WO2002045721A1 - Complexes a base de gaz noble - Google Patents

Complexes a base de gaz noble Download PDF

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Publication number
WO2002045721A1
WO2002045721A1 PCT/GB2001/005356 GB0105356W WO0245721A1 WO 2002045721 A1 WO2002045721 A1 WO 2002045721A1 GB 0105356 W GB0105356 W GB 0105356W WO 0245721 A1 WO0245721 A1 WO 0245721A1
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WO
WIPO (PCT)
Prior art keywords
cyclodextrin
complex
formulation
noble gas
xenon
Prior art date
Application number
PCT/GB2001/005356
Other languages
English (en)
Inventor
Rodney Stewart Mason
Alexei Uriah Moozyckine
John Dingley
Original Assignee
Uws Ventures Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0029586A external-priority patent/GB0029586D0/en
Application filed by Uws Ventures Limited filed Critical Uws Ventures Limited
Priority to AU2002220881A priority Critical patent/AU2002220881A1/en
Publication of WO2002045721A1 publication Critical patent/WO2002045721A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Definitions

  • the present invention is concerned with noble gases for use in pharmaceutical applications.
  • Xenon is a highly polarizable, inert but hydrophobic atom which has a van der aals radius of approximately 2A.
  • Xenon is a colourless, odourless and tasteless inert gas of atomic number 54.
  • Xenon has been proposed as an inhalation anaesthetic because it has both anaesthetizing and analgesic action.
  • the use of xenon as an inhalation anaesthetic involves a high consumption of the gas unless very sophisticated breathing circuits are used.
  • the use of xenon has previously been restricted due to the cost disadvantages which are incurred when such an expensive gas is exhausted to t the atmosphere.
  • treatment of a patient with such a gas requires the use of expensive technical equipment. It is for these reasons that xenon has not been widely used in anaesthesia.
  • Xenon has a number of advantages over other inhaled anaesthetic agents which are currently favoured.
  • One such advantage is the lack of side- effects on the cardiovascular system.
  • a further potential advantage of xenon is that it may have brain protecting properties. The use of xenon and xenon gas mixtures for treating neurointoxications is discussed in PCT patent application EP00/02025.
  • xenon in anaesthesia has other beneficial effects such as a short wake up time; a patient subjected to xenon induced anaesthesia wakes up from the anaesthesia quickly once the administration of xenon is stopped.
  • this advantage may not be considered a very important parameter if the xenon is being used for its lack of cardiovascular side effects rather than its short wake up time, or if the xenon is being used for another reason, for example as a protective drug for the nervous system.
  • PCT Patent Application EP98/01304 discloses a liquid preparation for inducing and/or maintaining anaesthesia, which contains a lipophilic inert gas (such as xenon) in a concentration effective as an anaesthetic.
  • a lipophilic inert gas such as xenon
  • the inert gas is said to be dissolved or dispersed in a carrier (such as a fatty emulsion) .
  • the liquid preparation disclosed however has a number of disadvantages.
  • the main disadvantage is the large volume of lipid that has to be infused in order to deliver enough dissolved xenon to achieve anaesthesia.
  • a further potential disadvantage is that xenon will diffuse out of the blood into the lungs as the blood passes through the lungs before reaching the brain; therefore a higher infused dose of xenon is required as the tendency for the xenon to diffuse out of the blood increases.
  • Cyclodextrins are able to form complexes with noble gases, for example, ⁇ -cyclodextrin with Kr and ⁇ - cyclodextrin with Xe.
  • Cyclodextrin complexes of krypton are discussed in: M Sakurai, M Kitagawa, H Hoshi, Y Inoue, R Chuio, "A molecular orbital study of cyclodextrin (cyclomalto-oligasaccharide) inclusion complexes. Ill, dipole moments of clyclodextrins in various types of inclusion complex", Carbohydr. Res . , 198, 1990, 181-191.
  • Natural (parent) cyclodextrins are cyclic carbohydrates derived from starch by the action of cyclodextrin glycosyl transferase (CGTase) .
  • the geometry of cyclodextrins can be described as toroidal frustum (or truncated cone) , which consist structurally of 6, 7 or 8 ⁇ -(l,4) linked D-glucopyranose units in a chair conformation.
  • Modifications in this way can be used to increase water solubility of cyclodextrins derivatives. Such modifications may also be used to optimise the attraction forces between xenon and cyclodextrin.
  • the cyclodextrin molecule therefore is capable of acting as a host to a xenon guest atom thereby forming a molecular inclusion complex.
  • the principle structure of a parent cyclodextrin containing a xenon atom is shown by way of illustration in Figure 1.
  • Cyclodextrins are not simply solubilising agents, but are chemicals able to form stable molecular inclusion complexes with guest atoms such as xenon. Therefore, these inclusion complexes, represent species that are characterised by unique physico-chemical properties and usually can be separated from solution, dried and purified without decomposition.
  • a molecular complex is defined as a non- covalently bound species of definite substrate-to- ligand stoichiometry that is formed in a facile equilibrium process in solution (K A Connors, Binding Constants - The measurement of molecular complex stability, Wiley Interscience, New York, 1987) . Therefore, the formation of a molecular complex cannot be described simply as a solubilising process of the guest, because the nature of the inclusion complex depends very little on the nature of the solution. In the complex formation process, the changes in solubility of the guest represent one of secondary effects (this can be either positive-solubilising, negative-desolubilising, or close to zero-solubility does not change) .
  • a formulation for inducing and/or maintaining anaesthesia including a complex of a noble gas and a molecular encapsulating agent .
  • an analgesic formulation which includes a complex of a noble gas and a molecular encapsulating agent.
  • a neuroprotective formulation which includes a complex of a noble gas and an encapsulating agent .
  • the noble gas may include krypton, however (as indicated above) xenon is preferred.
  • the encapsulating agent is a ⁇ -, ⁇ - or - ⁇ cyclodextrin or a derivative thereof.
  • the cyclodextrin is preferably ⁇ -cyclodextrin, ⁇ -cyclodextrin or derivatives thereof; ⁇ -cyclodextrin or a derivative thereof are particularly preferred.
  • the physiological effect of inhaled Xe is determined by the concentration of Xe dissolved in the blood. This concentration is proportional to the partial pressure of Xe in the gas mixture that accesses the lungs and the coefficient of solubility of Xe in blood. It is also inversely proportional to the temperature (that is about 37°C, which cannot, of course, be changed) .
  • the cyclodextrin derivative that has a highest binding constant with Xe is not necessarily the one that will show the best pharmacokinetics as the other processes involved, i.e. the transmission of Xe from the bloodstream to synapses or cell membranes might be better served by the modified cyclodextrin, where the Xe atom is correctly positioned within the host molecule cavity, thus allowing a better contact of Xe with the target site.
  • the issues of toxicity, arising from the high affinity of cyclodextrins to lipids can be particularly important for high concentrations of intravenously administered cyclodextrin/Xe complex and must also be considered.
  • introducing cyclodextrin derivative in the bloodstream can compliment the conventional respiratory xenon anaesthesia, making it possible to decrease the concentration of Xe in the gas mixture, whilst retaining the same therapeutic or anaesthetic effect. This would have the advantage that there will be a substantial reduction in the cost of using Xe as a routine anaesthetic.
  • An advantage of the present invention is that, when it is desirable, the anaesthetic effect could potentially be quickly negated via competitive binding, by introducing into the bloodstream a pharmaceutically- inert substance that forms a more stable complex with cyclodextrin than Xe.
  • This can be used as a controlled eliminating system, forcing Xe to be released from the soluble complex into the blood and ventilated out through the lungs, maintaining the desirable rate of Xe elimination by regulating the delivery of the inert competitive binding agent.
  • the formulation is in liquid form. Further preferably the formulation is dissolved in a pharmaceutically acceptable aqueous carrier for example.
  • a complex including a noble gas and an encapsulating agent, for use as a pharmaceutical substance.
  • a complex including a noble gas and an encapsulating agent (such as a cyclodextrin, or a derivative thereof) , as an anaesthetic.
  • an encapsulating agent such as a cyclodextrin, or a derivative thereof
  • a complex including a noble gas and an encapsulating agent (such as a cyclodextrin, or a derivative thereof) , as an analgesic.
  • an encapsulating agent such as a cyclodextrin, or a derivative thereof
  • a complex including a noble gas and an encapsulating agent (such as a cyclodextrin, or a derivative thereof) , in a neuroprotective formulation.
  • an encapsulating agent such as a cyclodextrin, or a derivative thereof
  • the encapsulating agent and/or the noble gas are substantially as described hereinbefore.
  • the complex is typically soluble in blood.
  • Preferred cyclodextrins for use in this aspect of the invention are as described above with reference to the formulation according to the invention.
  • a further advantage of the use of cyclodextrins in anaesthesia is that there will be a reduction (or removal) of the side effects from the deployment of gas mixtures with high Xe concentration.
  • the density of Xe is 4.5 times higher than that of air, therefore clinical applications of Xe anaesthesia with high Xe concentrations (up to 80% Xe) often have minor negative effects, that manifest themselves in diffusive hypoxia, changes in respiratory rate (lung compliance), etc.
  • lt is therefore possible to use Xe for therapeutic applications without recourse to complicated respiratory delivery systems, by introducing the soluble complex with cyclodextrin intravenously, maintaining a necessary concentration of Xe in the bloodstream through a drip.
  • an infusion agent which comprises a formulation according to the present invention.
  • the formulation of the invention can be used to produce anaesthesia in a patient.
  • non-covalent interactions that contribute to the complex formation are: electrostatic (ion-ion, ion- dipole, dipole-dipole and dipole-induced dipole) , van der Waals, hydrophobic, hydrogen bonding, charge- transfer, ⁇ - ⁇ stacking interactions and steric effects.
  • electrostatic ion-ion, ion- dipole, dipole-dipole and dipole-induced dipole
  • hydrophobic hydrogen bonding
  • charge- transfer charge- transfer
  • ⁇ - ⁇ stacking interactions steric effects.
  • the most important contributions to the complexation thermodynamics of cyclodextrins are penetration of the hydrophobic guest (or its part) into cyclodextrin cavity and dehydration of the organic guest.
  • Xe demonstrates quite clear hydrophobic properties; on the other side, its high polarizability makes it easy to interact with cyclodextrin molecule as induced dipole-dipole type, especially taking into account quite large dipole moments of cyclodextrins ( ca 12 Debye) .
  • the magnitude of binding depends on several factors, e.g. charge of the guest, co-included solvent, temperature, etc. Among these factors, the size and geometry of the guest are the most important.
  • van der Waals atomic diameters of Xe and Kr are 4.05A and 3.60A, respectively.
  • the water solubility of parent cyclodextrins may be increased dramatically by incorporation of hydrophilic groups into exterior original cyclodextrins, the degree of substitution usually ranging from 3 to 18.
  • solubility in water of hydroxypropyl and hydroxyethyl derivatives of ⁇ -cyclodextrin (the least soluble) with degree of substitution 3 to 18 is more than 60 g/lOOmL at 25°C.
  • the ionic class of derivatives are preferred encapsulating agents for parenteral administration; examples of such compounds currently available on the market include Captisol by CyDex Inc. which has proved to be suitable for intramuscular and intravenous injections to humans (does not cause irritation and completely and rapidly eliminated unmetabolized via the kidneys) .
  • Kr is not an anaesthetic at ambient (atmospheric) pressure but would be in a hyperboric chamber where the pressure is greater than atmospheric.
  • Kr is an anaesthetic generally employed in a hyperbaric chamber. It is envisaged that if cyclodextrins allowed large quantities to be delivered to the patient's brain then possibly Kr could work at atmospheric pressure.
  • Rotaxanes are the compounds where several (many) cyclodextrin moieties are threaded through by a linear or branched polymer chain, with substituents on the ends to stop threaded cyclodextrin units from coming off. If the polymer chain is relatively thin, threaded cyclodextrins retain their ability to encapsulate suitable guests (e.g. Xe or Kr) . These rotaxanes might have a high enough solubility in blood and also low toxicity to make it advantageous using such formulations for Xe delivery instead of simple cyclodextrins' derivatives. (See, for example, US Patent 6037387, N Yui, M Terano, H Mori, "Blood- compatible material of a supramolecular structure", 14 March 200) .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Anesthesiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition destinée à induire et/ou maintenir une anesthésie, cette composition comprenant un complexe d'un gaz noble et d'un agent d'encapsulation moléculaire. Il est également possible d'utiliser cette composition en tant que composition analgésique ou dans une composition neuro-protectrice.
PCT/GB2001/005356 2000-12-04 2001-12-04 Complexes a base de gaz noble WO2002045721A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002220881A AU2002220881A1 (en) 2000-12-04 2001-12-04 Noble gas complexes

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0029586.5 2000-12-04
GB0029586A GB0029586D0 (en) 2000-12-04 2000-12-04 Noble gas complexes
GB0109066A GB0109066D0 (en) 2000-12-04 2001-04-11 Noble gas complexes
GB0109066.1 2001-04-11

Publications (1)

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WO2002045721A1 true WO2002045721A1 (fr) 2002-06-13

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014145443A2 (fr) 2013-03-15 2014-09-18 The Board Of Regents Of The University Of Texas System Liquides riches en gaz noble et leurs procédés de préparation et d'utilisation
US10369103B2 (en) 2012-08-10 2019-08-06 The Board Of Regents Of The University Of Texas System Neuroprotective liposome compositions and methods for treatment of stroke
CN111821472A (zh) * 2019-04-17 2020-10-27 中国科学院武汉物理与数学研究所 一种可以递送疏水性药物的超极化129Xe磁共振分子探针

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0357163A1 (fr) * 1988-08-23 1990-03-07 Schering Aktiengesellschaft Milieu de contraste composé de complexes hôte/convive qui produisent des cavités ou des clathrates
US5334381A (en) * 1989-12-22 1994-08-02 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
EP0864328A1 (fr) * 1997-03-10 1998-09-16 Michael Dr. Georgieff Appareil pour l'anesthésie, l'analgésie et/ou la sédation contrÔlée
DE19833014A1 (de) * 1998-07-23 2000-01-27 Messer Griesheim Gmbh Edelgashaltige Injektionsanästhesiemittel
DE19851605A1 (de) * 1998-11-09 2000-05-11 Messer Griesheim Gmbh Mikropartikel enthaltendes Injektionsanästhesiemittel

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0357163A1 (fr) * 1988-08-23 1990-03-07 Schering Aktiengesellschaft Milieu de contraste composé de complexes hôte/convive qui produisent des cavités ou des clathrates
US5334381A (en) * 1989-12-22 1994-08-02 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
EP0864328A1 (fr) * 1997-03-10 1998-09-16 Michael Dr. Georgieff Appareil pour l'anesthésie, l'analgésie et/ou la sédation contrÔlée
DE19833014A1 (de) * 1998-07-23 2000-01-27 Messer Griesheim Gmbh Edelgashaltige Injektionsanästhesiemittel
DE19851605A1 (de) * 1998-11-09 2000-05-11 Messer Griesheim Gmbh Mikropartikel enthaltendes Injektionsanästhesiemittel

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10369103B2 (en) 2012-08-10 2019-08-06 The Board Of Regents Of The University Of Texas System Neuroprotective liposome compositions and methods for treatment of stroke
US11872312B2 (en) 2012-08-10 2024-01-16 The Board Of Regents Of The University Of Texas Systems Neuroprotective liposome compositions and methods for treatment of stroke
US10973764B2 (en) 2012-08-10 2021-04-13 The Board Of Regents Of The University Of Texas System Neuroprotective liposome compositions and methods for treatment of stroke
CN110354067A (zh) * 2013-03-15 2019-10-22 德克萨斯州大学系统董事会 富含稀有气体的液体及其制备和使用方法
JP6998929B2 (ja) 2013-03-15 2022-02-04 ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム 希ガスが豊富な液体ならびにその調製及び使用の方法
EP2968126A4 (fr) * 2013-03-15 2016-11-02 Univ Texas Liquides riches en gaz noble et leurs procédés de préparation et d'utilisation
US20160030470A1 (en) * 2013-03-15 2016-02-04 The Board Of Regents Of The University Of Texas System Liquids rich in noble gas and methods of their preparation and use
CN105228591B (zh) * 2013-03-15 2019-08-13 德克萨斯州大学系统董事会 富含稀有气体的液体及其制备和使用方法
WO2014145443A2 (fr) 2013-03-15 2014-09-18 The Board Of Regents Of The University Of Texas System Liquides riches en gaz noble et leurs procédés de préparation et d'utilisation
JP2020054353A (ja) * 2013-03-15 2020-04-09 ボード・オブ・リージエンツ，ザ・ユニバーシテイ・オブ・テキサス・システム 希ガスが豊富な液体ならびにその調製及び使用の方法
WO2014145443A3 (fr) * 2013-03-15 2014-12-11 The Board Of Regents Of The University Of Texas System Liquides riches en gaz noble et leurs procédés de préparation et d'utilisation
CN105228591A (zh) * 2013-03-15 2016-01-06 德克萨斯州大学系统董事会 富含稀有气体的液体及其制备和使用方法
US11491184B2 (en) 2013-03-15 2022-11-08 The Board Of Regents Of The University Of Texas System Liquids rich in noble gas and methods of their preparation and use
JP2016519571A (ja) * 2013-03-15 2016-07-07 ボード・オブ・リージエンツ，ザ・ユニバーシテイ・オブ・テキサス・システム 希ガスが豊富な液体ならびにその調製及び使用の方法
EP4082552A1 (fr) * 2013-03-15 2022-11-02 The Board of Regents of the University of Texas System Liquides riches en gaz noble et leurs procédés de préparation et d'utilisation
CN111821472B (zh) * 2019-04-17 2021-11-19 中国科学院武汉物理与数学研究所 一种可以递送疏水性药物的超极化129Xe磁共振分子探针
CN111821472A (zh) * 2019-04-17 2020-10-27 中国科学院武汉物理与数学研究所 一种可以递送疏水性药物的超极化129Xe磁共振分子探针

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