Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
  • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
  • B01F23/20—Mixing gases with liquids
  • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
  • B01F23/231—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids by bubbling
  • B01F23/23105—Arrangement or manipulation of the gas bubbling devices
  • B01F23/2312—Diffusers
  • B01F23/23124—Diffusers consisting of flexible porous or perforated material, e.g. fabric

Definitions

• the invention relates to a method for dissolving a gas having short-lived physical properties in a liquid.
• Radioactive gases are gases which contain a so-called radionuclide or a radioisotope. Such gases are used, inter alia, in positron emission tomography (PET).
• PET positron emission tomography
• NMR magnetic resonance spectroscopy
• MRI magnetic resonance imaging
• hyperpolarized gases used as signal generators, improved images or an improved signal-to-noise ratio can be achieved with the aforementioned methods based on the magnetic resonance.
• hyperpolarized noble gases for NMR or MRI techniques is e.g. described in US 6,491, 895 B2, US 2001/0041834 A1 or US 6,696,040 B2.
• US Pat. No. 6,488,910 B2 describes a method for introducing hyperpolarized 3 He and 129 Xe into a liquid by means of microbubbles.
• the fluid has a very low solubility for hyperpolarized 3 He and 129 Xe.
• a transition of the hyperpolarized 3 He and 129 Xe from the microsphere into the liquid should be largely prevented or at least inhibited, thus minimizing the depolarization and improving the relaxation time.
• EP 0968 000 B1 discloses blood circulating injectable contrast agent formulations for use in magnetic resonance analysis methods consisting of microvesicles filled with a mixture of hyperpolarized noble gas and a high molecular weight inert gas. The presence of the inert gas is believed to stabilize the hyperpolarized noble gas to avoid exiting the hyperpolarized gas through the vesicle shell and leaving the hyperpolarized gas in the microvesicles.
• the object of the present invention is to provide a method by means of which gases with short-lived physical properties can be brought into solution in a simple yet efficient manner.
• a method for dissolving a gas having short-lived physical properties in a liquid comprising the steps of providing the gas with short-lived physical properties, Providing the liquid, introducing the gas having short-lived physical properties into the liquid, the method being characterized in that the gas having short-lived physical properties is supplied to the liquid via a semi-permeable, gas-permeable membrane.
• the method according to the invention with semipermeable, gas-permeable membranes affects the half-life of the gases with short-lived physical properties to a much lesser extent than a method for the direct solution of the gases in the liquid.
• the half-life of the gas with short-lived physical properties is left at a high level by the method according to the invention. This is especially true for hyperpolarized gases, as it has been shown that semipermeable, gas-permeable membranes depolarize the hyperpolarized gases only slightly.
• gases having short-lived physical properties are understood to be those whose specific physical property decays over time, with half-lives of a few milliseconds to several hours.
• Radioactive gases include, as already mentioned, radioactive gases or hyperpolarized gases.
• Radioactive gases are e.g. used in positron emission tomography (PET).
• PET positron emission tomography
• the radioactive gases contain so-called radioisotopes or radionuclides.
• Hyperpolarized gases are used for magnetic resonance spectroscopy (NMR) or magnetic resonance imaging or magnetic resonance imaging (MRI).
• NMR magnetic resonance spectroscopy
• MRI magnetic resonance imaging
• the use of hyperpolarized gases significantly improves the signal-to-noise ratio.
• the xenon isotopes 129 Xe or 131 Xe or the helium isotope 3 He are mainly used here.
• molecular gases are also accessible by hydrogenation of suitable molecules with double or triple bonds with para- 1 H 2 or ortho- 2 H 2 (so-called PHIP or PASADENA experiment).
• the polarization of hydrogen isotopes can be transferred in the low field (ALTADENA effect) to other isotopes with a nuclear spin (eg 13 C or 19 F).
• the method according to the invention is characterized in that the gas with short-lived physical properties is supplied bubble-free via the membrane of the liquid.
• This provides a molecular solution of the gases with short-lived physical properties without foaming in the solution.
• the method is therefore suitable for a wide variety of liquids, solutions and emulsions (amphiphilic substances, protein solutions, blood plasma, fat emulsions, etc.), which in part tend to foam too much.
• the liquids should be as free of para- and ferromagnetic impurities as possible, as they would lead to rapid depolarization of hyperpolarized gases. The removal of dissolved Oz should therefore be taken into account.
• the membrane is embedded in a housing such that the housing is divided by the membrane into at least one space for the liquid and at least one space for the gas and the space for the liquid at least one inlet and an outlet and the space for the gas has at least one inlet for the gas, via which the gas is supplied to the membrane.
• a continuous countercurrent of gas and liquid, through which the gas is enriched in the solution is particularly preferred.
• the membrane used in the process according to the invention may be a flat membrane or at least one hollow-fiber membrane.
• hollow fiber membranes are used, wherein the hollow fiber membranes are arranged in a bundle.
• a wall thickness of the hollow fiber membrane between 5 and 150 ⁇ m, more preferably a thickness between 10 and 100 ⁇ m.
• the membrane used in the process according to the invention must on the one hand have a sufficient permeability to the gas with short-lived physical properties and on the other hand be impermeable to the liquid to which the gas is supplied for a sufficient period of time.
• the membrane used according to the invention may be hydrophilic or hydrophobic.
• a hydrophilic membrane it preferably has a sealing layer that is impermeable to gas, but permeable to gas.
• the membrane used according to the invention is a hydrophobic membrane.
• this hydrophobic membrane has a continuous microporous structure over its wall. Such membranes are described for example in DE 28 33 493 C3, DE 32 05289 C2 or GB 2 051 665.
• the hydrophobic membrane has an integrally asymmetric structure with a microporous support layer and a dense or nanoporous separating layer adjoining this support layer.
• dense or nanoporous release layer membranes are e.g. in EP 299 381 A1, WO 99/04891 or WO 00/43114.
• the membranes for dissolving gas having short-lived physical properties in a liquid are preferably made of a polymer based on polyolefins. This may be a single polyolefin or a mixture of several polyolefins.
• Particularly preferred for dissolving gas having short-lived physical properties in a liquid are such membranes made of polypropylene, polyethylene, polymethylpentene and modifications based thereon, Copolymers or blends or blends of these polyolefins are made with each other or with other polyolefins.
• membranes which consist of silicone compounds or have a silicone coating are suitable for the process according to the invention.
• membranes made from a polymer based on an aromatic sulfone polymer such as e.g. Polysulfone, polyethersulfone or polyarylethersulfone to call suitable.
• the method for dissolving gas having short-lived physical properties in a liquid is particularly suitable for dissolving hyperpolarized gases.
• the method according to the invention is characterized in that the hyperpolarized gas is xenon.
• liquids can be used to dissolve gas with short-lived physical properties.
• lipofundin, blood plasma, glucose solution or halogenated blood substitutes (perfluorocarbons) should be mentioned in addition to the fluids already mentioned.
• the liquid in which the hyperpolarized gas is dissolved is a physiological fluid.
• the liquid in which the hyperpolarized gas is dissolved is blood.
• a solution of hyperpolarized gas in a liquid prepared by the method of the invention is to be used as a contrast agent for analytical methods based on magnetic resonance.
• the utility of hyperpolarized gases as contrast agents for analytical methods based on magnetic resonance is described in detail in US Patent 6,630,126 B2.
• a solution of hyperpolarized gas in a liquid prepared by the process according to the invention can also be used for: • Xe-NMR or SPINOE-NMR in the field of biotechnology to elucidate the structure of giant molecules or the dynamics of proteins
• the method according to the invention for dissolving hyperpolarized gas in a liquid is suitable both for imaging analysis methods such as magnetic resonance imaging (MRI) and for magnetic resonance spectroscopic analysis methods such as magnetic resonance spectroscopy (NMR).
• imaging analysis methods such as magnetic resonance imaging (MRI)
• magnetic resonance spectroscopic analysis methods such as magnetic resonance spectroscopy (NMR).
• a solution of hyperpolarized gas in a liquid prepared by the method of the invention as a contrast agent for analytical methods based on magnetic resonance for use on human or animal organs and tissues.
• the hyperpolarized xenon was pumped through the lumens of the hollow fiber membranes of the membrane module, partially diffusing into the liquid. From here, the dissolved gas was transported to a reservoir, where it could be detected by an NMR measurement. In order to be able to compare the effectiveness of the method for different solvents, a tube with the xenon gas emerging from the membrane module was guided through the NMR coil in addition to the reservoir. The NMR spectra can thus be referenced to the gaseous xenon signal.
• Circulating compressed air membrane pump pumped through the experimental setup. Since the pump used contains no metallic or magnetic parts, it can also be operated in strong magnetic fields. Thus, this prototype was able to continuously produce hyperpolarized xenon solution.
• the gas volume flow was in both arrangements about 200ml / min at a gas pressure of about lOOmbar. The liquid volume flow was adjusted to about 240 ml / min.
• FIG. 1 schematically illustrates the second arrangement for dissolving hyperpolarized xenon in a liquid.
• the arrangement consists of a hollow fiber module 1 with hollow fibers 3 embedded in potting compound 2 at its ends.
• the outer space 4 around the hollow fibers 3 is transferred over Input port 5 and output port 6 flows through the liquid.
• the liquid is circulated by a pump 7.
• the liquid may also be manually reciprocated.
• the hollow fibers 3 are acted upon via inlet port 8 and outlet port 9 with hyperpolarized xenon.
• the hyperpolarized xenon dissolved in the liquid is detected in the NMR measuring cell 10.
• FIG. 3 shows the signal strength of the hyperpolarized xenon dissolved in lipofundin as a function of the time elapsed after the pump was switched on.
• the broken line in FIG. 3 marks the switch-on time of the pump.
• the second line marks the determined signal curve of the hyperpolarized xenon dissolved in lipofundin.
• Example 3 129 Xe was introduced via a membrane in a manner analogous to Example 2 into lipofundin (Example 3) or DMSO (Example 4).
• these liquids were covered with 129 Xe and flowed over by 129 Xe.
• Simple overlaying or overflow of the liquids with gas did not give a measurable signal in the case of the liquid lipofundin (Comparative Example 3a) or DMSO (Comparative Example 4a), whereas the membrane-mediated process according to the invention described was successful in both cases.
• Example 3 and Comparative Example 3a are shown in FIG.
• the upper signal curve a shows the 129 Xe signal in Lipofundin for Example 3 according to the method of the present invention and the lower signal curve b shows the 129 Xe signal in Lipofundin for Comparative Example 3a, determined using the overlay method.
• Example 4 and Comparative Example 4a are in FIG. 5 shown.
• FIG. 5 shows a comparison of the 129 Xe signal dissolved in DMSO, wherein the upper signal curve a (Example 4) for the method according to the present invention and the lower signal curve b (Comparative Example 4a) for the overlay method were determined.
• the signal curve a in both cases shows a peak characteristic for dissolved hyperpolarized 129 Xe, which could not be detected in the signal curves b.
• Hyperpolarized xenon was introduced into water using a high pressure hollow fiber module.
• the gas pressure of the hyperpolarized xenon flowing through the hollow fibers was 7 bar.
• the high pressure hollow fiber module contained X50 hollow fiber membranes, Celgard. These hydrophobic membranes based on polypropylene are typically used for the degassing of liquids. It could be shown that hyperpolarized xenon can be dissolved in water in comparatively large amounts with the method according to the invention, although the solubility coefficient of xenon in water has a very low value.
• Example 6 shows NMR spectra of hyperpolarized xenon in water, recorded using the method according to the invention at elevated gas pressure of 7 bar (Example 5), and of hyperpolarized xenon in water using the overlay method likewise at elevated gas pressure of 7 bar (Comparative Example 5a) ,
• the signal determined for the control of the gaseous hyperpolarized xenon used is 0 ppm
• the signal of the hyperpolarized xenon dissolved in water is about 190 ppm.
• the upper signal curve (Example 5) was determined using the method according to the invention. In this signal curve, a strong signal of dissolved hyperpolarized xenon at 190 ppm can be seen.
• the lower curve (Comparative Example 5a) was determined using the overlay method.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Radiology & Medical Imaging (AREA)
• Epidemiology (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Magnetic Resonance Imaging Apparatus (AREA)
• Separation Using Semi-Permeable Membranes (AREA)

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• 2005
  • 2005-06-09 DE DE102005026604A patent/DE102005026604A1/de not_active Withdrawn
• 2006
  • 2006-06-06 WO PCT/EP2006/005349 patent/WO2006131292A2/de not_active Ceased
  • 2006-06-06 EP EP06754128A patent/EP1901782B1/de not_active Not-in-force
  • 2006-06-06 US US11/916,662 patent/US20080199401A1/en not_active Abandoned
  • 2006-06-06 JP JP2008515120A patent/JP5080457B2/ja not_active Expired - Fee Related
  • 2006-06-06 ES ES06754128T patent/ES2393113T3/es active Active

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