Systems and methods for radioisotope generation

FIELD OF THE INVENTION

0001This invention relates generally to systems and methods for radioisotope generation. In one aspect, this invention relates to systems and methods for producing customized, predictable and reproducible supplies of radioisotopes for use in nuclear medicine.

BACKGROUND OF THE INVENTION

0002Nuclear medicine is a branch of medicine dealing with the use of radioisotopes as radiopharmaceuticals or radioactive tracers in the diagnosis and treatment of disease. Radioisotopes are natural or artificially created isotopes (isotopes being one of two or more atoms having the same atomic number but different mass numbers) of a chemical element that have an unstable nucleus that decays, emitting alpha, beta, or gamma rays until stability is reached.

0003Radioisotopes, such as the meta stable Technetium-99m (Tc-99m), are used in medical tests as radioactive tracers that medical equipment can detect in the body. Other generator-derived radioisotopes that are used as tracers include yttrium-90, rhenium-188, and gallium-68 . Tc-99m, in particular, emits readily detectable gamma rays, and it has a half-life of 6 hours. A variety of different radiopharmaceuticals based on Tc-99m are used for imaging and functional studies of the brain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, skeleton, blood and tumors. <nplcit id="ncit0001" npl-type="b"><text>Schwochau, Klaus. Technetium, Wiley-VCH (2000) (ISBN 3-527-29496-1</text></nplcit>). Scientists continue to find new uses for radioisotopes, such as Tc-99m. For example, doctors recently used Tc-99m to diagnose precisely the infected lymph nodes in breast cancer patients by injecting Tc-99m into the breast around the tumor to allow them to locate the node quickly and precisely before ever making an incision. <i>Brookhaven National Laboratory site on the history of the technetium cow.</i> (http://www.bnl.gov/bnlweb/history/Tc-99m.asp).

0004A Tc-99m generator, often called a technetium cow, is a device used to extract Tc-99m from decaying molybdenum-99 ("Mo-99"). Mo-99 has a half-life of 66 hours and can be transported over long distances to radiopharmacies and hospitals where its decay product Tc-99m is used for nuclear medicine diagnostic procedures. Removing the Tc-99m from the generator ("milking" the generator) is typically done every 6 hours or, at most, twice daily. Most commercial generators use column chromatography, in which Mo-99 is adsorbed onto alumina. Normal saline solution can be run through a column of immobilized Mo-99 to elute soluble Tc-99m, resulting in a saline solution containing the Tc-99m.

0005Today, commercial radiopharmacies typically replace their generators on a biweekly basis, since the useful life of a Tc-99m generator is about 6 half lifes or approximately two weeks. Hence, typical clinical nuclear medicine units purchase at least one such generator every two weeks or order several in a staggered fashion. The lead-lined generators are heavy and bulky and represent significant manipulation and toil for personnel to replace and to dispose of spent generators. Large quantities of lead, molded plastic containers, and packing materials are used only once and discarded after two weeks. Shipping costs and waste are real considerations for end-users. Further, conventional generator systems lack flexibility as they are limited to fixed activity denominations per unit sold, resulting in limited predictability and reproducibility. Typical generators also do not provide activity above 19 Ci.

0006It would be desirable therefore to provide systems and methods for producing customized, predictable and reproducible supplies of radioisotopes, including high activity levels, that do not require weekly replacement, handling and transport of heavy shielding materials associated with conventional generators.

SUMMARY OF THE INVENTION

0007In one aspect, the present invention provides a system comprising: <ul id="ul0001" list-style="none" compact="compact"><li>a reactor housing that is fabricated from a radioactive shielding material and has both an internal volume and a surface that comprises an entry port and an exit port;</li><li>a chromatographic column that is positioned within said internal volume wherein; said first chromatographic column is housed within a column assembly comprising: <ul id="ul0002" list-style="none" compact="compact"><li>a column housing defining an internal space for receiving said first chromatographic column;</li><li>a column adaptor plate;</li><li>an exit pipe in fluid communication with said first chromatographic column via said column housing and with an exit connection that is mounted on said column adaptor plate; and</li><li>an entry pipe in fluid communication with said first chromatographic column via said column housing and with an entry needle that is disposed in an adaptor plate entry port that is mounted on said column adaptor plate;</li></ul></li><li>wherein said column assembly is configured for insertion as a unit into the internal volume of said reactor housing through an opening in an upper portion of said reactor housing; and;</li><li>a filter module that is disposed external to said reactor housing and in fluid communication with said column.</li></ul>

0008The present invention also provides a method comprising the steps of: <ul id="ul0003" list-style="none" compact="compact"><li>providing a system that comprises: <ul id="ul0004" list-style="none" compact="compact"><li>a reactor housing that is fabricated from a radioactive shielding material and has both an internal volume and a surface that comprises an entry port and an exit port;</li><li>a first chromatographic column that is positioned within said internal volume wherein</li><li>said first chromatographic column is housed within a column assembly comprising:</li><li>a column housing defining an internal space for receiving said first chromatographic column;</li><li>a column adaptor plate;</li><li>an exit pipe in fluid communication with said first chromatographic column via said column housing and with an exit connection that is mounted on said column adaptor plate; and</li><li>an entry pipe in fluid communication with said first chromatographic column via said column housing and with an entry needle that is disposed in an adaptor plate entry port that is mounted on said column adaptor plate;</li><li>wherein said column assembly is configured for insertion as a unit into the internal volume of said reactor housing through an opening in an upper portion of said reactor housing; and;</li><li>a first filter module that is disposed external to said reactor housing and in fluid communication with said first chromatographic column; and</li><li>positioning a first delivery vessel comprising a solution of at least one radioisotope external to said reactor housing and in fluid communication with said first chromatographic column for a time and under conditions effective to elute said first chromatographic column with at least a portion of said solution; and,</li><li>positioning a collection vessel external to said reactor housing and in fluid communication with said exit port via said filter module.</li></ul></li></ul>

0009In yet another aspect, the present invention provides a method comprising the steps of: <ul id="ul0005" list-style="none" compact="compact"><li>providing a system that comprises: <ul id="ul0006" list-style="none" compact="compact"><li>a reactor housing that is fabricated from a radioactive shielding material and has both an internal volume and a surface that comprises an entry port and an exit port; and</li><li>a first chromatographic column that is positioned within said internal volume, wherein said first chromatographic column is housed within a column assembly comprising</li><li>a column housing defining an internal space for receiving said first chromatographic column;</li><li>a column adaptor plate;</li><li>an exit pipe in fluid communication with said first chromatographic column via said column housing and with an exit connection that is mounted on said column adaptor plate; and</li><li>an entry pipe in fluid communication with said first chromatographic column via said column housing and with an entry needle that is disposed in an adaptor plate entry port that is mounted on said column adaptor plate; wherein said column assembly is configured for insertion as a unit into the internal volume of said reactor housing through an opening in an upper portion of said reactor housing;</li><li>removing said first chromatographic column from said internal volume by extracting said column assembly through an opening in an upper portion of said reactor housing;</li><li>positioning a second chromatographic column within said internal volume by inserting a second column assembly through said opening in said reactor housing;</li><li>positioning a first delivery vessel comprising a solution of at least a first radioisotope external to said reactor housing and in fluid communication with said second chromatographic column for a time and under conditions effective to elute said second chromatographic column with at least a portion of said solution; and,</li><li>positioning a first collection vessel external to said reactor housing and in fluid communication with said second chromatographic column.</li></ul></li></ul>

BRIEF DESCRIPTION OF THE DRAWINGS

0010<figref idref="f0001">FIG. 1</figref> is a cutaway side view depicting one generator system according to the invention.

0011<figref idref="f0002">FIG. 2</figref> is a cutaway side view depicting one shielded filter module according to the invention.

0012<figref idref="f0003">FIG. 3</figref> is an isometric view of one cart according to the invention.

0013<figref idref="f0004">FIG. 4</figref> is a cutaway side view of one generator system according to the invention.

0014<figref idref="f0005">FIG. 5</figref> is a perspective view of a column assembly being inserted into an internal volume of a reactor housing according to the invention.

0015<figref idref="f0006">FIG. 6</figref> is a perspective view of a radioactive shielding plug being inserted into an opening in a reactor housing according to the invention.

0016<figref idref="f0007">FIG. 7</figref> is a perspective view of an adapter disk disposed on the surface of a reactor housing according to the invention.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

0017With reference to the drawings, <figref idref="f0001"><b>FIG. 1</b></figref> shows one type of generator system <b>2</b> according to the invention. The generator system may include a reactor housing <b>4</b> fabricated from a radioactive shielding material such as lead, tungsten, or depleted uranium. The reactor housing <b>4</b> may be substantially cylindrical, as shown in <figref idref="f0001"><b>FIG. 1</b></figref>. In another embodiment, the reactor housing may be substantially rectilinear. The reactor housing <b>4</b> may include a first end <b>6,</b> a second end <b>8</b>, and a wall <b>10</b> extending between said first end <b>6</b> and said second end <b>8.</b> The reactor housing <b>4</b> may have both an internal volume <b>12</b> and a surface <b>14</b> that comprises an opening <b>16</b> for inserting a column <b>18</b> (said column may be included in a column assembly <b>20</b>, shown in more detail in <figref idref="f0005"><b>FIG. 5</b></figref>), an entry port <b>22</b>, and an exit port <b>24</b>. The opening <b>16</b>, entry port <b>22</b> and exit port <b>24</b> may be positioned at said first end <b>6</b> of said housing <b>4</b>. A radioactive shielding plug <b>26</b> may be disposed in said opening <b>16</b> in said surface <b>14</b> above said column <b>18</b>. The radioactive shielding plug <b>26</b> may be fabricated from a radioactive shield material such as lead, tungsten, or depleted uranium. The reactor housing <b>4</b> may have an adapter disk <b>28</b> disposed on the surface <b>14</b> of said reactor housing <b>4</b> that comprises a ridge of guide material <b>30</b> that may extend around said entry port <b>22</b> and a ridge of guide material <b>32</b> that may extend around said exit port <b>24</b>. Preferably, the adapter disk <b>28</b> and ridges of guide material <b>30</b> and <b>32</b> are plastic. A ridge of radioactive shielding material <b>34</b> may extend around said exit port <b>24</b>.

0018A chromatographic column <b>18</b> may be positioned within said internal volume <b>12</b> such that a first end <b>36</b> of said column <b>18</b> is in fluid communication with said entry port <b>22</b> and a second end <b>38</b> of said column <b>18</b> is in fluid communication with said exit port <b>24</b>. In one embodiment, the column <b>18</b> may be included in a column assembly <b>20</b>. The column assembly <b>20</b>, in turn, may comprise a column adaptor plate <b>40</b> having a radioactive shielding plug opening <b>42</b>, an adaptor plate entry port <b>44</b> and an adaptor plate exit port <b>46</b> corresponding to said entry port <b>22</b> and said exit port <b>24</b> of said reactor housing, respectively, an adaptor plate vent port <b>48</b> (which may include a vent filter), and a column housing <b>50</b>, preferably fabricated from radioactive shielding material such as lead, tungsten, or depleted uranium. The column assembly <b>20</b> may comprise an entry needle <b>52</b> and a vent needle <b>54</b> disposed in said adaptor plate entry port <b>44</b>, and an exit connection <b>56</b>, adapted for fluid communication with a changeable sterile needle <b>58</b> of a filter module <b>60</b>. An entry pipe <b>62</b> may extend from said entry needle <b>52</b> to said first end <b>36</b> of said column <b>18</b>. A vent pipe <b>64</b> may extend from said vent needle <b>54</b> to a safety valve 55 (said safety valve 55 protecting said vent filter by preventing back pressure from being released onto said vent filter) and said safety valve <b>55</b> may extend to said vent port <b>48</b>. An exit pipe <b>66</b> may extend from said second end <b>38</b> of said column <b>18</b> to said exit connection <b>50</b>. The column <b>18</b> may be inserted into said internal volume <b>12</b> of said reactor housing <b>4</b> through said opening <b>16</b> in said surface <b>14</b> of said reactor housing <b>4</b>. Alternatively, said, column assembly <b>20</b> may be positioned such that said column <b>18</b> is disposed in said internal volume <b>12</b> of said reactor housing <b>4</b>. The column <b>18</b> may comprise at least one radioisotope, including but not limited to Mo-99, Tc-99m, Y-90, Re-188, or Ga-68. In preferred embodiments, the column <b>18</b> is fabricated from glass. The column <b>18</b> may contain alumina in the form of aluminum oxide, Al₂O₃ (mp of about 2,000°C and specific gravity of about 4.0). Preferably, the column <b>18</b> is a glass column that contains aluminum oxide. The aluminum oxide powder preferably has a particle size of from about 20 to about 200 µm. In addition to the aluminum oxide powder, the column <b>18</b> may also include silica gel having a particle size of from about 20 to about 100 µm. The column <b>18</b> may also comprise one or more layers or polypropylene filter membranes, deactivated fused silica wool, and/or one or more glass filter membranes. The filter membranes preferably measure from about 0.2 to about 10 µm and may comprise polyether sulfone, Acetal plastic plugs with funnel drains, or stainless steel tubing with needle and filter adaptors. Particularly preferred filter membranes are those fabricated from polyether sulfone at a size of 0.2 µm.

0019A delivery vessel <b>68</b> may be disposed external to said reactor housing <b>4</b> and in fluid communication with said entry port <b>22</b>. The delivery vessel <b>68</b> may be a 3 to 20 ml (preferably 10 ml) borosilicate glass vessel. The delivery vessel <b>68</b> may be contained within a delivery housing <b>70</b> that is fabricated from radioactive shielding material such as lead, tungsten, or depleted uranium. The delivery housing <b>70</b> preferably is fabricated from radioactive shielding material and has a first end <b>72</b> that includes a first coupling <b>74</b>, a second end <b>76</b> that includes a second coupling <b>78</b>, and a <b>wall 80</b> extending between said first end <b>72</b> and said second end <b>76</b>. The first coupling <b>74</b> and second coupling <b>78</b> may be threaded or may form a lure lock. In certain embodiments, delivery vessel <b>68</b> comprises a solution of at least one radioisotope, including but not limited Mo-99 or Tc-99m in the form of sodium molybdate Mo-99 or sodium pertechnetate Tc-99m, respectively. In such embodiments, delivery vessel <b>68</b> preferably comprises from about 1 to about 50 Ci (1 curie (Ci) is 37 gigabecquerels (GBq) exactly and 1 Bug = 2.027×10^-11 Ci). In other embodiments, delivery vessel <b>68</b> comprises Normal Saline [0.9%] solution. The delivery housing <b>70</b> may abut a ridge of guide material <b>30</b> that may be external to said reactor housing <b>4</b> and may extend around said entry port <b>22</b>. The delivery housing <b>70</b> may be at least partially contained within a ridge of guide material <b>30</b> that may be external to said reactor housing and may extend around said entry port <b>22</b>. In certain embodiments, an adapter guide ridge <b>81</b> may be disposed on said adapter disk 28 circumferentially internal to said ridge of guide material <b>30</b>. A saline vessel <b>82</b> may be disposed external to said reactor housing <b>4</b>, and in fluid communication with said entry port <b>22</b> and may abut said adapter guide ridge <b>81 (</b><figref idref="f0004"><b>FIG. 4</b></figref><b>)</b> that extends around said entry port <b>22</b>. The saline vessel <b>82</b> may comprise Normal Saline [0.9%] solution.

0020The generator system <b>2</b> may comprise a collection vessel <b>84</b> that is disposed external to said reactor housing <b>4</b> and in fluid communication with said exit port <b>24</b> via a filter module <b>60</b>, discussed below with reference to <figref idref="f0002"><b>FIG. 2</b></figref>. The collection vessel <b>84</b> may be evacuated, and ultimately is used to collect a solution of at least one radioisotope. The collection vessel <b>84</b> may be a 10 to 30 ml borosilicate glass vessel. Preferably, the collection vessel <b>84</b> is a 20 to 30 ml sterile, evacuated, borosilicate glass vessel. As shown in <figref idref="f0001"><b>FIG. 1</b></figref>, collection vessel <b>84</b> is contained within a collection housing <b>86</b> that is fabricated from radioactive shielding material.

0021As shown in <figref idref="f0002"><b>FIG. 2</b></figref>, a filter module <b>60</b> may be disposed external to the reactor housing <b>4</b> and may be in fluid communication with said exit port <b>24</b>. The filter module <b>60</b> may include a radioactive shielding material insert <b>88</b> that is positioned between said collection vessel <b>84</b> and said reactor housing <b>4</b>. The filter module <b>60</b> preferably holds a sterile 13 to 25 mm filter membrane <b>90</b> of 0.1 to 0.22 µm size, preferably of 0.2 µm size. The filter module <b>60</b> may be attached via a tread type adaptor to join the reactor to a sterile evacuated collection vessel <b>84</b>. A changeable sterile needle <b>58</b> may be attached to the sterile filter <b>90</b> for daily sterile eluting procedures. The filter module <b>60</b> may abut a ridge of radioactive shielding material <b>34</b> and/or may abut a ridge of guide material <b>32</b> that is external to said reactor housing <b>4</b> and extends around said exit port <b>24</b>. The filter module <b>60</b> may be at least partially contained within said ridge of radioactive shielding material <b>34</b> and/or said ridge of guide material <b>32.</b> The radioactive shielding material may be lead, tungsten, or depleted uranium.

0022The generator system may include a cart <b>92,</b> as shown in <figref idref="f0003"><b>FIG. 3</b></figref>. The cart <b>92</b> preferably is fabricated from steel and lead. The frame is preferably fabricated from steel. The walls of cart <b>92</b> are preferably lead plates or lead brick. The cart <b>92</b> may hold a plurality of reactor housings <b>94, 96, 98, 100, 102, 104, and 106</b> that may be fabricated from radioactive shielding material The cart <b>92</b> may also comprise a plurality of delivery vessels <b>68</b> and/or a plurality of evacuated collection vessels <b>84</b> and/or a plurality of saline vessels <b>82</b>. The cart <b>92</b> may include a transfer tool <b>108</b> that comprises a pick-up and release rod <b>110</b> having a handle <b>112</b> at a first end <b>114</b> thereof and a coupling <b>116</b> at a second end <b>118</b> thereof that is compatible with the first coupling <b>74</b> of said delivery housing <b>70</b>. The transfer tool <b>108</b> preferably is a universal T-bar handle. The cart <b>92</b> may also include a conveyor belt <b>120</b>, or other motion enhancing device, to assist a user with moving a delivery housing <b>70</b> proximate to a reactor housing <b>(<i>e.g.</i>, 94, 96, 98,100, 102, 104, and 106).</b>

0023Methods of radioisotope generation according to the invention may be described with reference to <figref idref="f0001"><b>FIGs. 1</b></figref> and <figref idref="f0002"><b>2</b></figref><b>.</b> In certain embodiments, such methods involve positioning a first delivery vessel <b>68</b> comprising a solution of at least one radioisotope external to said reactor housing <b>4</b> and in fluid communication with said entry port <b>22</b> for a time and under conditions effective to elute said chromatographic column <b>18</b> with at least a portion of said solution. The first delivery vessel <b>68</b> may be positioned by mating said first coupling <b>74</b> at said first end <b>72</b> of said delivery housing <b>70</b> with transfer tool <b>108</b> and lifting the delivery housing <b>70.</b> The coupling <b>78</b> at said second end <b>76</b> of said first delivery housing <b>70</b> may be mated with a coupling on said reactor housing <b>4</b> that is compatible with said coupling <b>78</b> at said second end <b>76</b> of said first delivery housing <b>70</b>. The delivery vessel <b>68</b> may be removed from said position relative to said reactor housing <b>4</b> by lifting said delivery housing <b>70</b>. Subsequent delivery vessels comprising saline solution or a solution of at least one radioisotope may be used to elute said column <b>18</b> with at least a portion of said solutions. A collection vessel <b>84</b> may be positioned external to said reactor housing <b>4</b> and in fluid communication with said exit port <b>22</b> via said filter module <b>60</b>. The column <b>18</b>, column assembly <b>20</b>, filter module <b>60</b>, filter membrane <b>90</b>, sterile needle <b>58</b>, delivery vessel <b>68</b>, collection vessel <b>84</b> and/or saline vessel <b>82</b> may be removed from said reactor housing <b>10</b> and may be replaced by subsequent columns, column assemblies, filter modules, filter membranes, sterile needles, delivery vessels, collection vessels and/or saline vessels, respectively, as appropriate.

0024In certain embodiments, methods of radioisotope generation according to the invention involve the receipt of customer information including a target output of a radioisotope, the addition of a solution of a parent radioisotope to a delivery vessel in an amount sufficient to produce said target output upon decay of said parent radioisotope, and the shipment of said delivery vessel to said customer. The customer's generator system, in turn, may be loaded and re-loaded with varying volumes of said parent radioisotope effective to collect specific target concentrations of the desired radioisotope. The generator systems may be re-loaded more than 2 times, more preferably more than 4 times, and most preferably more than 6 times. Preferably, the customer information received includes a target output of Tc-99m from 1 to 50 Ci, and the solution added to the delivery vessel includes Mo-99 in an amount sufficient to produce said target output upon decay of said Mo-99.

0025A kit for radioisotope generation is also contemplated and may be described with reference to <figref idref="f0001 f0002 f0003"><b>FIGs. 1-3</b></figref>. The kit may include a column <b>18</b> or a column assembly <b>20</b>, a delivery housing <b>70</b> containing a delivery vessel <b>68</b> comprising at least one radioisotope, a filter module <b>60</b> comprising a radioactive shielding material insert <b>88</b>, a transfer <b>tool 108</b>, a plurality of evacuated collection vessels <b>84</b> and a plurality of saline vessels <b>82</b>. The kit can be used to replenish existing reactor housings <b>4</b> and thereby avoids shipment and disposal thereof. In addition, exemplary steps for radioisotope generation according to the invention may be described with reference to <figref idref="f0001 f0002 f0003 f0004 f0005 f0006 f0007"><b>FIGs. 1-7</b></figref>. As shown in <figref idref="f0005"><b>FIG. 5</b></figref>, a column assembly <b>20</b> may be inserted into an internal volume <b>12</b> of a reactor housing <b>4</b> (said reactor housing having an entry port <b>22</b> and an exit port <b>24</b>), through an <b>opening 16</b> in the surface <b>14</b> of the reactor housing <b>4</b>. Then, as shown in <figref idref="f0006"><b>FIG. 6</b></figref>, the opening <b>16</b> above the column <b>18</b> may be plugged with a radioactive shielding plug <b>26</b>. Then, as shown in <figref idref="f0007"><b>FIG. 7</b></figref>, an adapter disk <b>28</b>, comprising a ridge of guide material <b>30</b> extending around the entry port <b>22</b> and a ridge of guide material <b>32</b> extending around the exit port <b>24</b>, may be disposed on the surface <b>14</b> of the reactor housing <b>4.</b> A filter module <b>60</b> may then be disposed external to the reactor housing <b>4</b> in fluid communication with the exit port <b>24</b>. A delivery vessel <b>68</b> containing a radioisotope, contained in a delivery housing <b>70</b>, may then be disposed external to the reactor housing <b>4</b> and in fluid communication with the entry port <b>22.</b> An evacuated collection vessel <b>84</b>, contained with a collection housing <b>86</b>, may then be disposed external to the reactor housing <b>4</b> in fluid communication with the exit port <b>24</b> via the filter module <b>60.</b> After waiting a suitable amount of time (<i>e.g</i>., more than about three minutes), the collection vessel <b>84</b> and then the delivery vessel <b>68</b> may be removed. An adapter guide ridge <b>81</b> may then be disposed on the surface of the adapter disk <b>28</b> such that it extends around the entry port <b>22</b>. A saline vessel <b>82</b> may then be disposed external to the reactor housing <b>4</b> and in fluid communication with the entry port <b>22</b>. An evacuated collection vessel <b>84</b>, contained within a collection housing <b>86</b>, may then be disposed external to the reactor housing <b>4</b> and in fluid communication with the exit port <b>24</b> via the filter module <b>60.</b> After again waiting a suitable amount of time, said collection housing <b>86</b> may be removed. An evacuated collection vessel <b>84</b>, contained within a collection housing <b>86</b>, may then be disposed external to the reactor housing <b>4</b> and in fluid communication with the exit port <b>24</b> via the filter module <b>60</b>. The aforementioned exemplary steps may be repeated with subsequent delivery vessels, columns, filter modules and collection vessels as may be appropriate.

0026Thus, there have been described systems and methods for producing customized, predictable and reproducible supplies of radioisotopes that do not require weekly replacement, handling and transport of heavy shielding materials associated with conventional generators. It will be appreciated that numerous modifications may be made to the example embodiments described herein, and that such modifications do not depart from the scope of the invention as defined by the following claims.