Meted hyperpolarized noble gas dispensing methods and associated devices

Methods of extracting and removing hyperpolarized gas from a container include introducing an extraction fluid into the container to force the hyperpolarized gas out of an exit port. The hyperpolarized gas is forced out of the container separate and apart from the extraction fluid. Alternatively, if the fluid is a gas, a portion of the gas is mixed with the hyperpolarized gas to form a sterile mixed fluid product suitable for introduction to a patient. An additional method includes engaging a gas transfer source such as a syringe to a transport container and pulling a quantity of the hyperpolarized gas out of the container in a controlled manner. Alternatively, one or more gas syringes can be employed to mete out predictable quantities of hyperpolarized gas or gas mixtures including quantities of buffer gases. Another method includes introducing a quantity of liquid into a container and covering at least one predetermined internal surface or component with the liquid to mask the surfaces and keep the hyperpolarized gas away from the predetermined internal surface, thereby inhibiting any depolarizing affect from same. Examples of surfaces or components suitable for masking include valves, seals, and the like. Yet another extraction method includes expanding a resilient member inside the container to force the hyperpolarized gas to exit therefrom. Containers include a resilient member positioned in fluid communication with the hyperpolarized gas in the container. An additional container includes inlet and outlet ports in fluid communication with the chamber and positioned on opposing sides or end portions of the container. Another container includes a port configured to receive a portion of a syringe therein. An additional aspect of the disclosure relates to calibration methods and apparatus for identifying the hyperpolarization status of the gas.

FIELD OF THE INVENTION
 1. Related Inventions
 The present invention relates to equipment and methods used to remove or
 dispense hyperpolarized gases from containers. The invention is
 particularly suitable for dispensing sterile or pharmaceutical
 hyperpolarized gases for Magnetic Resonance Imaging ("MRI") applications.
 2. Background of the Invention
 Conventionally, MRI has been used to produce images by exciting the nuclei
 of hydrogen molecules (present in water protons) in the human body.
 However, it has recently been discovered that polarized noble gases can
 produce improved images of certain areas and regions of the body which
 have heretofore produced less than satisfactory images in this modality.
 Polarized Helium-3 (".sup.3 He") and Xenon-129 (".sup.129 Xe") have been
 found to be particularly suited for this purpose. Unfortunately, as will
 be discussed further below, the polarized state of the gases is sensitive
 to handling and environmental conditions and can potentially rapidly decay
 from the polarized state.
 Hyperpolarizers are used to produce and accumulate polarized noble gases.
 Hyperpolarizers artificially enhance the polarization of certain noble gas
 nuclei (such as .sup.129 Xe or .sup.3 He) over the natural or equilibrium
 levels, i.e., the Boltzmann polarization. Such an increase is desirable
 because it enhances and increases the MRI signal intensity, allowing
 physicians to obtain better images of the substance in the body. See U.S.
 Pat. No. 5,545,396 to Albert et al., the disclosure of which is hereby
 incorporated by reference as if recited in fill herein.
 The hyperpolarized gas is typically produced by spin-exchange with an
 optically pumped alkali metal. The alkali metal is removed from the
 hyperpolarized gas prior to introduction into a patient to form a
 non-toxic and/or sterile composition. Unfortunately, the hyperpolarized
 state of the gas can deteriorate or decay relatively quickly and therefore
 must be handled, collected, transported, and stored carefully.
 The "T.sub.1 " decay constant associated with the hyperpolarized gas'
 longitudinal relaxation time is often used to describe the length of time
 it takes a gas sample to depolarize in a given situation. The handling of
 the hyperpolarized gas is critical because of the sensitivity of the
 hyperpolarized state to environmental and handling factors and the
 potential for undesirable decay of the gas from its hyperpolarized state
 prior to the planned end use, ie., delivery to a patient for imaging.
 Processing, transporting, and storing the hyperpolarized gases--as well as
 delivery of the gas to the patient or end user--can expose the
 hyperpolarized gases to various relaxation mechanisms such as magnetic
 gradients, contact-induced relaxation, paramagnetic impurities, and the
 like.
 In the past, rigid containers have been used to transport the
 hyperpolarized gas from a polarization site to an imaging site such as a
 hospital. Unfortunately, these conventional transport containers can leave
 relatively large residual amounts of the gas in the container at the end
 use point. For example, absent active pumping (which generally introduces
 unacceptable depolarization to the hyperpolarized gas) an atmosphere of
 hyperpolarized gas typically remains in the transport vessel, in
 equilibrium with the ambient air pressure. As such, a larger volume of gas
 is typically transported to the imaging site to provide the volume desired
 for clinical use. Unfortunately, the hyperpolarized gas is relatively
 expensive to produce and this wasted residual gas can disadvantageously
 escalate the cost of the hyperpolarized product even further. Further, as
 noted above, conventional pump delivery systems which attempt to extract
 the gas from the transport container can cause the polarization of the
 hyperpolarized gas to rapidly decay, thereby limiting the life of the
 product and providing potentially severe time constraints in which
 successful clinical imaging can be performed.
 Further, bag containers have also been used in the past to administer
 hyperpolarized gas to a subject via inhalation. Unfortunately, the
 quantity of gas actually dispensed into the bag can vary. Therefore, it
 can be problematic, especially when blending hyperpolarized gas with a
 buffer gas, to provide reliable repeatable concentrations and/or
 quantities of the inhalable hyperpolarized gas or gas mixtures over a
 plurality of doses. In addition it may be desirable to use different
 amounts of gas or gas mixtures as well as different sized dose containers,
 patient to patient.
 For example, it may be beneficial to provide different known concentrations
 of hyperpolarized gases (25%, 50%, and the like) within a relatively
 constant overall volume of inhalable gas mixture such as a 1 or 1.5 liter
 volume (the remainder of the mixture being formed by suitable buffer
 gases). That is, it is often desirable to have a subject inhale a
 sufficient quantity of the hyperpolarized gas mixture to either partially
 or substantially "filly" inflate the lungs. For image calibration and/or
 regulatory agency guidelines of human or animal administered
 hyperpolarized gas, it can be desirable to provide reliable doses of
 predetermined inhalable volumes of the hyperpolarized gas mixture.
 Unreliable concentrations can, unfortunately, yield varying signal
 intensities, dose to dose. On the other hand, dispensing only
 hyperpolarized gas (no buffer gas) can be more costly, and unnecessary
 from an image viewpoint, as successful images can be obtained with lower
 concentrations of hyperpolarized gas.
 Accordingly, there remains a need to provide improved extraction systems
 and containers to reduce the depolarizing effect of the extraction system,
 to relatively efficiently deliver the hyperpolarized gas to the desired
 subject, and provide more reliable concentrations and/or dosages of
 hyperpolarized gas.
 OBJECTS AND SUMMARY OF THE INVENTION
 In view of the foregoing, it is an object of the present invention to
 provide improved methods to extract hyperpolarized gases from polarization
 cells or vessels, collection, and transport vessels in a way which reduces
 the de-polarization of the gas attributed thereto.
 It is another object of the invention to reduce the residual amounts of
 hyperpolarized gas in collection vessels or transport vessels at the end
 use site.
 It is an additional object of the present invention to provide improved gas
 dispensing and metering methods and systems which allow more reliable dose
 quantities of hyperpolarized gases and/or concentrations of hyperpolarized
 gas mixtures to be dispensed.
 It is yet another object of the invention to provide improved gas
 dispensing methods and associated containers and apparatus to reduce any
 degrading effect that the dispensing may have on the polarized life of a
 hyperpolarized product so that the hyperpolarized product retains
 sufficient polarization at the end use site to allow effective imaging at
 delivery.
 It is still another object of the present invention to provide dual purpose
 transport containers which are configured to both collect and transport
 the hyperpolarized gas.
 It is another object of the present invention to provide improved dose
 metering of the hyperpolarized gas into containers in a manner which
 reduces depolarizing activity associated with the dispensing and delivery
 of the hyperpolarized gas to a subject.
 It is yet another object of the invention to provide methods and apparatus
 which can reduce the de-polarizing effects on the hyperpolarized state of
 the gas attributed to active dispensing of the gas from a polarization
 cell, collection, or transport vessel.
 It is an additional object of the present invention to provide a masking
 method which inhibits the direct contact of hyperpolarized gas with a
 potentially de-polarizing material or surface.
 It is another object of the present invention to provide a polarization
 verification method which can identify the expiration date of the
 hyperpolarized gas externally so that hospital personnel can visually
 determine the status of the gas prior to delivery to a patient.
 These and other objects are satisfied by the present invention which is
 directed to hyperpolarized gas extraction systems, methods, and associated
 containers which are configured to remove or extract the hyperpolarized
 gas from a container and reduce the amount of residual gases unrecovered
 therefrom in a way which reduces the depolarization of the hyperpolarized
 gas. In particular, a first aspect of the present invention is directed to
 a method for extracting a quantity of hyperpolarized noble gas from a
 container which includes directing a liquid into a container holding a
 quantity of hyperpolarized gas therein. The liquid contacts the
 hyperpolarized gas and forces the gas to exit the container separate from
 the liquid into an exit path operably associated with the container,
 thereby extracting the hyperpolarized noble gas from the container. In a
 preferred embodiment, the liquid comprises water which has been sterilized
 and partially, and more preferably, substantially de-oxygenated and/or
 de-ionized.
 Another aspect of the present invention is directed towards a method
 similar to that described above, but this method introduces a quantity of
 fluid (such as gas or liquid) into the container to push the
 hyperpolarized gas out of the container. The liquid aspect is similar to
 that described above.
 In one embodiment, wherein the fluid is a gas, the gas is preferably
 non-toxic and suitable for inhalation by a patient. As such, the
 extraction gas can mix with the hyperpolarized gas to form a
 hyperpolarized gas mixture as it exits from the container.
 In another embodiment, the hyperpolarized noble gas exits the container
 separate from the extraction gas. In this embodiment, the extraction gas
 has a density which is substantially different from the hyperpolarized
 gas. For example, for .sup.129 Xe, the extraction gas is preferably
 selected so that the hyperpolarized gas has a density which is greater
 than the extraction gas so that the extraction gas has a density which is
 less than the hyperpolarized gas. In this embodiment, the exit path is
 preferably positioned on the bottom portion of the container during the
 extraction while the extraction gas is introduced into the top portion of
 the container. This allows the heavier .sup.129 Xe to exit out of the
 bottom of the container while the lighter weight extraction gas remains
 therein.
 In another embodiment, the hyperpolarized gas is .sup.3 He, and the
 extraction gas is preferably selected such that it has a density which is
 greater than that of .sup.3 He. In this embodiment, the exit path is
 preferably positioned on the top portion of the container while the
 extraction gas is introduced into the bottom of the container. As such,
 the lighter .sup.3 He exits from the top of the container while the
 heavier extraction gas remains in the container.
 In an additional aspect of the present invention, the extraction method
 includes engaging a gas transfer source with the container and drawing a
 quantity of hyperpolarized gas from a container such that the gas is
 controllably removed therefrom. In a preferred embodiment, the gas
 transfer source is a syringe which is inserted into the sealed exit path
 (via an access port) of the container to remove the hyperpolarized gas
 therefrom. Preferably, the gas transfer source is configured with gas
 contact surfaces which are friendly to the hyperpolarized state of the
 gas, ie., coated with or formed of materials which do not cause excessive
 depolarization or which inhibit depolarization.
 Another aspect of the present invention is directed to a method of masking
 the potentially depolarizing effects of internal components or surface
 areas associated with the container. This method includes introducing a
 quantity of fluid (preferably a liquid) into the container and covering at
 least one predetermined exposed internal surface of the container with the
 fluid (liquid) to inhibit direct contact between the internal surface and
 the hyperpolarized noble gas, thereby masking the exposed surface with a
 fluid (liquid) to inhibit the depolarization of the gas in the container.
 In a preferred embodiment, the container is oriented to direct the masking
 fluid (liquid) into the desired area and the predetermined area includes
 covering a valve or seal in fluid communication with the container.
 Yet another aspect of the invention is directed to a method of decreasing
 the residual amount of hypexpolarized gas remaining in the container when
 not using an active pumping or removal system. The method includes
 introducing a quantity of hyperpolarized noble gas into a small container
 (preferably less than about 500 cm.sup.3, and more preferably less than
 about 200 cm.sup.3) at a pressure of about 3-10 atm. The container is then
 sealed and transported to a use site remote from the polarization site
 where the container is opened to release the gas by allowing the container
 to depressurize to ambient pressure. This is a high pressure, low volume
 container/method which decreases the amount of residual gas left in low
 pressure, relatively high volume containers typical of conventional
 delivery methods/containers. This method is particularly suitable for
 .sup.3 He as higher pressures introduced to the hyperpolarized .sup.3 He
 still yield relatively long T.sub.1 's.
 An additional aspect of the invention is directed to a method of extracting
 hyperpolarized gas from a container by positioning a resilient member in
 fluid communication with the internal chamber of the container holding
 hyperpolarized noble gas. The resilient member is then expanded to extend
 into the container and contact the hyperpolarized gas. The gas is forced
 to exit the container away from the expanded resilient member. Preferably,
 the resilient member is sealed to the container to prevent the fluid used
 to expand or inflate the resilient member from contacting the
 hyperpolarized noble gas. Also, it is preferred that the resilient member
 be formed from or coated with a material which is friendly to polarization
 of the gas in the container. Stated differently, a material which is
 (substantially) not depolarizing to or which inhibits depolarization
 associated with surface contact with the hyperpolarized gas.
 Another aspect of the present invention is directed to improved containers
 for processing and transporting hyperpolarized gases. In one embodiment,
 the container comprises a chamber and a quantity of hyperpolarized gas
 disposed therein. The container includes a resilient member which is
 positioned to be in communication with the hyperpolarized gas in the
 chamber. The resilient member has a first collapsed position and a second
 expanded position. When in the second position, the resilient member
 extends into the chamber a further distance relative to the first
 position. Preferably, the resilient member expands and retracts responsive
 to fluid introduced into an inlet port operably associated with the
 resilient member. Also, it is preferred that the resilient member is
 sealed such that it inhibits any expansion fluid from contacting the
 hyperpolarized gas. In operation, the expansion of the resilient member
 pushes/forces the hyperpolarized gas to exit the container, thereby
 actively forcing the hyperpolarized gas out of the container.
 Advantageously, this configuration can reduce the residual amounts of the
 gas left in the container while also minimizing potentially depolarizing
 interactions attributed to the active removal apparatus.
 In an alternative embodiment, the container includes a hyperpolarized gas
 holding chamber and a quantity of hyperpolarized gas disposed therein. The
 container also includes an access port which is in fluid communication
 with the holding chamber and which is resiliently configured to receive a
 portion of a syringe therein. Preferably, the container also includes a
 valve and an externally accessible connector, such as a lure or septum
 type connection, which provides an "air-tight" seal for drawing the
 hyperpolarized gas from the container in a manner which reduces the
 possibility of the introduction of air therewith. Preferably, the syringe
 plunger and body and septum are formed from or coated with polarization
 friendly materials. Advantageously, controlled amounts of the gas can be
 removed from the transport vessel and conveniently be delivered to the
 patient by simply reversing the plunger to inject or deliver the desired
 quantity of hyperpolarized gas without complex machinery and the like.
 Additionally, masking liquid can be used in the container as noted above.
 In an additional embodiment, the container comprises a gas holding chamber,
 a quantity of hyperpolarized gas, and two ports (an inlet port and an
 outlet port) in fluid communication with the chamber. The inlet and outlet
 ports are positioned on different sides of the chamber. Preferably, the
 two ports are radially misaligned and positioned at least 90 degrees apart
 from the other. It is also preferred that the two ports be offset relative
 to the other. For example, in one embodiment (during extraction of the
 gas) the exit port is above the inlet port. Similarly, in another
 embodiment, the inlet port is above the exit port.
 The containers or transport vessels are preferably configured to reduce
 surface or contact depolarization by forming a contact surface of a
 material of a thickness which acts to minimize any associated surface or
 contact depolarization. In addition, the outer layer is preferably
 configured to define an oxygen shield overlying the inner layer and is
 configured to minimize the migration of oxygen into the container.
 Suitable materials and thicknesses and the like are described in
 co-pending application to Deaton et al., Ser. No. 09/126,448, filed Jul.
 30, 1998, entitled Containers for Hyperpolarized Gases and Associated
 Methods, and identified by Attorney Docket number 5770-12. The contents of
 this disclosure is hereby incorporated by reference as if recited in full
 herein. More preferably, the container material comprises one or more of a
 high-purity metal film, high-purity impermeable glass, high-purity metal
 oxide, and high-purity insulator or semiconductor (for example, high
 purity silicon).
 It is additionally preferred that the container use seals such as O-rings
 which are substantially free of paramagnetic impurities. The proximate
 position of the seal with the hyperpolarized gas can make this component a
 dominant factor in the depolarization of the gas. Accordingly, it is
 preferred that the seal or O-ring be formed from substantially pure
 polyethylene or polyolefins such as ethylene, propylene, copolymers and
 blends thereof. Of course, fillers which are friendly to the
 hyperpolarization can be used (such as substantially pure carbon black and
 the like). Alternatively, the O-ring or seal can be coated with a surface
 material such as LDPE or deuterated HDPE or other low-relaxivity property
 material or high purity metal.
 Another aspect of the present invention is directed towards a method for
 improving the transfer efficiency of the hyperpolarized gas such as from
 the polarization cell in the hyperpolarization apparatus. Preferably, the
 method comprises the steps of positioning a chamber in fluid communication
 with the polarization cell, directing a quantity of hyperpolarized gas out
 of the polarization cell and into the chamber, and cooling the chamber to
 improve the transfer of hyperpolarized gas from the polarization cell.
 Preferably, the cooling step cools the container substantially, such as
 below the freezing point of water, and more preferably to the temperature
 of dry ice (195 K), and most preferably to cryogenic temperatures (such as
 by exposing the chamber to a bath of liquid nitrogen (77K)). In one
 embodiment, the hyperpolarized gas is .sup.3 He. In another embodiment,
 the chamber is closed or configured to capture all the gas exiting the
 polarization cell. Advantageously, the cooling of the chamber can increase
 the pressures and volumes of gas received into the chamber (and thus out
 of the polarization cell), improving the transfer efficiency thereby.
 Still another aspect of the present invention is a method of identifying
 the hyperpolarization state of a quantity of hyperpolarized gas
 (preferably at a use-facility or site). The method includes positioning a
 container having a quantity of hyperpolarized substance in a magnetic
 field and determining the polarization level of the hyperpolarized
 substance in the container. An externally visible indicia of polarization,
 i.e., an identifying mark such as a use-by date is affixed to the
 container. The identified container is then protected from de-polarizing
 factors. For example, storing the identified container in a stable
 magnetic field. Advantageously, this identification can preclude or
 minimize the delivery of inactive gases to a patient by indicating a shelf
 life associated with a desired level of polarization of the hyperpolarized
 substance in the container to hospital personnel. Preferably, the magnetic
 field has a low field strength, and the determining step includes
 transmitting a signal to the hyperpolarized substance in the container and
 receiving a signal back therefrom. The signal back corresponds to the
 hyperpolarization level of the substance in the container.
 Another aspect of the present invention is a method of meting a quantity of
 hyperpolarized gas into a container. The method includes the step of
 providing an enclosed sealable gas flow path, the gas flow path extending
 between a hyperpolarized gas source and a first gas syringe, and between
 the first gas syringe and a sealable container different from the
 hyperpolarized gas source. The first gas syringe has a translatable
 plunger held therein and a port configured to receive gas into and expel
 gas from the syringe. A quantity of hyperpolarized gas is released in
 gaseous form from the hyperpolarized gas source such that it flows into
 the gas flow path. The hyperpolarized gas is directed in the gas flow path
 into the first syringe and received in gaseous form into the first
 syringe. The plunger is translated a distance in the first syringe away
 from the port in response to the quantity of hyperpolarized gas received
 therein. Subsequently, the plunger is advanced a desired distance in the
 first syringe toward the port to direct a desired quantity of
 hyperpolarized gas in gaseous form from the first syringe into the gas
 flow path and then into the sealable container thereby meting a desired
 amount of the hyperpolarized gas into the sealable container.
 In a preferred embodiment, a buffer gas can be similarly meted into the
 sealable container (from a gas syringe). The same syringe as used for the
 hyperpolarized gas dispensing can be used to dispense or mete the buffer
 gas. Alternatively, a separate syringe (ie., a dual syringe system) can be
 used. In any event, a more reliable predictable quantity of hyperpolarized
 gas can be meted into the sealable container to provide for more reliable
 quantities and/or concentrations of the hyperpolarized gas and the buffer
 gas mixture over conventional procedures.
 A related aspect of the present invention is a hyperpolarized gas
 dose-meting apparatus. The apparatus includes a hyperpolarized gas source,
 a first valve operably associated with the hyperpolarized gas source and a
 first gas syringe in fluid communication with the hyperpolarzed gas
 source. The apparatus also includes a first enclosed flow path extending
 between the hyperpolarized gas source and the first syringe, a second
 valve operably associated with the first flow path positioned intermediate
 the hyperpolarized gas source and the first syringe, and at least one
 receiving container in fluid communication with the first gas syringe. The
 apparatus additional includes at least one second enclosed flow path
 extending between the first syringe and the at least one receiving
 container, at least one third valve operably associated with the receiving
 container; and at least one release mechanism operably associated with the
 second flow path positioned in the second flow path upstream of the third
 valve and the receiving container to allow the receiving container to be
 released and sequentially replaced with a second receiving container
 thereat.
 In a preferred embodiment, the hyperpolarized gas source is a polarization
 cell in a polarizer unit. It is also preferred that the apparatus include
 a second syringe holding a quantity of buffer gas therein, a third
 enclosed flow path extending between the second syringe and the receiving
 container, and a fourth valve operably associated with the third enclosed
 flow path. The first and second gas syringes are preferably sized to hold
 from about 0.5-2 liters of gas therein.
 Preferably, the hyperpolarized gas dose-meting apparatus also includes a
 holding apparatus configured and sized to hold the first and second
 syringes therein in side by side alignment. The at least one receiving
 container can be a single (of sequentially filled containers) or a
 plurality of containers. In one embodiment, the receiving container has
 collapsible walls.
 An additional aspect of the present invention is directed to a
 hyperpolarized gas dose-meting gas syringe holding apparatus. The syringe
 holding apparatus/assembly comprises a first gas syringe having a body
 with a length, a port formed in a first end portion thereof, and a
 translatable plunger held therein. The syringe and the plunger having
 hyperpolarized gas-contacting surfaces formed of polarization friendly
 materials. The syringe includes externally visual indicia along the length
 thereof allowing a quantitative assessment of the gas volume held therein.
 The apparatus further includes a holding shell configured and sized to
 hold at least the first syringe therein. The holding shell has opposing
 first and second platform portions. The first platform portion includes an
 aperture formed therein for allowing the plunger to translate
 therethrough.
 In a preferred embodiment, the apparatus also includes a second syringe,
 and the holding shell is configured to hold the second syringe
 substantially alongside the first syringe therein. Preferably, the
 syringes are substantially the same size and shape (capable of holding
 from about 0.5-2 liters or more of gas therein) and the holding shell is
 configured to hold the first and second syringes in side by side
 alignment.
 For each of the above, a magnetic field generator either comprising an
 electromagnet or a plurality of discrete permanent magnets can be arranged
 to provide (surround) the first syringe and/or the hyperpolarized gas flow
 paths/receiving container with a substantially homogeneous magnetic
 holding field. An NMR excitation coil can also be used to monitor the
 polarization level of the polarized gas at desired locations within the
 extraction system.
 Advantageously, the methods and containers of the present invention can
 improve the relaxation time (ie., lengthen the T.sub.1) of the
 hyperpolarized gas such as by allowing active dispensing of the gas from a
 container in a manner which inhibits depolarization of the hyperpolarized
 gas. The methods and apparatus of the present invention can also allow for
 more predictable meting of the hyperpolarized gas so as to meet regulatory
 guidelines and/or provide more reliable concentrations or quantities of
 hyperpolarized gases/mixture, and, thus, provide suitable in vivo
 mammalian (preferably human) doses. Further, the active dispensing can
 reduce the amount of residual gases left in the container at the removal
 point, thereby improving the delivery efficiency.
 The foregoing and other objects and aspects of the present invention are
 explained in detail herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
 The present invention will now be described more fully hereinafter with
 reference to the accompanying figures, in which preferred embodiments of
 the invention are shown. This invention may, however, be embodied in many
 different forms and should not be construed as limited to the embodiments
 set forth herein. Like numbers refer to like elements throughout. Layers
 and regions may be exaggerated for clarity. For ease of discussion, the
 term "hyperpolarized gas" will be used to describe a hyperpolarized gas
 alone, or a hyperpolarized gas which contacts or combines with one or more
 other components, whether gaseous, liquid, or solid. Thus, the
 hyperpolarized gas described herein can be a hyperpolarized gas
 composition/mixture (preferably non-toxic such that it is suitable for in
 vivo introduction) such that the hyperpolarized noble gas can be combined
 with other noble gases and/or other inert or active components. Also, as
 used herein, the term "hyperpolarized gas" can include a product in which
 the hyperpolarized gas is dissolved into another liquid (such as a carrier
 fluid) or processed such that it transforms into a substantially liquid
 state, ie., "a liquid polarized gas". Thus, although the term includes the
 word "gas", this word is used to name and descriptively track the gas
 produced via a hyperpolarizer to obtain a polarized "gas" product. In
 summary, as used herein, the term "gas" has been used in certain places to
 descriptively indicate a hyperpolarized noble gas which can include one or
 more components and which may be present in one or more physical forms.
 BACKGROUND--HYPERPOLARIZATION
 Various techniques have been employed to polarize, accumulate and capture
 polarized gases. For example, U.S. Pat. No. 5,642,625 to Cates et al.
 describes a high volume hyperpolarizer for spin polarized noble gas and
 U.S. patent application Ser. No. 08/622,865 to Cates et al. describes a
 cryogenic accumulator for spin-polarized .sup.129 Xe. The disclosures of
 this patent and application are hereby incorporated herein by reference as
 if recited in fill herein. As used herein, the terms "hyperpolarize" and
 "polarize" are used interchangeably and mean to artificially enhance the
 polarization of certain noble gas nuclei over the natural or equilibrium
 levels. Such an increase is desirable because it allows stronger imaging
 signals corresponding to better MRI images of the substance and a targeted
 area of the body. As is known by those of skill in the art,
 hyperpolarization can be induced by spin--exchange with an optically
 pumped alkali-metal vapor or alternatively by metastability exchange. See
 U.S. Pat. No. 5,545,396 to Albert et al. The alkali metals capable of
 acting as spin exchange partners in optically pumped systems include any
 of the alkali. metals. Preferred alkali metals for this hyperpolarization
 technique include Sodium-23, Potassium-39, Rubidium-85, Rubidium-87, and
 Cesium-133.
 Alternatively, the noble gas may be hyperpolarized using metastability
 exchange. (See e.g., Schearer L D, Phys Rev, 180:83 (1969); Laloe F,
 Nacher P J, Leduc M, and Schearer L D, AIP ConfProx #131 (Workshop on
 Polarized .sup.3 He Beams and Targets) (1984)). The technique of
 metastability exchange involves direct optical pumping of, for example,
 .sup.3 He without need for an alkali metal intermediary. Metastability
 exchange optical pumping will work in the same low magnetic fields in
 which spin exchange pumping works. Similar polarizations are achievable,
 but generally at lower pressures, e.g., about 0-10 Torr.
 Generally described, for spin-exchange optically pumped systems, a gas
 mixture is introduced into the hyperpolarizer apparatus upstream of the
 polarization chamber. Most xenon gas mixtures include a buffer gas as well
 as a lean amount of the gas targeted for hyperpolarization and is
 preferably produced in a continuous flow system. For example, for
 producing hyperpolarized .sup.129 Xe, the pre-mixed gas mixture is about
 85-98% He, about 5% or less .sup.129 Xe, and about 1-10% N.sub.2. In
 contrast, for producing hyperpolarized .sup.3 He, a typical mixture of
 about 99.25% .sup.3 He and 0.75% N.sub.2 is pressurized to 8 atm or more
 and heated and exposed to the optical laser light source, typically in a
 batch mode system. In any event, once the hyperpolarized gas exits the
 pumping chamber it is directed to a collection or accumulation container.
 A 5-20 Gauss alignment field is typically provided for the optical pumping
 of Rb for both .sup.129 Xe and .sup.3 He polarization. The hyperpolarized
 gas is collected (as well as stored, transported, and preferably
 delivered) in the presence of a magnetic field. It is preferred for
 .sup.129 Xe that the field be on the order of at least 500 Gauss, and
 typically about 2 kilo Gauss, although higher fields can be used. Lower
 fields can potentially undesirably increase the relaxation rate or
 decrease the relaxation time of the polarized gas. As regards .sup.3 He,
 the magnetic field is preferably on the order of at least 10-20 gauss
 although, again, higher fields can be used. The magnetic field can be
 provided by electrical or permanent magnets. In one embodiment, the
 magnetic field is provided by a plurality of permanent magnets positioned
 about a magnetic yoke which is positioned adjacent the collected
 hyperpolarized gas. Preferably, the magnetic field is homogeneously
 maintained around the hyperpolarized gas to minimize field-induced
 degradation.
 Referring to the drawings, FIG. 1 illustrates a preferred xenon
 hyperpolarizer unit 10. As shown, the unit 10 includes a noble gas supply
 12 and a supply regulator 14. A purifier 16 is positioned in the line to
 remove impurities such as water vapor from the system as will be discussed
 further below. The hyperpolarizer unit 10 also includes a flow meter 18
 and an inlet valve 20 positioned upstream of the polarizer cell 22. A
 optic light source such as a laser 26 (preferably a diode laser array) is
 directed into the polarizer cell 22 through various focusing and light
 distributing means 24, such as lenses, mirrors, and the like. The light
 source is circularly polarized to optically pump the alkali metals in the
 cell 22. An additional valve 28 is positioned downstream of the polarizer
 cell 22. A more detailed explanation of the hyperpolarizer is described in
 Cates et al., supra, and in co-pending application to Driehuys et al.,
 Ser. No. 08/989,604, filed Dec. 12, 1997, entitled Methods of Collecting,
 Thawing, and Extending the Useful Life of Polarized Gases and Associated
 Accumulators and Heating Jackets, and identified by Attorney Docket No.
 5770-4. The contents of these disclosures are hereby incorporated by
 reference as if recited in full herein. In order to transport the
 hyperpolarized gas in a gaseous state, the hyperpolarized .sup.129 Xe is
 preferably cryogenically accumulated in a cold finger or container 30
 which is positioned in a cryogenic bath 43. The frozen polarized .sup.129
 Xe gas is then thawed out of the cold finger or container 30 and captured
 by a collection or transport vessel 50A positioned in fluid communication
 with the on-board exit tap 50.
 FIG. 1A illustrates a preferred helium hyperpolarizer unit 10'. Similar to
 the .sup.129 Xe hyperpolarizer unit 10 generally discussed above, the
 .sup.3 He hyperpolarizer unit 10' polarizes the .sup.3 He in a
 polarization cell 22 and collects the gas at the gas exit tap 50 into the
 storage or transport container 50A. Certain of the plumbing of the helium
 device differs from the xenon apparatus, because the helium is batch
 process unlike the continuous process used to hyperpolarize xenon.
 Prior to use in the unit 10, the storage containers 50A (and other storage,
 transport, or collection chambers) are preferably (repeatedly) purged
 and/or evacuated to remove oxygen, moisture, and the like. Preferably, a
 rough vacuum pump is used to perform a first evacuation, then a
 high-purity gas is introduced into the container to purge residual
 contaminants. Preferably, additional evacuations are performed such that
 the O.sub.2 concentration is about 10.sup.-6 -10.sup.-10 atm or lower. Of
 course, turbo-molecular pumps, cryopumps, and/or diffusion pumps (with or
 without heating) may also be used to treat or evacuate the vessel to
 remove any monolayers of moisture or water or other minute contaminants on
 the surface and thus further reduce contact-induced depolarization for the
 hyperpolarized gas.
 Polarized Gas Relaxation Processes
 Once hyperpolarized, there is a theoretical upper limit on the relaxation
 time (T.sub.1) of the polarized gas based on the collisional relaxation
 explained by fundamental physics, i.e., the time it takes for a given
 sample to decay or depolarize due to collisions of the hyperpolarized gas
 atoms with each other absent other depolarizing factors. For example,
 .sup.3 He atoms relax through a dipole-dipole interaction during .sup.3
 He-.sup.3 He collisions, while .sup.129 Xe atoms relax through
 N.multidot.I spin rotation interaction (where N is the molecular angular
 momentum and I designates nuclear spin rotation) during .sup.129
 Xe-.sup.129 Xe collisions. Stated differently, the angular momentum change
 associated with flipping a nuclear spin over is conserved by being taken
 up by the rotational angular momentum of the colliding atoms. In any
 event, because both processes occur during noble gas-noble gas collisions,
 both resulting relaxation rates are directly proportional to gas pressure
 (T.sub.1 is inversely proportional to pressure). At one atmosphere, the
 theoretical relaxation time (T.sub.1) of .sup.3 He is about 744-760 hours,
 and for .sup.129 Xe the corresponding relaxation time is about 56 hours.
 See Newbury et al., Gaseous 3He--3He Magnetic Dipolar Spin Relaxation, 48
 Phys. Rev. A., No. 6, p. 4411 (1993); Hunt et al., Nuclear Magnetic
 Resonance of .sup.129 Xe in Natural Xenon, 130 Phys Rev. p. 2302 (1963).
 Unfortunately, other relaxation processes prevent the realization of these
 theoretical relaxation times. For example, the collisions of gaseous
 .sup.129 Xe and .sup.3 He with container walls ("surface relaxation") have
 historically dominated most relaxation processes. For .sup.3 He, most of
 the known longer relaxation times have been achieved in special glass
 containers having a low permeability to helium. U.S. Pat. No. 5,612,103 to
 Driehuys et al. describes using coatings to inhibit the surface-induced
 nuclear spin relaxation of hyperpolarized noble gases, especially .sup.129
 Xe. The contents of this patent are hereby incorporated by reference as if
 recited in full herein. Similarly, U.S. patent application to Deaton et
 al., identified by Attorney Docket Number 5770-12, supra, describes
 preferred gas-contact surface materials and associated thicknesses,
 O-ring, and valve or seal materials and/or coatings which are friendly to
 the polarized state of the gas, i.e., which can inhibit
 surface/contact-induced relaxation mechanisms.
 Once the hyperpolarized gas is collected, it is typically delivered to a
 hospital or end user. This means that either a hyperpolarizer unit is
 proximately stationed in the hospital so that the hyperpolarized gas can
 be delivered directly to the patient, or that the gas is transported from
 a central, albeit remote polarization site. The remote polarization
 station typically requires a longer T.sub.1 's relative to an onsite
 apparatus to allow adequate shipping and transport times. However, a
 centrally stationed polarizer can reduce equipment and maintenance costs
 associated with a plurality of on-site units positioned at each imaging
 site. In any case, the hyperpolarized gas is typically removed from the
 collection container or transport vessel and dispensed to the patient via
 some patient delivery system temporally limited such that the
 hyperpolarized state of the gas at delivery is sufficient to produce
 useful clinical images.
 Extraction Systems
 It will be appreciated by those of skill in the art that certain of the
 descriptions herein are primarily directed to either a liquid or a gas,
 but that the methods of the inventions can use multiple types of fluids
 and are not intended to be limited to the specific description used
 herein. As such, as used herein, the term "fluid" includes liquids, gases,
 and blends and mixtures thereof.
 A. Liquid Extraction
 Turning now to the drawings, FIG. 2B illustrates one embodiment of a
 hyperpolarized gas extraction system according to the present invention.
 In this embodiment, a container 50A (FIG. 2A) is removed from the
 hyperpolarizer unit and transported away from the polarization site. The
 container is then prepared to release the gas therefrom. As shown in FIG.
 2B, a liquid source 70 is attached to a liquid entry port 72. A valve 35
 is opened and liquid is directed into the container 30. A valve 38 is
 opened to allow the hyperpolarized gas to exit the exit path 76. FIG. 2B
 shows an optional second valve 37 which can assist in holding degassed
 liquid in the container. As shown in FIG. 2B, during extraction, the
 container 50A is preferably oriented such that the gas exit path 76 is
 above the liquid entry port 72. In operation, the increasing liquid level
 contacts the hyperpolarized gas and pushes or forces the hyperpolarized
 gas out of the container 50A and into the exit path 76. It is preferred
 that the liquid level be adjusted so that the liquid remains in the
 container separate from the extracted gas, especially for gas inhalation
 applications. This method advantageously allows for substantially all of
 the hyperpolarized gas in the container 50A to be removed with minimal
 dilution and/or depolarization of the hyperpolarized gas.
 FIG. 3 illustrates a liquid extraction system with a modified container
 50A. In this embodiment, the container 50A has two ports; an inlet port
 230 and an outlet port 234. As shown, the outlet port 234 is on a
 different (preferably opposing) side of the container and offset relative
 to the inlet port 230. As shown in FIGS. 6 and 9, an axis 200 drawn
 through the center of the container sections the container into four
 quadrants. Preferably, the inlet port 230 is positioned in one of the
 bottom quadrants and the outlet port 234 is positioned in the opposing top
 quadrant. Each of the ports 234, 230 is operably associated with a valve
 235, 231 to control the release of the gas and introduction of the liquid,
 respectively. During extraction, this configuration allows the container
 50A to be oriented such that the outlet port 234 is on a top end portion
 of the container and above the inlet port 230. As shown, the liquid source
 70 preferably uses gravity to feed the liquid 70' into the container. Of
 course, other controlled or active feed systems can also be employed (such
 as pumps, compression cuffs, syringes, and the like).
 Referring again to FIG. 3, as illustrated, the inlet port 230 includes a
 connector 232 which allows the liquid source 70 to be attached to the
 container 50A. Similarly, the outlet port 234 includes a connector 236
 which can attach to a patient delivery vessel 250. The patient delivery
 vessel 250 is preferably a collapsible bag. Of course, as an alternative
 to a patient delivery vessel 250, the gas can be directly routed from the
 outlet port/exit path 234 to the patient (such as to an inhalation mask
 positioned over a patient's nose/mouth FIG. 13, 255).
 FIG. 4 shows another embodiment of a liquid extraction system. In this
 embodiment, the liquid source 370 is a syringe. As such, the extraction
 liquid 371 is inserted/injected via the syringe 370 into an access port
 310 positioned in fluid communication with the container 50C. As shown,
 the access port 310 is positioned in an elbow 311 which is in fluid
 communication with the gas in the container 50C and is configured to
 receive a portion of the syringe therein. Preferably, the access port 310
 is resilient in that it is configured with resilient material to receive
 the septum therein in a manner which provides an air tight seal. In one
 embodiment, the access port 310 is a lure-type connector. Also, preferably
 the access port is self-healing such that it forms an air-tight seal with
 the syringe when inserted therein and automatically collapses or closes to
 seal the port when the syringe 370 is withdrawn.
 As noted, the liquid contacts the hyperpolarized gas. As such, for in vivo
 applications, it is preferred that the extraction liquid be selected so as
 to be non-toxic and non-depolarizing to the hyperpolarized gas. It is
 further preferred, for liquids which have a relatively high oxygen
 solubility value, that the liquid be processed to be more compatible to
 the hyperpolarized gas. For example, it is preferred that the liquid be at
 least partially de-oxygenated and/or partially de-ionized prior to
 introduction into the container or transport vessel with the
 hyperpolarized gas. It is more preferred that the liquid be sterilized and
 substantially de-oxygenated and/or substantially de-ionized. Other
 modifications and treatment processes can also be performed on the liquids
 to make them more polarization friendly. For example, certain elements of
 the liquids can be substituted or deuterated and the like. It is
 additionally preferred that the liquid be selected such that the
 hyperpolarized gas is substantially insoluble in the liquid. It is
 preferred that the solubility of the hyperpolarized gas in the fluid be
 less than about 0.2. For example, xenon has a solubility of about 0.14 in
 H.sub.2 O (with helium being about 0.01). In contrast, for example, xenon
 has a solubility of about 2.0 in hexane making this a poor choice for an
 extraction fluid for this gas (even aside from its toxicity issues).
 Of course, a plurality of liquids can also be used as the extraction
 liquid, such as a liquid mixture, or blend whether miscible or immiscible.
 Tests indicate that one suitable liquid is water. Water is compatible and
 substantially non-depolarizing to both .sup.3 He and .sup.129 Xe.
 In one example, adding about 20 cubic centimeters of partially degassed
 water into the chamber of a 250 ml container changed the associated
 T.sub.1 of the gas in the container from about 8 hours to about 5 hours.
 As shown in FIG. 5, the polarization decay curves observed from this test
 fit the exponential decay curve. This test supports the
 suitability/viability of this active extraction system. Preferably,
 immediately after the extraction is completed (especially when used with
 .sup.3 He), the extracted hyperpolarized gas maintains a T.sub.1 equal to
 at least about 80% or more, most preferably, 90% or more of the value of
 the T.sub.1 immediately prior to initiation of the extraction method
 (assuming a properly processed, cleaned, and appropriate transfer
 container).
 B. Liquid as a Masking Agent
 An additional aspect of the present invention is directed to using liquid
 as a masking agent in physical systems or containers which potentially
 contact the hyperpolarized gas. As is now understood, the effective
 T.sub.1 of gas in a container is additive in relationship to the materials
 that the gas contacts. That is, the effective T.sub.1 will increase
 nonlinearly according to the following equation.
EQU 1/T.sub.1chamber +1/T.sub.1material =1/T.sub.1effective Equation 1.0
 Therefore, the effective T.sub.1 is dependent on the chamber surface area
 and material, as well as any other materials which contact the gas. By
 inhibiting the gas from contacting degrading materials, the effective
 T.sub.1 can be extended or preserved.
 As shown in FIG. 6B, a (predetermined) exposed internal surface 533 of the
 container 50D is covered with liquid. Preferably, the liquid 570 is
 selected such that it displays a greater compatibility with the
 hyperpolarized gas than the degrading contact surface or component (such
 as conventional O-rings, valves, seals, and the like) and is introduced
 into the container 50D to inhibit direct contact between the undesirable
 surface and the hyperpolarized gas. Advantageously, other properties
 typically attributed to the undesirable surface (seals, etc.) can be
 retained. Further, if used as shown to mask seals and the like,
 commercially available seals can be used without requiring specialized
 (and potentially costly) formulations of materials. This is because the
 liquid (or fluid) covers the surface or component, thereby masking the
 potentially depolarizing area from the hyperpolarized gas by contacting
 the gas with a material which has improved relaxivity relative to the
 undesirable surface or component. Also preferably, the liquid is chosen
 such that it is substantially non de-polarizing to the hypeipolarized gas
 (and resistant to hyperpolariz ed gas dissolution therein), so that it
 increases the length of the polarized life of the gas in the container
 over the life of the gas without the liquid mask. As discussed above, the
 liquid is also preferably non-toxic in that it contacts the (in a
 preferred embodiment, inhalable) hyperpolarized gas. For liquids which
 have high oxygen solubility, it is preferred that the liquid be at least
 partially de-oxygenated/de-ionized as discussed above. Further, one or
 more liquids can be used and the liquids may otherwise or additionally
 modified or processed as described above.
 In operation, as shown by FIGS. 6A and 6B, a quantity of liquid is placed
 in the container 50D housing the polarized gas. The container 50D is then
 oriented such that the liquid in the container covers and thus inhibits
 the gas from contacting the valve 530 or other undesirable material or
 component, i.e., is positioned intermediate of the gas and the valve to
 mask the valve from the polarized gas. For example, in one test, fifteen
 cubic centimeters of de-ionized/de-oxygenated water were injected into a
 one-liter plastic bag with a valve thereon that had been previously filled
 with polarized gas. The bag was then positioned such that the water in the
 bag completely masked the valve from the polarized gas. The addition of
 water to the plastic bag increased the T.sub.1 by about one hour.
 C. Extraction Using a Gas
 In this embodiment, a second gas is used to transfer the hyperpolarized gas
 from one vessel to another. In as much as a preferred embodiment of the
 liquid transfer was described above, this description will be directed to
 the use of an extraction gas or extraction gas mixture (a plurality of
 gases) to transfer the hyperpolarized gas out of a container or transport
 vessel.
 Turning now to FIGS. 7 and 8, two embodiments of a gas extraction system
 600, 700 are shown. In these embodiments, the container 50C is the same as
 that described above, although, of course, the method and containers
 contemplated by this invention are not limited thereto. As shown, the
 container 50C includes the inlet and outlet ports 230, 234, respectively.
 In this embodiment, the extraction gas 670 is introduced into the inlet
 port 230 to contact the hyperpolarized gas in the container and force the
 gas out of the container through the outlet or exit port 234. As the
 extraction gas 670 contacts the hyperpolarized gas, it is preferred that
 it is non-toxic (so as not to contaminate the hyperpolarized gas) and
 substantially non-depolarizing to the hyperpolarized gas. Preferably, the
 second gas or extraction gas (or gas mixture) 670 has a substantially
 different density relative to the hyperpolarized gas. For example, N.sub.2
 would be suitable to use with both .sup.3 He and .sup.129 Xe because it is
 inert, non-toxic, and its density is higher than that of .sup.3 He and
 lower than that of .sup.129 Xe. Alternatively, helium is also inert and
 non-toxic and can be used to extract the .sup.129 Xe. In any event, it
 will be appreciated by one of skill in the art that at 20.degree. C.,
 helium has a density of about 0.17 g/l, xenon about 5.49 g/l and, N.sub.2
 about 1.17 g/l and as such, these density variations allow the successful
 extraction of the hyperpolarized gas according to the present invention.
 In one embodiment, as shown in FIG. 7, the hyperpolarized gas is .sup.3 He
 which is a relatively light gas (low density). As such, the extraction gas
 670 is fed into the bottom of the container and the increasing volume of
 the extraction gas into the container 50C forces the lighter weight gas
 (.sup.3 He) to exit the top of the container through the exit port 234
 into a collection vessel 250 or delivery site. In contrast, as shown in
 FIG. 8, the hyperpolarized gas is .sup.129 Xe, which is a relatively heavy
 gas (high density). As such, the extraction gas 770 is introduced into the
 top of the container and forces the heavy hyperpolarized gas out of the
 bottom through the exit port 234. In one embodiment, the extraction gas
 670, 770 is introduced at a rate and in a way which allows it to contact
 the hyperpolarized gas at a front boundary plane but remain substantially
 independent of the hyperpolarized gas as the hyperpolarized gas is
 pushed/forced out of the container (ie., the gases remain substantially
 unmixed). In another embodiment, the extraction gas 670, 770 is introduced
 to mix with the hyperpolarized gas to form a gas mixture--preferably by
 the time the gas reaches the exit port 234. The amount of hyperpolarized
 gas in the mixture is preferably such that the mixture provides a
 sufficient amount of the hyperpolarized gas for signal imaging (for useful
 MRI clinical images) and is suitable for patient inhalation. Preferably,
 for this embodiment, the container is configured and sized to provide at
 least one patient-inhalable dose of the hyperpolarized gas mixture. It is
 also preferred that the container be configured with the ports 230, 234
 positioned on opposing sides or ends of the container and offset (side to
 side) relative to the other. As shown, the inlet and outlet ports 230, 234
 are positioned on opposing sides of the centerline of the container and
 more preferably on opposing sides and ends (opposing quadrants) of a
 two-dimensional axis 200 drawn through the center thereof (see FIG. 7).
 D. Mechanical Extraction
 In this embodiment, mechanical extraction means such as pumps (diaphragm,
 rotary, or centrifugal pumps) or other mechanical devices are employed to
 act as a gas transfer source to pull or extract the hyperpolarized gas
 from the container in a manner which is minimally depolarizing to the
 hyperpolarized gas. If pumps or other active mechanisms are employed,
 preferably the gas contact surfaces and components of the devices are
 masked to inhibit direct contact with the hyperpolarized gas, as described
 above, and/or, alternatively, formed or coated from
 hyperpolarization-friendly materials.
 1. Syringe Extraction
 Providing reliable dose quantities of hyperpolarized gas can be important
 to ensure that a patient receives an appropriate amount of hyperpolarized
 gas which will yield clinically useful data. Hyperpolarized gas can be
 characterized as having several primary "image related" variables: (1) the
 extent of polarization (i.e., what percent of the noble gas nuclei are
 hyperpolarized); (2) the volume of the hyperpolarized gas dispensed (such
 as inhaled or injected); and (3) the polarization life of the
 hyperpolarized gas (the polarized state of the gas will end, sooner or
 later, depending on several factors). The extent of polarization can be
 measured in a number of ways as is known to those of skill in the art,
 some of which are described in co-pending and co-assigned U.S. patent
 application Ser. Nos. 09/333,571 and 09/344,000, the contents of which are
 hereby incorporated by reference as if recited in full herein. See also
 published PCT application Ser. No. WO/9917105.
 As regards dispensing hyperpolarized gas in the gaseous state, because
 gases by their very nature expand to fill the volume of the container they
 occupy, and are compressible to high pressures, measuring or meting the
 volume of a hyperpolarized gas in gas phase can be problematic.
 Nonetheless, measuring or meting the hyperpolarized gas in manner which
 can yield a predictable or substantially controlled quantity is desirable
 for proper dosing (and maybe, for commercial approval, even mandated by
 federal regulatory agencies). The present invention provides extraction
 and/or dispensing methods which can yield metered and relatively reliable
 (preferably "precise") quantitative doses of hyperpolarized gases.
 In a preferred embodiment, as shown in FIGS. 9A and 9B, a gas-tight syringe
 870 is introduced into the container or transport vessel 50D such that it
 is in fluid communication with the hyperpolarized gas therein. Preferably,
 the syringe 870 enters the container through an externally accessible port
 810 which is configured to provide the gas-tight (and air-tight) seal.
 Suitable seal configurations include septum and luer-type connectors. As
 shown in FIG. 9A, the container 50D preferably includes a valve 831
 positioned intermediate the chamber 834 and the access port 810 for
 helping facilitate the integrity of the seal 810 during increased
 pressures sometimes experienced by the container during shipping and
 storage. In operation, the valve 831 is opened, one end of the syringe 871
 is introduced into the access port of the container 810 and a controlled
 quantity of hyperpolarized gas is withdrawn into the chamber 872 of the
 syringe (pulled out) upon retraction of the plunger 873 therein. The
 hyperpolarized gas is then enclosed in the syringe 870 and can
 conveniently be discharged into the patient delivery unit (such as an
 inhalation mask) or into another delivery vessel such as a collapsible bag
 250 as shown in FIG. 9B. Preferably, the syringe 870 is formed from a
 polymer or coated with a polymer or high purity metal coating on the gas
 contact surfaces to inhibit or minimize any depolarization attributed
 thereto. Also preferably, the syringe 870 is pre-conditioned to
 de-oxygenate the residual gas in the chamber 872 such as by evacuating and
 purging as described above. See also U.S. patent application Ser. No.
 09/126,448, the contents of which are incorporated herein by reference as
 stated above.
 As illustrated by FIG. 9B, to deliver or discharge the hyperpolarized gas,
 the syringe 870 is preferably inserted into a port which is positioned in
 communication with the patient delivery vessel 250. The plunger of the
 syringe 873 is depressed and the gas is "pumped" out of the syringe and
 discharged into the patient delivery vessel 250. Similar to the access
 port 810 above, the delivery access port 885 preferably forms an airtight
 seal with the syringe 870 to introduce the hyperpolarized gas into the
 container/port 885 without contaminating the hyperpolarized gas sample
 with oxygen.
 As shown by FIG. 9B, a coupling member 880 is configured to provide the
 sealed pathway to deliver the gas from the syringe 870 to the delivery
 container 250. The coupling member 880 provides the path connections 885,
 888 to the syringe 870 and the patient delivery vessel 250 or inhalation
 mask (FIG. 13, 255) respectively. Although not shown, valves and other
 seal arrangements can also be employed as discussed above.
 In another preferred embodiment as shown in FIG. 16, a gas-tight syringe
 870 is used to extract a desired amount of hyperpolarized gas from a first
 container 50. In a preferred embodiment, the first container 50 is the
 optical or polarization cell held within the polarizer 10' itself The
 gas-tight syringe 870 is connected at the exit port 106 of the polarizer
 10' as shown in FIG. 16, the exit port 106 being in fluid communication
 with the polarization cell 50. However, the methods of the instant
 invention are not limited to the use of a polarization cell as the first
 container 50; they can also be used to dispense from other containers such
 as multi-dose transport or collection containers and the like.
 As is illustrated in FIG. 16, the syringe 870 is configured such that it is
 in fluid communication with the first container 50 and also in fluid
 communication with a second vessel 250 via tubing 881, 892 (or other
 pathway means such as conduit or pipe). The first container 50 is the
 vessel used to supply or fill the syringe 870 and the second vessel 250 is
 the vessel to which the syringe 870 metes the gas. The second vessel 250
 can either be sized and configured for a single patient dose or for
 multiple doses. Most preferably, the second vessel 250 is a single dose
 collapsible container. The second vessel 250 (and associated transfer of
 gas from the syringe 870 thereto) can be located at the production site or
 at a remote distribution site (or even at the end use site itself). The
 syringe 870 itself is preferably sized to hold from about 0.5 liters to
 about 5.0 liters of gas, and more preferably sized from about 1.0-2.0
 liters of gas. Of course, a plurality of various sized gas syringes can
 also be used spanning desired volumes, thereby allowing an operator to
 select the size appropriate for the particular application (thereby
 reducing the likelihood that undue quantities of hyperpolarized gas will
 be wasted from the meted transfer).
 Generally described, in operation, after suitable preparation to remove
 contaminants from the flow path (such as the syringe 870 and the tubing
 881, 892), hyperpolarized gas is directed out from the first container 50
 into the syringe 870. The syringe plunger 873 translates away from the
 inlet/outlet port region of the syringe 870p in response to gas directed
 therein. Preferably, the syringe 870 includes graduations or visual
 indicia of volume 870g which allows identification of the quantity
 received therein (and directed out therefrom when dispensing from same).
 When a sufficient supply of gas has been introduced into the syringe 870,
 the supply source is shut off via a valve means associated therewith
 (typically mounted on/integral with the polarizer unit 10') to prevent
 additional gas from exiting the polarizer exit port 106.
 To mete out a desired quantity, the second vessel 250 (suitably prepared to
 remove contaminants) is positioned to be in fluid communication with the
 syringe 870. The plunger 873 is advanced toward the inlet/outlet port end
 of the syringe 870p to push the gas out of the syringe 870 into the tubing
 or conduit 892 toward the second container 250. When the plunger 873 has
 advanced to a desired graduation mark or visual indicia 870g, an operator
 (or computer if the filling process is automated) halts the movement of
 the plunger 873 and closes valves 890, 891 or other shutoff means operably
 associated with the syringe 870 and the second container 250. As such, the
 receiving container 250 captures the meted quantity of gas. The second
 vessel 250 with the meted quantity of hyperpolarized gas can then be
 detached from the flow path. Thus, a meted quantity of gas is dispensed
 into the receiving container 250 allowing for predictable hyperpolarized
 doses.
 As shown in FIG. 16, the supply source or container 50, the syringe 870,
 and the second vessel 250 form part of an extraction system 800. As is
 also shown, the extraction system 800 includes conduit or tubing 881, 892
 as well as a plurality of valves 890, 891 and connectors 888 positioned
 therealong. Generally stated, the valves 890, 891 are configured to
 control the directional flow of the gas associated with the preparation
 (cleaning/purging), filling, and dispensing or meting of the gas into and
 out of the syringe 870 and secondary container 250.
 In the embodiment shown, the syringe 870 and the second vessel 250 are each
 associated with valving means 890, 891, respectively, such that each can
 be individually isolated from the remainder of the extraction system 800.
 Suitable valving means include, but are not limited to, tubing clamps,
 hemostats, luer-type valves, stopcocks, and glass or aluminum (or formed
 or coated with other polarization friendly material) valves. Preferably,
 the second vessel 250 is configured such that it can be detached (with its
 associated valve 891) via a gas-tight connector 888 from the remainder of
 the extraction system 800. Acceptable connectors include but are not
 limited to luer type connectors, Chemthread.TM. connectors, and
 compression fittings.
 Additionally, as noted above, when the polarization cell 50 is used as the
 polarized gas source, the secondary vessel 250 is placed in fluid
 connection with both the syringe 870 and the first vessel 50. Valves 890,
 891 can isolate the syringe 870 and the second vessel 250. Prior to
 filling the syringe 870 with a gas, a vacuum can be used to check for
 leaks in the connections of the extraction system 800. In addition, the
 syringe 870, secondary vessel 250, and connecting tubing 881, 892 are
 pre-conditioned such as by purge/evacuation methods to clean out residual
 deleterious elements within, such as oxygen.
 The syringe 870 is connected to the first vessel 50 via a connector 106 and
 tubing 881 (such as Tygon.RTM.). Preferably, the tubing 881 is sized with
 a small inner diameter gas flow passage to reduce the volume of gas held
 therein (this allows the volume of gas trapped therein after the gas is
 meted from the syringe to be disregarded as it contains a negligible
 quantity) while also being sufficiently large to allow free flow of the
 gas and to evacuate same (typically to levels of about 50 millitorr). Of
 course, the extraction system 800 can be sized and configured with a known
 volume to dispense a quantity larger than the amount which will be meted
 into the second vessel 250. The dead volume quantity will be predetermined
 and can be added to the quantity of gas remaining in the syringe. The two
 volumes can be added together and subtracted from the quantity of gas
 initially held in the syringe thereby providing a reliable accounting of
 the quantity of gas dispensed. In addition, the syringe can include a set
 of correction graduation marks adjusting the volume to offset the dead
 volume thus visually identifying by graduation marks disposed on the
 syringe body itself. For example, for a quantitative conventional
 graduation mark that indicates that 1.1 liters of gas has been transmitted
 from the syringe, and for a dead volume of about 0.10 liters, an
 alternative graduation mark can be disposed on the syringe to read 1.0 on
 the corrected graduation to reflect the quantity that is dispensed into
 the receiving container.
 Preferably, at least the gas-contacting surfaces of the syringe 870 are
 comprised of non-depolarizing materials such as aluminum, titanium, or a
 substantially non-depolarizing plastic. More preferably, the
 gas-contacting surfaces of the syringe 870 are comprised of
 non-depolarizing plastics such as one or more of polyolefins,
 polymethylmethacrylate, polycarbonate, polystyrene, polymethacrylate,
 polyvinyl, polydiene, polyester, polyamide, polyimide, polynitriles,
 cellulose and cellulose derivatives and blends and mixtures thereof. It is
 also preferred that the syringe 870 is further lubricated (to enhance the
 movement of the plunger 873) with a non-toxic, substantially
 non-depolarizing vacuum grease such as one or more of a hydrocarbon grease
 (such as Apiezon N) and/or an inert chlorofluorocarbon grease (such as
 Halocarbon 25-5S).
 In another embodiment, the meted quantity of hyperpolarized gas may be
 mixed with a meted and/or predictable or controlled (preferably,
 substantially precise) amount of a buffer gas. Adding a buffer gas can
 advantageously decrease the rate at which the hyperpolarized gas atoms
 collide with each other, thereby decreasing the rate of depolarization.
 Additionally, it is advantageous to be able to vary the volume of
 hyperpolarized gas to accommodate different polarization levels in order
 to obtain the same dose. Suitable buffer gases are those which can be
 administered in vivo to a subject (pharmaceutical grade/quality) and
 preferably include, but are not limited to, one or more of high
 purity/substantially pure (Grade 5 or better) helium, nitrogen, and argon.
 As shown in FIG. 16, the extraction system 800 can be configured such that
 a single syringe 870 is used to dispense both the hyperpolarized gas and
 the buffer gas. In this embodiment, the buffer gas and hyperpolarized gas
 are sequentially metered out into the syringe 870 from the first container
 50 (preferably the polarizer 10') via the outlet port 106. The syringe 870
 and tubing 881, 892 can be evacuated before the second gas is added to
 increase the reliability/accuracy of the resulting gas mixture. Therefore,
 a valve 891 on the secondary container 250 is used for single syringe 870
 dispensing if a buffer gas is used. Preferably, the buffer gas is meted
 into the syringe 870 first because it does not have a decay time
 associated with it.
 If a buffer gas is used, at least (and preferably more than) the ultimately
 desired amount of buffer gas is preferably dispensed into the syringe 870
 with the valve 891 for the secondary container 250 closed and the
 secondary container 250 pre-conditioned and evacuated. The valve 891 for
 the secondary container 250 is then opened and the desired amount of
 buffer gas is forced into the secondary container 250 by depressing the
 plunger 873. The valve 891 for the secondary container 250 is closed
 again, and the tubing 881, 892 and syringe 870 are evacuated again. The
 hyperpolarized gas is then dispensed into the syringe 870, in an amount
 equal to or exceeding the amount of hyperpolarized gas desired for
 dispensing into the second container 250. As above, after the valve to the
 secondary container 891 is opened, the desired amount of hyperpolarized
 gas is forced into the secondary container 250 by depressing the plunger
 873 on the syringe 870. The valve 891 on the secondary container 250 is
 closed again, and the secondary container 250 is removed from the
 extraction system 800 via its connector 888.
 A dual syringe alternative embodiment is shown in FIGS. 17A and 17B. In
 this embodiment, a second syringe 870' can be used to dispense the buffer
 gas separate from the syringe 870 used to dispense the hyperpolarized gas.
 In this embodiment, the buffer gas is directed into and held in the second
 syringe 870' and subsequently meted into a patient delivery vessel or
 other container 250. Preferably, the buffer gas is dispensed into the
 buffer gas syringe 870' prior to the introduction of the hyperpolarized
 gas into its syringe 870 to reduce depolarization of the hyperpolarized
 gas as it waits to be directed into the second container 250.
 In operation, when the two syringe system is used, the buffer gas is
 dispensed into its syringe 870', as before, while both the secondary
 container 250 and the hyperpolarized gas syringe 870 are closed by their
 associated valves (891 and 890 respectively). The valve 891 on the
 secondary container 250 is opened and the desired amount of buffer gas is
 forced into the secondary container 250. The valves of the secondary
 container and buffer gas syringe 891 and 890', respectively, are closed
 again while the tubing 881, 892, 892' (the `dead volume`) is evacuated.
 The valve 891 associated with the hyperpolarized gas syringe 870 is then
 opened and an appropriate amount of hyperpolarized gas is directed
 therein. The valve associated with the hyperpolarized gas syringe remains
 open. Next, the valve 891 on the secondary container 250 is opened and the
 desired amount of hyperpolarized gas is dispensed from the syringe 870 to
 the secondary container 250. Finally, the valves on the hyperpolarized gas
 syringe and secondary container 890, 891 (with the valve for the buffer
 gas syringe remaining closed) are closed which then allows the secondary
 container 250 to be removed from the extraction system 800 via the
 connector 888 without disrupting the remainder of the extraction system
 800 or contaminating any residual hyperpolarized gas in the hyperpolarized
 gas syringe 870. Another secondary container 250 can then be attached to
 the system and the process can be repeated.
 Alternatively, the hyperpolarized gas can first be directed into the second
 container 250 with the buffer gas subsequently directed therein. For
 example, a quantity of buffer gas such as nitrogen can be dispensed into
 the buffer gas syringe 870'. The dead volume associated with the gas flow
 paths 881, 892, 892' is then evacuated. A desired amount of the
 hyperpolarized gas is then directed into the hyperpolarized gas syringe
 870. The syringes are isolated from the remainder of the system and the
 dead volume (and second container 250 if desired) is evacuated. A desired
 amount of hyperpolarized gas is meted out of the hyperpolarized gas
 syringe 870 and then the buffer gas is used to push the hyperpolarized gas
 into the second container 250 out of the dead volume 881, 892, 892' and to
 top off the gas mixture with a desired volume of the buffer gas. Thus, in
 this embodiment, the buffer gas can push the hyperpolarized gas from the
 tubing into the second container 250. In an additional alternative
 embodiment, a first quantity of buffer gas can be first directed into the
 second container 250, then the hyperpolarized gas can be directed therein,
 and finally, a second quantity of the same or a different buffer gas can
 be directed into the second container 250. Preferably, for a 0.5-2 liter
 quantity of buffer gas and hyperpolarized gas mixture, about 10-90% of the
 gas mixture is hyperpolarized gas, and more preferably about 20-75% of the
 gas in the mixture is hyperpolarized gas. It is also noted that a
 pre-filled buffer gas syringe can be employed with the meting system
 according to the present invention. That is, because no polarization decay
 is associated therewith, the buffer gas syringe can be conveniently
 pre-filled in advance of the polarization of the gas, stored for use, and
 then connected to the gas extraction system at the appropriate time such
 as proximate the meting operation. In addition, the second container 250
 can include two sealable ports and the gas flow path can be connected such
 that the hyperpolarized gas has a first flow path extending from the first
 syringe 870 into the container 250 and the buffer gas has a second flow
 path extending from the second syringe 870' to the container 250 such that
 the second flow path is different from the first flow path (not shown);
 this configuration which can allow concurrent meting of buffer gas and
 hyperpolarized gas therein.
 Advantageously, this dual syringe system decreases the likelihood that the
 relatively expensive hyperpolarized gas will be unduly wasted. For
 example, since the syringe 870 is not required to be evacuated after the
 extraction procedure commences, if an excess of hyperpolarized gas is
 dispensed into the syringe 870 accidentally, that hyperpolarized gas is
 not wasted and can be used to fill a subsequent secondary container 250.
 FIG. 17B illustrates that the two syringes 870, 870' can be held side by
 side in a holding apparatus for convenient interconnection to the first
 container 50 (preferably via the exit port on the polarizer 10'). If the
 buffer gas syringe 870' is held in close proximity to the hyperpolarized
 gas syringe 870, then preferably it is formed of substantially
 non-depolarizing materials to reduce the likelihood that is presence will
 promote polarization decay. As is shown, the holding apparatus 801
 includes a first platform 801a and a second opposing platform 801b sized
 and configured to hold the syringes 870, 870' in substantial side by side
 alignment therebetween. A plurality of ribs 801r can be used to
 interconnect and provide the desired rigidity to the holding apparatus.
 Preferably, the ribs and platforms 801r, 801a, 801b are configured to hold
 the syringes 870,870' recessed a distance into the body of the apparatus
 801 to reduce the likelihood that the syringes will be hit by inadvertent
 contact during operation. In any event, it is preferred that the holding
 apparatus 801 be configured such that the graduations/visual indicia 870g,
 870g' are visible during use.
 The first platform 801a includes two apertures 801o sized to allow the
 plunger rod 873e to extend and translate therefrom. The second platform
 801b includes apertures (not shown) for the inlet/outlet port 870p, 870p'
 to allow the gas to flow to the desired syringe therein. Of course, other
 holding apparatus configurations can also be used. As a non-limiting
 example, two separate holding apparatus (one for each of the syringes)
 which can be joined together or held in a desired position on a cart or
 other structure (stationary or not as shown in FIG. 16) to help maintain
 secure air tight connections during operation (and preferably connected to
 reduce the length of the conduit used to mete the gas(es)). As shown in
 FIG. 16, a similar holding apparatus can be used for a single syringe
 system.
 In another preferred embodiment as shown in FIG. 18, a plurality of
 secondary containers 250A-250E can be filled sequentially with an
 extraction system 800 according to the present invention. As shown in FIG.
 18, a plurality of secondary containers 250A-250E can be connected via
 gas-tight individually detachable connectors 888A-888E from the extraction
 system 800. Thus, similar to the embodiment described above, each of the
 plurality of secondary containers 250A-250E is associated with a valve
 891A-891E with which it is in fluid communication. The valves 891A-891E
 advantageously allow the secondary containers 250A-250E to be
 pre-processed (as described hereinabove) and filled independently of the
 others. Therefore, the plurality of secondary containers 250A-250E can be
 filled sequentially, and can be filled utilizing one (not shown) or two
 syringes (870, 870'). As before, it is more preferable that a substantial
 quantity of the buffer gas, if used, be dispensed into each secondary
 container 250A-250E before the hyperpolarized gas is extracted from the
 primary container 50. Of course, the filling of a plurality of second
 containers 250A-250E can also be carried out simultaneously.
 Preferably, particularly for longer dispensing time periods (ie., longer
 than about five to ten minutes), a magnetic field generator means is
 positioned proximate the hyperpolarized gas to enclose the hyperpolarized
 gas syringe 870 with a magnetic field as shown in FIG. 19. In one
 embodiment, the magnetic field generator means can be mounted onto the
 cart shown in FIG. 15. The magnetic field generator means can either
 comprise permanent magnets (not shown) or electromagnets 820A, 820B, as
 long as the field strength is sufficient to shift the resonant frequency
 of the gas above the region of ambient noise and minimize the effect of
 ambient gradients on the gas. A more complete discussion of magnetic
 holding fields can be found in co-assigned and co-pending U.S. patent
 application Ser. No. 09/333,371, the contents of which were incorporated
 by reference hereinabove. It is also preferred that if a magnetic field
 generator is used, a mans for assessing the extend of polarization in the
 gas is also used. For example, an NMR excitation coil can be positioned
 proximate the hyperpolarized gas syringe 870 or in the flow path or even
 adjacent the first or second container (or even at multiple of these or
 other locations within the extraction system).
 EXAMPLE
 A suitable precision fluid measuring product gas tight syringe is available
 from the Hamilton Company located in Reno, Nevada. This syringe can be
 modified by changing the fitting 870p and the plunger 873. That is, the
 magnetic metal fitting conventionally used on this syringe where the line
 connects to the body of the plunger was replaced with a plastic
 (polypropylene) fitting and the plunger was replaced with a plunger formed
 of polyethylene plastic.
 T.sub.1 measurements were taken for the syringes holding only or
 (substantially pure or about 100%) .sup.3 He. For about a one liter
 quantity of .sup.3 He gas in the syringe held within a protective magnetic
 holding field of about 7 Gauss a T.sub.1 of about 3 hours was measured.
 For about 950 cc's (a similar quantity) of the substantially pure .sup.3
 He not held in a protective holding field a T.sub.1 from about 10-17
 minutes was obtained.
 Additionally T.sub.1 measurements were taken for gas mixtures meted
 according to the present invention into a disposable patient collapsible
 bag holding a one liter mixture of hyperpolarized .sup.3 He gas with about
 a 50% concentration of the polarized gas and about a 50% blend of N.sub.2
 buffer gas, using the single syringe meting method discussed above, the
 T.sub.1 for the bag was measured at about 11.4 hours. In comparison, when
 the hyperpolarized .sup.3 He gas was dispensed directly into the bag from
 the polarizer, the measured T.sub.1 was about 12 hours. Thus, the meting
 method of the present invention resulted in only a very minor loss of
 polarization.
 Advantageously, these methods allow controlled amounts of the gas to be
 introduced into the delivery device/vessel, thereby allowing more precise
 and/or reliable amounts of hyperpolarized gases and gas mixtures to be
 transported, which in turn can reduce residual waste caused by unused gas
 left in the container as well as provide for more repeatable dose
 quantities. Further, controlled delivery and extraction allows a more
 predictable delivery dosage and potentially decreases product costs
 (particularly for commercial sized production runs and/or use) over that
 of typical conventional systems.
 2. Inflatable Extraction
 FIGS. 10 and 11 illustrate another embodiment of the present invention. The
 container 50E includes a resilient member 910 positioned in the container
 50E such that it is in fluid communication with the hyperpolarized gas in
 the container. In operation, the resilient member 910 expands from a first
 position (shown in FIG. 10) to a second position (shown in FIG. 11). Thus,
 the expanded resilient member 910 translates a further distance or depth
 into the container to expel the hyperpolarized gas out of the exit port
 936 into the delivery path or patient delivery vessel 250. The expansion
 is responsive to fluid introduced into the fluid entry port upstream of
 the container. As shown, the resilient member 910 is positioned
 intermediate the fluid entry port 915 and the hyperpolarized gas in the
 container 50E. The exit port/path 934 of the container 50E is preferably
 positioned opposing the inlet port 915 as described for the liquid
 extraction method above. As shown in FIG. 11, the collapsed resilient
 member 910 extends a small.
 Preferably, the resilient member 910 is securely attached to the container
 such that it forms a fluid-tight seal around the walls or circumference of
 the inlet port 915. A valve 916 can be positioned upstream of the
 resilient member to minimize oxygen entry into the container. As shown in
 FIG. 11, this sealed attachment will permit the resilient member to act as
 a barrier surface 925 to contain the fluid(s) introduced to expand the
 resilient member 910 separate and apart from the hyperpolarized gas.
 Alternatively, the resilient member 910 can be configured to expand with
 fluid introduced therein, while also letting a portion of the expansion
 fluid enter the container 50E downstream of the resilient member 910 to
 form a gas mixture as was described for the gas extraction method above.
 For example, an expansion gas comprising nitrogen can be introduced into
 the fluid entry port 915 and used to inflate the resilient member 910. The
 resilient member 910 can include apertures or be secured to the container
 in a way to define apertures to allow a portion of the nitrogen to pass
 therethrough (not shown). The nitrogen and hyperpolarized gas are then
 pushed out of the exit port 934 by the inflated positions of the resilient
 member 910.
 In any event, as the resilient member barrier surface 925 contacts the
 hyperpolarized gas, it is preferred that it be formed from a
 polarization-friendly material (or coated with same) so as to inhibit
 contact induced polarization attributed thereto.
 Once the hyperpolarized gas has been extracted from the transport vessel it
 can be captured in a patient delivery system such as a collapsible bag 250
 as shown in FIG. 11. The bag can be conveniently compressed to force the
 hyperpolarized gas into an inhalation mask 255 positioned on a subject.
 Alternatively, the hyperpolarized gas can be extracted as described
 herein, but delivered directly to the subject as illustrated in FIG. 13.
 E. High Efficiency Transport Vessel
 In one embodiment, which can reduce the need for an active or mechanical
 secondary means of extraction, the container itself can be alternatively
 configured to reduce the amount of gas remaining in the vessel over
 conventional vessels. In this embodiment, a low volume, high pressure
 transport vessel is configured to transport hyperpolarized gas. Even
 without a secondary means of mechanical extraction, the gas in the
 container can be released to stabilize with atmospheric pressure as
 described for conventional extraction methods. However, because containers
 with smaller chambers are used, a lesser volume of gas remains in the
 chamber at the I atm condition compared to larger low-pressure transport
 vessels.
 In a preferred embodiment, the container is sized and configured to be 500
 cc's (cubic centimeters) or smaller, and pressurized to about 3-10 atm of
 pressure. For .sup.3 He, the container is preferably sized to be less than
 about 200 cc's and pressurized at about 5-10 atrn. More preferably, the
 .sup.3 He container is sized at about 200 milliliters or less, and
 pressurized to about 6-10 atm. This will allow an equivalent gas content
 of about 1.2 liters, which allows a fill one liter to be extracted just by
 opening the valve to equalize to ambient pressure at the desired delivery
 point.
 In another embodiment, the transport container 22 according to the present
 invention can be configured to act as the polarization chamber (FIG. 1,
 22). In this embodiment, the transport container is the polarization
 chamber 22 and is detachable from the hyperpolarizer 10 (not shown). Thus,
 the transport container can be configured as a dual purpose vessel to
 allow polarization and still be configured to be a transport container as
 described hereinabove; this configuration can reduce the number of gas
 transfers, thereby improving the transfer efficiency and reducing the
 amount of residual gas that is wasted.
 F. Cryo-Cooled Gas Extraction
 FIG. 14 illustrates yet another aspect of the present invention. This
 figure illustrates one embodiment of an improved transfer method according
 to the present invention. More particularly, this figure shows cooling the
 container 50A to a desired temperature (preferably below the freezing
 point of water, i.e., sub-zero temperatures). More preferably, the
 container is cooled to at least about 195.degree. K. (such as by exposing
 the container to a dry ice (CO.sub.2). Most preferably, the cooling is
 carried out by exposing the container or chamber to cryogenic
 temperatures, such as to liquid nitrogen or liquid helium temperatures.
 For example, as shown in FIG. 14, the cooling is performed by exposing the
 container 50A to a liquid nitrogen bath (77.degree. K.) 140. In this
 figure, a dewar 141 is configured to hold a quantity of cooling liquid and
 the container 50A is at least partially immersed therein. Although
 illustrated as immersed, the invention is not limited to thereto. The
 dewar 141 can be alternately configured to receive only a portion of the
 container therein, or to have a smaller amount of cooling liquid therein.
 In addition, of course, other cooling means can be used which are known to
 those of skill in the art including but not limited to refrigeration
 systems, ice baths, other cryogenic exposure techniques and the like, to
 cool the container to a desired temperature. In operation, the
 hyperpolarized gas exits the polarizer cell 22 and enters the cooled
 transport container chamber. The cooled walls of the container allow
 increased volumes of hyperpolarized gas in the chamber (compared to
 non-cooled chambers) thereby increasing the quantity of hyperpolarized gas
 captured therein. Stated differently, at lower temperatures, gas
 compresses according to the equation PV=nRT, therefore more gas can be
 contained in a chamber having a lower pressure.
 Generally stated, the gas "packing effect" can be described by the ratio of
 room temperature to the coolant temperature. For liquid nitrogen, the
 packing effect can be expressed as 295/77 or 3.8. Thus, the packing effect
 for dry ice is about 295/195 or 1.51, while the value for the freezing
 point of water is only about 295/273 or 1.08. Thus, it is preferred that
 the coolant temperature be selected to provide a packing effect which is
 at least about 1.08, more preferably at least about 1.51 and most
 preferably at least about 3.8, although other values can be used. Of
 course, as noted above, preparing the container such as by evacuating and
 purging (to clean it before use) is important.
 In one preferred embodiment, hyperpolarized .sup.3 He is collected in the
 cooled container or chamber. In another preferred embodiment, either
 .sup.3 He or .sup.129 Xe exits the polarizer cell 22 and is directed into
 a closed container 50A such that the hyperpolarized gas mixture (with the
 alkali metals removed) which exits the polarizer cell (e.g., the "exhaust"
 mixture) is captured and enclosed by the container. The container can then
 be sealed and allowed to warm to ambient temperature. This is unlike the
 cryogenic cold finger apparatus used to continuously process .sup.129 Xe
 (by retaining only the .sup.129 Xe and directing the remainder of the gas
 mixture out of the container). In addition, tubing and other chambers
 positioned after the polarizer cell 22 or transferor vessel can also be
 cooled.
 In another aspect of a preferred embodiment, the cryo-cooled gas extraction
 is carried out under temperature control to provide a more "controlled" or
 exact filling amount of gas to be directed into the container. One way to
 control temperature during the cryo-cooling process is to direct cold
 nitrogen gas to flow across a heater element positioned proximate to the
 transport container. A temperature sensor can be positioned adjacent the
 transport container to measure temperature of the container. This
 information feeds back to the heater element to automatically turn it
 "off" or "on" so as to maintain the desired temperature of the transport
 vessel (between room temperature and the coolant temperature). This would
 allow variable temperature (from about 77 K to room temperature) across
 the transport container. This controlled temperature gradient can allow
 consecutive transfer or receiving vessels to be filled with
 (substantially) the same amount of hyperpolarized gas. This controlled
 amount is desired (within certain tolerance ranges) so that a precise
 dosage can be delivered or administered to a patient. For example, upon
 extraction of gas into a first container, the polarizer cell starts with a
 pressure of about 8 atm. However, before the next consecutive container is
 filled, the cell pressure could be depleted. Thus, one could control the
 rate of extraction via temperature gradients to control the amount of gas
 which exits the cell into the temperature controlled (temperature
 gradient) container to deliver a substantially equal amount to the two
 consecutively filled containers.
 Alternatively, multiple containers (not shown) can be plumbed to be filled
 simultaneously such as by concurrently engaging two or three or more
 (preferably similarly sized) containers with the polarization cell such
 that each is cooled to the same temperature. The hyperpolarized gas flow
 could be directed down an main exit channel and split into channels
 equidistant from the cell. Preferably the multiple containers have the
 same size, volume, and (cooled) temperature. The split channels direct the
 gas into the containers in communication therewith to obtain substantially
 the same amount of gas in each container.
 G. Container/Materials
 Because the shape of the container area can impact the rate of
 depolarization, it is preferred that container configurations be selected
 to maximize the free-gas volume of the container (V) while minimizing the
 surface area (A) which contacts the hyperpolarized gas (that is, to
 decrease the value of the ratio A/V). More preferably, the container is
 sized and configured to provide a A/V ratio of about less than 1.0, and
 even more preferably less than about 0.75. In one embodiment, the
 container is substantially spherical.
 Preferred container materials include non-magnetic high-purity metal films,
 high-purity metal oxides, high purity insulators or semi-conductors (such
 as high purity silicon) and polymers. As used herein, "high purity"
 includes materials which have less than about 1 ppm ferrous or
 paramagnetic impurities and more preferably less than about 1 ppb ferrous
 or paramagnetic impurities. Preferred polymers for use in the containers
 described herein include materials which have a reduced solubility for the
 hyperpolarized gas. For the purposes of the inventions herein, the term
 "polymer" to be broadly construed to include homopolymers, copolymers,
 terpolymers and the like. Similarly, the terms "blends and mixtures
 thereof" include both immiscible and miscible blends and mixtures.
 Examples of suitable materials include, but are not limited to,
 polyolefins (e.g., polyethylenes, polypropylenes), polystyrenes,
 polymethacrylates, polyvinyls, polydienes, polyesters, polycarbonates,
 polyamides, polyimides, polynitriles, cellulose, cellulose derivatives and
 blends and mixtures thereof. It is more preferred that the coating or
 surface of the container comprise a high-density polyethylene,
 polypropylene of about 50% crystallinity, polyvinylchloride,
 polyvinylflouride, polyamide, polyimide, or cellulose and blends and
 mixtures thereof.
 Of course, the polymers can be modified. For example, using halogen as a
 substituent or putting the polymer in deuterated (or partially deuterated)
 form (replacement of hydrogen protons with deuterons) can reduce the
 relaxation rate. Methods of deuterating polymers are known in the art. For
 example, the deuteration of hydrocarbon polymers is described in U.S. Pat.
 Nos. 3,657,363, 3,966,781, and 4,914,160, the disclosures of which are
 hereby incorporated by reference herein. Typically, these methods use
 catalytic substitution of deuterons for protons. Preferred deuterated
 hydrocarbon polymers and copolymers include deuterated paraffins,
 polyolerms, and the like. Such polymers and copolymers and the like may
 also be cross-linked according to known methods.
 It is further preferred that the polymer be substantially free of
 paramagnetic contaminants or impurities such as color centers, free
 electrons, colorants, other degrading fillers and the like. Any
 plasticizers or fillers used should be chosen to minimize magnetic
 impurities contacting or positioned proximate to the hyperpolarized noble
 gas.
 Alternately, in another embodiment, the contact surface can be formed from
 a high purity metal. The high purity metal can provide advantageously low
 relaxivity/depolarization resistant surfaces relative to hyperpolarized
 noble gases.
 As noted above, any of these materials can be provided as a surface coating
 on an underlying substrate or formed as a material layer to define a
 friendly contact surface. If used as a coating, the coating can be applied
 by any number of techniques as will be appreciated by those of skill in
 the art (e.g., by solution coating, chemical vapor deposition, fusion
 bonding, powder sintering and the like). Hydrocarbon grease can also be
 used as a coating. The storage vessel or container can be rigid or
 resilient. Rigid containers can be formed of Pyrex.TM. glass, aluminum,
 plastic, PVC or the like. Resilient vessels are preferably formed as
 collapsible bags, preferably collapsible polymer or metal film bags.
 Examples of materials which can provide oxygen resistance as well as
 low-solubility include but are not limited to PET (polyethylene
 terphthalate), PVDC (polyvinylidene dichloride), Tedlar.TM.
 (polyvinylfluoride), cellophane and polyacrylonitrile.
 Preferably, care is taken to insure all fittings, seals, and the like which
 contact the hyperpolarized gas or which are located relatively near
 thereto are manufactured from materials which are friendly to polarization
 or which do not substantially degrade the polarized state of the
 hyperpolarized gas. For example, many commercially available seals are
 made from fluoropolymers which (with the exception of Tedlarm noted above)
 are not particularly good for the preservation of either .sup.129 Xe or
 .sup.3 He hyperpolarized gases because of the solubility of the
 hyperpolarized gas in the material.
 Inasmuch as most common gasket materials are fluoropolymers, they can
 potentially have a substantially depolarizing effect on the gas. This
 effect, which can be particularly acute for .sup.3 He, can be attributed
 to a relatively high solubility of helium in most fluoropolymers due to
 the larger void space in the polymer attributable to the large fluorine
 atoms. It is preferred that the containers of the present invention employ
 seals, O-rings, gaskets and the like with substantially pure
 (substantially without magnetic impurities) hydrocarbon materials such as
 those containing polyolefins (including but not limited to polyethylene,
 polypropylene, copolymers and blends thereof). Additionally, hydrocarbon
 grease can be used to further facilitate or produce a vacuum tight seal.
 Thus, if a valve is used to contain the gas in the chamber 30, it is
 preferably configured with a magnetically pure (at least the surface)
 O-ring and/or with hydrocarbon grease. Of course, where fillers and
 plasticizers are employed, then it is preferred that they be selected to
 minimize the magnetic impurities such as substantially pure carbon black.
 In an alternative embodiment, the O-ring seal can be configured with the
 exposed surface coated with a high purity metal as discussed for the
 container surface.
 Similarly, the O-ring or seal can be coated or formed from an outer exposed
 layer of a polymer at least "L.sub.p " thick. the inner layer thickness
 ("L.sub.th ") is at least as thick as the polarization decay length scale
 ("L.sub.p ") which can be determined by the equation:
EQU L.sub.p =T.sub.p +L D.sub.p +L
 where T.sub.p is the noble gas nuclear spin relaxation time in the polymer
 and D.sub.p is the noble gas diffusion coefficient in the polymer.
 For example, a layer of substantially pure polyethylene can be positioned
 over a commercially available O-ring. One preferred O-ring material for
 .sup.129 Xe is a Teflon.TM. coated rubber.
 When bags with long surface relaxation times are used, other relaxation
 mechanisms can become important. One of the most important additional
 relaxation mechanisms is due to collisions of the noble gas with
 paramagnetic oxygen. Because O.sub.2 has a magnetic moment, it can relax
 hyperpolarized gases in the same manner as protons. Given this problem,
 care should be taken to reduce the oxygen content in the storage container
 through careful preconditioning of the container, such as by repeated
 evacuation and pure gas purging procedures. Preferably, the container is
 processed such that the O.sub.2 concentration yields a T.sub.1 of about
 1000 hours or more. More preferably, the container is processed to obtain
 an O.sub.2 concentration on the order of about 6.3.times.10.sup.-6 atm or
 less or about 10.sup.-7 atm or less, and even more preferably less than
 about 1.times.10.sup.-10 atn. Additionally, as discussed above, the
 evacuation/purge procedures can include heating the container or other
 evacuating or pumping methods to additionally facilitate the removal of
 any remaining (monolayer) residual amounts of moisture or water.
 Preferably, the patient interface and storage chambers and associated
 apparatus and tubing are prepared in advance of use to minimize any
 preparation required at the hospital or extraction site. Therefore,
 preferred pre-conditioning or equipment preparation methods such as
 cleaning, evacuating, and purging the connectable tubing and patient
 delivery vessel (see FIG. 3, 250, 251) or other components to remove
 oxygen and paramagnetic contaminants are preferably done off-site. After
 preparation/conditioning, the tubing 251 and delivery bag 250 can be
 stored at the hospital for use under pressure with a noble gas or benign
 liquid therein. This pre-filled gas or fluid storage can minimize the
 potential for the containers or components to de-gas (gas from the matrix
 of a material such as oxygen can migrate into the chamber onto the contact
 surfaces), and can also minimize air leaking into the container.
 Alternatively, or in addition to the pre-conditioning, the pressurized
 tubing and delivery vessels (and/or syringes) can be sealed with check
 valves or other valved ports. In another alternative, vacuum tight valves
 can allow the tubes and containers to be stored for use under vacuum
 rather than under positive pressure.
 H. Calibration Station
 Preferably, prior to introduction and/or delivery to a patient, the
 hyperpolarized gas is preferably calibrated for identification of the
 efficacy or polarization strength of the gas. Advantageously, this
 calibration will allow a "shelf-life" to be affixed to the delivery
 container alerting personnel as to the temporally limited useful life of
 the product. This positive identification can minimize the delivery of
 non-effective hyperpolarized gas to the patient. In a preferred
 embodiment, the calibration is performed on the hyperpolarized gas at the
 end use site. Preferably, the calibration is performed on the gas
 subsequent to when it has been extracted from the shipping or transport
 container 50A-E. More preferably, the hyperpolarized gas is calibrated
 when the gas is captured in the delivery vessel 250. It is also preferred
 that the gas be calibrated when it is positioned in a protected area (ie.,
 stable magnetic field) proximate to the end use site at the clinic or
 hospital facility. This allows a reliable representative calibration to be
 established on the product when it is in its final delivery container, or
 at its destination site, and/or when it is in a protected environment
 (such as proper shielding and/or homogenous magnetic fields) and is
 protected from potentially degrading elements (i.e., EMI, etc.) especially
 problematic during shipping. Also preferably, after calibration the
 container is configured with an external indicia of validation/inspection
 corresponding to an inspection date and a use-by date and or time.
 In a preferred embodiment, the transport container is sized and configured
 to ship multiple dosages of the hyperpolarized gas, and then extracted at
 a protected destination site to form single dose patient delivery vessels.
 The single dose vessels can be tested for efficacy and externally
 dated/stamped or otherwise encoded with a preferred use date/time. This
 calibrated and externally visually identified product will allow operators
 to conveniently identify and remove "old" or "depolarized" product in
 advance of the patient delivery/end use.
 Generally described, as shown in FIG. 15, the calibration is carried out at
 a calibration station 150 which preferably uses a low-field NMR
 spectrometer 155 to transmit RF pulses to surface coils 160 positioned
 proximate to the hyperpolarized gas sample. The spectrometer then receives
 at least one signal 165 back corresponding to the hyperpolarized gas which
 are processed to determine the polarization level of the hyperpolarized
 gas (preferably contained in a single dose patient delivery vessel). As
 shown, the calibration station 150 preferably includes a set of Helmholtz
 coils 152 (preferably of about 24 inches in diameter) to provide the low
 magnetic field and a (NMR) surface coil 170 (preferably sized and
 configured at about 1 inch in diameter and with about 350 turns). The
 surface coil 170 sits on a platform 172 to preferably position the surface
 coil 170 in the center of the Helmholtz coils 152. The term "low field" as
 used herein includes a magnetic field under about 100 Gauss. Preferably,
 the calibration station is configured with a field strength of about 5-40
 gauss, and more preferably a field strength of about 20 gauss.
 Accordingly, the corresponding .sup.3 He signal frequency range is about
 16 kHz-128 Khz, with a preferred frequency of about 64 kHz. Similarly, the
 .sup.129 Xe signal frequency range is about 5.9 kHz-47 kHz, with a
 preferred signal frequency of about 23.6 kHz.
 Preferably, the container 250 is positioned on the top surface of the
 surface coil 170 and substantially in the center of the Helmholtz coils
 152. Generally described, in operation, a selected RF pulse (of
 predetermined pulse, frequency, amplitude, and duration) is transmitted
 from the NMR device 155 to the surface coil 170. The frequency corresponds
 to the field strength of the magnetic field and the particular gas,
 examples of which are noted above. This RF pulse generates an oscillating
 magnetic field which misaligns at least some of the hyperpolarized .sup.3
 He or .sup.129 Xe nuclei from their static magnetic field alignment
 position. The misaligned nuclei start processing at their associated
 Larmour frequency (corresponding to pulse frequency). The precessing spins
 induce a voltage in the surface coil which can be processed to represent a
 signal 165. The voltage is received back (typically amplified) at the
 computer and the signal fits an exponentially decaying sinusoid pattern.
 As shown, the signal 165 received back at the computer is the Fourier
 transform of the received signal. The peak-to-peak voltage of this signal
 is directly proportional to polarization (using a known calibration
 constant). The computer can then calculate the polarization level, and
 generate calculated preferred use dates and times associated with desired
 polarization levels. As will be recognized by those of skill in the art,
 other calibration or hyperpolarization level determination methods can
 also be employed and still be within the product identification and
 calibration or product-use or expiration determination methods
 contemplated by the present invention. For example, detecting the minute
 magnetic field generated by the polarized .sup.3 He spins. Also, as shown
 in FIG. 15, a purge gas cylinder 177 and associated vacuum and purge
 equipment 178 are positioned proximate to the calibration station. In one
 preferred embodiment, the purge and vacuum equipment are positioned on or
 proximate to the calibration station so that the container can be cleaned
 (evacuated and pure-gas purged) at the calibration station 150 prior to
 the calibration. Thus, the calibration station can advantageously be
 combined with a filling and cleaning station. For example, a rigid
 transport vessel can transport the hyperpolarized gas from a
 hyperpolarization site to the calibration station at a use site. The
 delivery container 250 can be cleaned at the calibration station (or
 pre-cleaned as discussed above). The gas can be extracted from the
 transport container into the delivery container 250 right at the
 calibration station, preferably according to one of the methods of the
 instant invention. The extracted gas now captured in the container 250 can
 be easily and instantly measured or identified/calibrated as to its
 efficacy or hyperpolarization level and marked for instant or future use.
 The foregoing is illustrative of the present invention and is not to be
 construed as limiting thereof. Although a few exemplary embodiments of
 this invention have been described, those skilled in the art will readily
 appreciate that many modifications are possible in the exemplary
 embodiments without materially departing from the novel teachings and
 advantages of this invention. Accordingly, all such modifications are
 intended to be included within the scope of this invention as defined in
 the claims. In the claims, means plus function clause are intended to
 cover the structures described herein as performing the recited function
 and not only structural equivalents but also equivalent structures.
 Therefore, it is to be understood that the foregoing is illustrative of
 the present invention and is not to be construed as limited to the
 specific embodiments disclosed, and that modifications to the disclosed
 embodiments, as well as other embodiments, are intended to be within the
 scope of the appended claims. The invention is defined by the following
 claims with equivalents of the claims to be included therein.