Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2001-06-28
2003-07-29
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009320, C436S173000
Reexamination Certificate
active
06599497
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to hyperpolarized Helium-3 (“
3
He”) and is particularly suitable for Magnetic Resonance Imaging (“MRI”) and NMR spectroscopic medical diagnostic applications.
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
3
He and Xenon-129 (“
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 are sensitive to handling and environmental conditions and, undesirably, can decay from the polarized state relatively quickly.
“Polarization” or hyperpolarization of certain noble gas nuclei (such as
129
Xe or
3
He) over the natural or equilibrium levels, i.e., the Boltzmann polarization, is desirable because it enhances and increases 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 herein by reference as if recited in full herein.
For medical applications, after the hyperpolarized gas is produced, it is processed to form a non-toxic or sterile composition prior to introduction into a patient. Unfortunately, during and after collection, the hyperpolarized gas can deteriorate or decay (lose its hyperpolarized state) relatively quickly and therefore must be handled, collected, transported, and stored carefully. The “T
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 container. 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, i.e., delivery to a patient. 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, ambient and contact impurities, and the like.
In the past, various hyperpolarized delivery modes such as injection and inhalation have been proposed to introduce the hyperpolarized gas to a patient. Inhalation of the hyperpolarized gas is typically preferred for lung or respiratory type images. To target other regions, other delivery paths and techniques can be employed. However, because helium is much less soluble than xenon in conventional carrier fluids such as lipids or blood,
3
He has been used almost exclusively to image the lungs rather than other target regions.
Recent developments have proposed overcoming the low solubility problem of helium by using a micro-bubble suspension. See Chawla et al.,
In vivo magnetic resonance vascular imaging using laser
-
polarized
3
He microbubbles,
95 Proc. Natl. Acad. Sci. USA, pp. 10832-10835 (September 1998). Chawla et al. suggests using radiographic contrast agents as the injection fluid to deliver microbubbles of hyperpolarized
3
He gas in an injectable formulation. This formulation can then be injected into a patient in order to image the vascular system of a patient.
Generally stated, one way currently used to load or produce the microbubble mixture is via “passive” permeability. That is, the hyperpolarized
3
He typically enters the walls of the micro-bubbles based on the helium permeability of the bubble itself. Thus, this gas loading method can take an undesirable amount of time, which can allow the hyperpolarized gas to decay unduly. Further, contact with the fluid or even the microbubble can result in contact-induced depolarization which can dominate the relaxation mechanisms of the hyperpolarized
3
He and cause an undesirable reduction in the hyperpolarized life of the gas.
As such, there remains a need to improve micro-bubble
3
He formulations and loading methods to minimize the decay of the polarized gas and improve the T
1
of the micro-bubble formulation.
In addition, there is also a need to increase the ease of solubilizing hyperpolarized gaseous xenon, which, in the past, has been problematic.
OBJECTS AND SUMMARY OF THE INVENTION
It is therefore an object of the present invention to improve the T
1
for a hyperpolarized
3
He microbubble injectable solution.
It is another object of the present invention to reduce the effect of contact-induced depolarization to increase the hyperpolarized life of an injectable microbubble product.
It is an additional object of the present invention to produce an injectable microbubble solution in a way which increases the concentration of hyperpolarized
3
He in the microbubbles in the injectable formulation.
It is another object of the invention to provide methods and devices for administering polarized microbubble injectable formulations to a subject in a manner which can rapidly mix and deliver the formulation to capitalize on the polarized state of the gas before it deleteriously decays.
It is another object of the present invention to process and form a hyperpolarized
3
He gas mixture in improved containers and injection delivery systems which are configured to inhibit depolarization in the collected polarized gas.
It is yet another object of the invention to provide methods, surface materials and containers which will minimize the depolarizing effects of the hyperpolarized state of the
3
He gas in a microbubble solution attributed to one or more of paramagnetic impurities, oxygen exposure, stray magnetic fields, and surface contact relaxation.
It is another object of the present invention to provide a dissolution assist method for facilitating the transition of hyperpolarized
129
Xe from a gaseous to a liquid state.
These and other objects are satisfied by the present invention, which is directed to microbubble related hyperpolarized gas injectable solution (solubilized or liquid) products and related production and delivery methods, systems, and apparatus.
A first aspect of the present invention is directed to a method of producing an injectable formulation of hyperpolarized
3
He. The method includes the steps of introducing a plurality of microbubbles into a chamber and then directing a quantity of hyperpolarized
3
He into the chamber with the plurality of microbubbles. The pressure in the container is increased to above one atmosphere. A quantity of liquid is then directed into the chamber after the quantity of hyperpolarized gas and the microbubbles are located therein. The microbubbles with the (filled) hyperpolarized
3
He contact the liquid thereby producing an injectable formulation of hyperpolarized
3
He microbubbles.
In a preferred embodiment, the pressure is increased to above 2 atmospheres, and preferably increased to between about 2-10 atm. It is also preferred that the increasing step is performed after the microbubbles are introduced into the chamber and before the liquid is introduced therein.
Preferably, the liquid solution is selected such that it inhibits the depolarization of the gas based on contact with same. For example, in one embodiment, the fluid is selected such that it has low solubility values for
3
He (preferably less than about 0.01, and more preferably less than about 0.005-0.008) or high diffusion coefficient value for
3
He. In operation, the microbubble surface or walls are configured in the absence of the injection liquid to allow the hyperpolarized
3
He to freely enter through the exterior cage-like shell of the bubble, then the fluid or liquid wraps around the openings in the cage-like shell to trap the hyperpolarized gas therein in such a way as to inhibit the transfer or leaching of the gas out of the mic
Hartley Michael G.
Medi--Physics, Inc.
Myers Bigel & Sibley Sajovec, PA
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