaine, proxymetacaine, ropiv k k k k k