|Publication number||US3791982 A|
|Publication date||Feb 12, 1974|
|Filing date||Jul 19, 1972|
|Priority date||Jul 19, 1972|
|Also published as||DE2336199A1|
|Publication number||US 3791982 A, US 3791982A, US-A-3791982, US3791982 A, US3791982A|
|Inventors||L Hanson, R Lewis|
|Original Assignee||Gen Electric|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (3), Classifications (15)|
|External Links: USPTO, USPTO Assignment, Espacenet|
Feb. 12, 1974 gw s ETAL 3,791,982
RADIOACTIVE XENON SOLUT ION .Filed July 19, 1972 United States Patent Office 3,791,982 RADIOACTIVE XENON SOLUTION Robert E. Lewis and Lloyd A. Hanson, Pleasanton, Cahfi, assignors to General Electric Company Filed July 19, 1972, Ser. No. 273,095 Int. Cl. C01f 13/00 US. Cl. 252-301.1 R 23 Claims ABSTRACT OF THE DISCLOSURE An aqueous solution having dissolved therein an isotopic mixture comprising natural xenon and a radioactive isotope of xenon is presented along with a method of preparing the aqueous solution.
BACKGROUND OF THE INVENTION This invention relates to aqueous solutions having dissolved therein an isotopic mixture comprising natural xenon and a radioactive isotope of xenon and to methods of preparing the aqueous solutions.
Natural xenon is a rare noble gas composed of nine stable isotopes and is commercially obtained by extraction from liquid air. Radioactivee isotopes of xenon do not occur naturally and are produced by several techniques such as irradiation of uranium for production of xenon-133 or by bombarding iodine or another suitable target element in a charged particle accelerator for production of xenon 127. Xenon-133 is one of the longer lived radioactive isotopes of xenon having a half life of 5.3 days and is produced at the rate of 6.6 atoms per 100 atoms of uranium fissioned. Xenon-127 has a half life of 36.4 days and is produced at the rate of fractions of an atom per 100 atoms of iodine or other suitable target element bombarded in a charged particle accelerator.
These two radioactive isotopes of xenon are useful in the field of medicine. There is increasing use of xenon-133 in the medical field for studying blood flow in the muscles, scanning the lungs for lung functional disorders (e.g., emphysema and emboli), scanning the brain and scanning for cardia abnormalities. For scanning of the lungs, xenon- 133 can be introduced into a human body by one of two practices. In an inhalation process, the patient breathes a gas containing xenon-133 and the xenon-l33 is drawn directly into the patients lungs. The gas containing xenon- 133 could be evolved from a water solution having the gas dissolved therein. In an injection process, a solution containing xenon-133, with or without a physiological salt, is injected into the blood stream of the patient and through perfusion the xenon-133 goes mainly to the patients lungs. Where longer lived injectable radioactive solutions are desired, other radioactive isotopes of xenon, such as xenon-127 could be used for patient scanning.
The current practice of formulating a xenon-133 solution for medical applications is to dissolve the xenon-133 directly into a saline solution containing a physiological salt to achieve gas concentrations appreciably below saturation of the xenon-133 in the solution at the temperature of dissolution. This avoids any occurrence of bubble formation in the solution during use. In further detail, the present procedure used in the medical profession for preparing injectable doses of xenon-133 as an aqueous solution involves crushing an ampoule containing xenon-133 in a container filled with a normal saline solution.
The difiiculties in handling and storage of this radiopharmaceutical solution are set forth in the Journal of Patented Feb. 12., 1974 Nuclear Medicine in volume 11 at page 352 (1970) and volume 13 at page 231 (1972). These difliculties can be summarized as follows: (a) there is loss of xenon-133 into air spaces resulting as individual doses are removed from multidose vials since it is difiicult to prevent the introduction of air bubbles when replacing the volume withdrawn from the vial; (b) there is diffusion of xenon-133 into rubber components such as at the end of cylindrical glass capsules and rubber septics on multidose vials; and (c) there is diffusion of xenon-133 into both the plastic and rubber components of disposable syringes used for injection of the patient.
Studies have been made regarding the trapping of radioactive xenon in various materials, and these studies show that elastomers and a variety of materials will take up significant quantities of such xenon. As a result of these studies, only glass syringes, which take up less than 1% of the xenon-133 from the solution, are used for dispensing such radioactive xenon solutions. However it has remained desirable to minimize the foregoing difliculties and to further reduce the loss of radioactive xenon isotopes from solutions to the materials used to package the solutions.
SUMMARY OF THE INVENTION The foregoing disadvantages associated with the use of the prior art aqueous xenon solutions are minimized when an aqueous solution formulated according to this invention and containing an isotopic mixture comprising natural xenon and a radioactive isotope of xenon are used in medical applications. In one preferred form the aqueous solution has an additional component of a physiological salt. The aqueous solution is prepared by dissolving natural xenon in water to form an aqueous solution thereof, isolating a substantially pure radioactive isotope of xenon in a container zone and contacting the radioactive isotope of zenon with the aqueous solution of natural xenon to dissolve the radioactive isotope of xenon in the aqueous solution.
Accordingly it is an object of this invention to substantially minimize the loss of radioactive isotopes of xenon dissolved in an aqueous solution for medicinal use over the useful life of the solution.
Another object of this invention is to provide a method for preparing an aqueous solution having dissolved therein an isotopic mixture comprising natural xenon and a radioactive isotope of xenon.
Still another object of this invention is to provide an aqueous solution having a substantially uniform concentration of a radioactive isotope of xenon.
Other objects and advantages of this invention will become apparent to a person having ordinary skill in the art from a reading of the following specification and the appended claims along with reference to the attached drawing described immediately hereinafter.
DESCRIPTION OF THE DRAWING The attached figure presents a schematic drawing of apparatus useful in preparing aqueous solutions according to the teaching of this invention.
DESCRIPTION OF THE INVENTION This invention presents a novel aqueous solution having dissolved therein a gaseous isotopic mixture having the essential components of natural xenon and a radioactive isotope of xenon. In addition the aqueous solution can contain an additional component of a physiological salt with a concentration of at least about 0.5 percent by weight, preferably about 0.5 to about 2.0 percent by weight, and with an especially preferred concentration of about 0.9 percent by weight. The physiological salt can be comprised of sodium chloride, potassium chloride, magnesium chloride, calcium chloride or a selected mixture of two or more of the foregoing. Radioactive isotopes of xenon used in the solutions of this invention include xenon-122, xenon-125, xenon-127, xenon-129m, xenon- 131m, xenon-133, xenon-133m, xenon-135m and mixtures thereof. Preferred radioactive isotopes of xenon include xenon-133 and xenon-127 with the concentration of radioactive xenon being sufficient to yield at least about 1.0 millicurie per cubic centimeter and preferably about 1.0 to about 100 millicuries per cubic centimeter. The concentration of the natural xenon is at least about 5 cubic centimeters per liter and preferably about 5 to about 70 cubic centimeters per liter.
The aforementioned aqueous solution is prepared by a process having the steps of dissolving natural xenon in water to form an aqeous solution of natural xenon, iso lating a radioactive isotope of xenon in a container zone and contacting the radioactive isotope of xenon with the aqueous solution to form an aqueous solution of natural xenon and the radioactive isotope of xenon.
The foregoing steps of the process of preparing an aqueous solution according to the teaching of this invention will be discussed in detail in the sequence in which they are practiced after a discussion of preliminary preparation of materials used in this process.
Before the step of dissolving the natural xenon in water, a preliminary step can be practiced where the water contains dissolved gases such as air, oxygen, etc. This preliminary step consists of removing the dissolved gas and a preferred practice includes drawing a vacuum on the water to degas the water. Typically a vacuum in the range of about 150 to about 300 millimeters of mercury is applied to a container holding the water at about 60 to about 80 C. and held for about 3 to 5 minutes until there is no more gas evolution.
In the practice of this process it will be necessary to have a source of a radioactive isotope of xenon. In practice one preferred isotope of xenon is xenon-133 which is obtained by irradiating uranium-235 in a reactor. Typically the U-235 is introduced to the reactor in a thin cross section and is encapsulated in aluminum while exposed to neutron irradiation typically at a flux of at least about 1X10 neutrons per square centimeter per second. The xenon-133 is withdrawn from the capsule, purified and stored until introduced into the process of this invention. In another practice a preferred isotope is xenon-127 which is obtained by bombardment of a target material, typically iodine or an iodine salt, with capture of the xenon-127 product.
In the first step of the process of this invention, natural xenon is dissolved in water, preferably a substantially gasfree water, such as by passing the xenon through a diffuser stone to disperse the natural xenon in tiny bubbles which more readily go into solution. In one preferred practice the natural xenon is introduced into water at a temperature (e.g., about 50 to about 60 C.) above body temperature (about 37 C.) for injectable solutions.
Where it is desired to have a physiological salt solution, an additional step is practiced of dissolving a physiological salt in the aqueous solution of natural xenon so that a salt concentration of at least 0.5 percent by weight results. The physiological salt can be sodium chloride, potassium chloride, calcium chloride, magnesium chloride or mixtures thereof.
The next step involves isolating a radioactive isotope of xenon in a holder or container zone for later contact with the aqueous solution of natural xenon and in one practice the radioactive xenon is fI9Zn in a container such as a U-tube which is placed in liquid nitrogen. Liquid nitrogen is used since the 196 C. temperature provides a selective freezing of the radioactive xenon but does not freeze other gases typically associated with the radioactive xenon so that the radioactive xenon can be purified by evacuating any remaining gases from the container zone with application of a vacuum to the container zone in the range of 150 to 200 microns of mercury. This is useful in removing any residual gases from the container zone.
A further step involves contacting the radioactive isotope of xenon with the aqueous solution of natural xenon to form an aqueous solution of natural xenon and a radioactive isotope of xenon. The radioactive xenon is more efliciently dissolved in the aqueous solution by the foregoing step than if the radioactive xenon gas is bubbled through the aqueous solution at the same time as the natural xenon. If the radioactive xenon was frozen in the container zone, it is preferably raised above 0 C. to avoid freezing the aqueous solution.
The product of this process is an aqueous solution having dissolved therein an isotopic mixture comprising about 5 to about cubic centimeters per liter of natural xenon and a radioactive isotope of xenon yielding about 1.0 to about millicuries per cubic centimeter. The aqueous solution may also have an additional component at least about 0.5 percent by weight of a physiological salt. The aqueous solution of this invention offers distinct advantages over the solutions of the prior art in that an approximately uniform concentration is maintained throughout the period for which the solution is used. Any loss of radioactive xenon to air spaces in multidose vials resulting from removal of doses from the vial or loss of radioactive xenon to plastic and rubber components on such vials will be diluted according to the ratio between the natural xenon and the radioactive isotope of xenon.
The use of the freezing technique in preparing the aqueous solution enables purification of the gaseous radioactive xenon when it comes in an impure condition.
Those skilled in the art will gain a further understanding of this invention from the following illustrative, but not limiting, example of the invention.
EXAMPLE An apparatus is assembled as schematically shown in the attached figure. A source 10 of radioactive xenon-133 with valve 11 controlling the release of xenon-133 is connected to the apparatus by conduit (line) 12 containing valve 13 and line 12 is connected to U-tube 16. An aqueous reservoir 18 is connected to U-tube 16 by conduit (line) 19 with valve 20 in line 19 to regulate flow in line 19. Valve 21 is used to regulate flow in conduit (line) 22 from U-tube 16. Line 22 connects to chamber 23 which has compression plunger 24. Line 25 leads from chamber 23 to chamber 37 which has plunger 38. Line 25 has valves 26 and 28 along with connection joint (coupling) 27. Line 30 leads from chamber 23 to vacuum pump 32 and has a valve 29 and vacuum gauge 31. Line 33 runs between lines 30 and 25 and has valves 34 and 36 along with connection joint (coupling) 35. Valve 39 and filter 40 are in line 41 which leads from chamber 37 to a dispensing point (not shown).
An aqueous solution containing dissolved natural xenon is prepared -by heating water to boiling in a large Pyrex vacuum flask and then evacuating the flask to remove ab sorbed air. This procedure is repeated several times until there is only little gas evolution on evacuation to 20" of mercury. The solution is then cooled to 60 C. with natural xenon gas being passed into the solution through a diifuser stone. The temperature is held at 60 C. until the xenon gas is no longer absorbed into the solution (as evidenced by bubbles from the diffuser stone). At this time a physiological salt of sodium chloride is added to give a concentration of 0.9 weight percent. The solution is then bottled up in containers with an aluminum foil seal. This solution is then used as needed to prepare xenon-133 saline solution.
The aqueous solution of this invention is prepared using the foregoing apparatus. An aqueous solution containing dissolved natural xenon of suitable preparation and concentration as discussed above is stored in reservoir 18. Vacuum pump 32 is used to evacuate the system with valves 29, 21 and 13 being open and the remaining valves being closed. When the pressure is reduced in the range of to 20 microns valves 29 and 21 are closed with plunger 24 being in a lowered position. 2000 millicuries of xenon-133 are transferred from source 10 through open valves 11 and 13 to U-tube 16 and U-tube 16 is cooled to l96 C. with liquid nitrogen, freezing the xenon gas onto the wall of the U-tube 16. Valves 11 and 13 are then closed and valve 21 is opened (if the xenon gas is felt to contain impurities, valve 29 can also be opened to withdraw these impurities). The U-tube 16 is then warmed to ambient temperature and valves 20 and 21 are opened to allow solution from reservoir 18 into U-tube 16 and chamber 23 (with plunger 24 being in a raised position). Sufficient vacuum is also drawn on line 22 prior to introduction of solution from reservoir 18 to enable the solution to be drawn into chamber 23. With all other valves including valves 21 and 29 remaining closed, valves 26 and 28 are opened so that the solution in chamber 23 is transferred to chamber 37 with plunger 38 being in a raised position. Plunger 24 can also be used to apply pressure to promote removal of the solution from chamber 23. This transfers the aqueous solution having dissolved therein an isotopic mixture of natural xenon and a radioactive isotope of xenon to a second chamber which had previously been evacuated to 5010() microns of pressure. After all of the solution is removed from chamber 23, valves 20 and 21 are opened and the plunger 38 is raised in chamber 37 to draw in an additional amount (about 20 milliliters in practice) of solution from reservoir 18 to flush the lines, U-tube 16 and chamber 23 and this additional amount is mixed with the aqueous solution in chamber 37. Valves 20, 21, 26 and 28 are then closed and the solution in chamber 37 is put under pressure by forcing down plunger 38 until it is tight. Various means such as a magnetic stirrer in chamber 37 are used to stir the solution to give uniformity. The concentration of xenon-133 (mCi./ml.) is determined by taking a 1 milliliter sample of the solution from chamber 37 and measuring the radiation output in a calibrated chamber using vials of known geometry. If this results in a concentration other than in the desired range, the concentration of xenon-133 in the saline can be either lowered by drawing additional solution from reservoir 18 into chamber 37 or raised by mixing a higher concentration of xenon-133 with solution from reservoir 18 and drawing this into chamber 37. Connection joints 27 and 35 can be disconnected so that chamber 37 can be shipped to a location for utilization (in a protective shielding device to prevent radiation exposure). The product solution is delivered for usage through a membrane filter 40 from chamber 37 by screwing down the plunger 38 and opening valve 39. The aqueous solution containing xenon-133 is sufficiently stabilized so that the loss of xenon-133 is less than 1 weight percent during transfer of the solution to vials.
The final volume of aqueous solution containing xenon- 133 was 50 milliliters and the concentration of xenon-133 was 35 mCi./ml. Samples taken over a 4-hour period remained uniform in concentration. Samples taken after 3 weeks were also uniform and contained a reading in mCi./ml. of xenon-133 corrected for decay of the 5.3 day isotope. The concentration of natural xenon was 70 cubic centimeters per liter and the concentration of sodium chloride was 0.9 weight percent.
Additional solutions have been prepared following the foregoing procedure and varying the concentration of natural xenon giving solutions with the following properties:
Solution 250 cc./ liter of natural xenon, 35 mCi./ml. of xenon-133 and 0.9 weight percent sodium chloride; Solution 322 cc./ liter of natural xenon, 35 mCi./ ml. of
xenon-133 and 0.9 weight percent sodium chloride; and Solution 4-5 cc./liter of natural xenon, 35 mCi./ml. of xenon-133 and 0.9 weight percent sodium chloride.
It is to be understood that, although the invention has been described with specific reference to particular embodiments thereof, it is not to be so limited, since changes and alterations therein may be made which are within the full intent and scope of this invention as defined by the appended claims.
What is claimed is:
1. A composition comprising an aqueous solution having dissolved therein a mixture comprising (a) natural xenon and (b) a radioactive isotope of xenon.
2. A composition according to claim 1 containing in addition an additive of from about 0.5 to about 2 percent by weight of a physiological salt selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride and mixtures thereof.
3. A composition according to claim 2 in which the physiological salt is sodium chloride.
4. A composition according to claim 2 physiological salt is potassium chloride.
5. A composition according to claim 2 physiological salt is magnesium chloride.
6. A composition according to claim 2 physiological salt is calcium chloride.
7. A composition according to claim 1 radioactive isotope of xenon is xenon-133.
8. A composition according to claim 1 radioactive isotope of xenon is xenon-127.
9. A composition according to claim 1 in which the concentration of the natural xenon is at least about five cubic centimeters per liter.
10. A composition according to claim 1 in which the concentration of the radioactive isotope of xenon yields at least about 1.0 millicurie per cubic centimeter.
11. A composition according to claim 1 in which the concentration of the radioactive isotope of xenon yields about 1.0 to about millicuries per cubic centimeter.
12. A composition according to claim 1 in which the concentration of the natural xenon is at least about five to about seventy cubic centimeters per liter.
13. A method of preparing an aqueous solution having dissolved therein a mixture comprising natural xenon and a radioactive isotope of xenon, comprising the steps of (a) dissolving natural xenon in water to form an aqueous solution of natural xenon,
(b) isolating a radioactive isotope of xenon in a container zone and (c) contracting the radioactive isotope of xenon with the aqueous solution of natural xenon to form an aqueous solution of natural xenon and a radioactive isotope of xenon.
14. The method of claim 13 in which is performed the preliminary step of removing dissolved gas from the water of step (a).
15. The method of claim 13 in which is performed an additional step of dissolving from about 0.5 to about 2 percent by weight of a physiological salt selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride and mixtures thereof in the aqueous solution of natural xenon.
16. The method of claim 15 in which the physiological salt is sodium chloride.
17. The method of claim 15 in which the physiological salt is potassium chloride.
18. The method of claim 15 in which the physiological salt i magnesium chloride.
in which the in which the in which the in which the in which the 21. The method of claim 13 in which there is a concen- 5 tration of the radioactive isotope of xenon yielding at least about 1.0 millicurie per cubic centimeter.
22. The method of claim 13 in which the radioisotope of xenon is xenon-133.
23. The method of claim 13 in which the radioisotope of xenon is xenon-127.
References Cited UNITED STATES PATENTS 3,509,919 5/1970 Tilbury et al. 252301.1 R X 8 OTHER REFERENCES Handling and Dispcrsing of Xenon-133, Int. Journal of Applied Radiation and Isotopes, vol. 16, No. 6, June 1965, pp. 385-7.
BENJAMIN R. PADGETT, Primary Examiner R. L. TATE, Assistant Examiner US. Cl. X.R.
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|US5415843 *||Jan 13, 1994||May 16, 1995||Scanditronix Ab||Apparatus for the manufacture of radiopharmaceuticals|
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|U.S. Classification||424/1.11, 376/198, 423/249, 423/210, 376/170, 423/262, 376/189, 376/190, 376/168|
|International Classification||A61K51/12, A61K51/00, G21H5/02|
|Cooperative Classification||A61K51/1206, A61K2123/00|