VIAL HEATER FOR PREPARING A RADIOPHARMACEUTICAL

Field of the Invention The present invention is directed to the field of radiopharmaceutical preparation, More specifically, the present invention is directed to an apparatus and method for preparing a radiopharmaceutical formulation.

Background of the Invention The technetium radioisotope ^99m Tc is used to label various radiopharmaceutical products, such as ^99m Tc-sestamibi that is manufactured by Bristol Myers Squibb and sold under the tradename CARDIOLITE™. Technetium ^99m Tc- MERTIATIDE is another labeled radiopharmaceutical that is manufactured by Mallinckrodt and sold under the tradename MAG3™. Such ^99rπ Tc products are used primarily as imaging agents.

A formulation of the technetium-labeled radiopharmaceutical imaging agent is prepared for use by injecting a volume (on the order of approximately one to three milliliters) of a non-pyrogenic sodium pertechnetate^Tc solution derived from a generator into a vial containing a lyophilized form of other non-radioactive ingredients. The vial is itself placed within a suitable radiation shield, typically a cylindrical can-like member with a fitted cap. Label instructions may require that after reconstitution the vial containing the mixture of the radioactive and the lyophilized non-radioactive ingredients be removed from the radiation shield, and heated. Such heating is necessary for some radiopharmaceuticals to achieve the desired radiochemical purity.

Some methods of heating the mixture include placing the vial with the mixture in a boiling water bath for at least ten minutes. After heating in the boiling bath the vial is returned to the shield for a cool-down period of approximately fifteen minutes. A radiochemical purity analysis is performed to ensure that the radiopharmaceutical formulation so prepared exhibits the desired labeling efficiency prior to use.

These timing restrictions on the preparation of the radiopharmaceutical formulation may, in instances such as emergency cases, limit its availability. In order to reduce the preparation time and, consequently, enhance the availability of the " ¹⁷¹ Tc imaging formulation, several alternative methods of preparation have been proposed.

One method, discussed in the article by Tallifer, Gagnon, Lambert and Levilie, "Labeling procedure and in-vitro stability of ^99m Tc methoxy isobutyl isonitrile (MIBI): practical considerations", appearing at J Nucl Med 1989; 30; 865 (abs), demonstrates that bath times as low as one (1) minute may be sufficient to provide a Technetium Tc solution having an acceptable labeling efficiency and a radiochemical purity in excess of ninety percent. However, this method still requires a significant amount of time (on the order often to twenty-five minutes) be expended to heat to boil the water used for the immersion bath. Thus, the time gain obtained from the reduction in the actual immersion time is lost because time is still required to heat the water for the immersion bath.

Other proposed methods of preparation of a ^99m Tc formulation have focused on the use of alternative heat sources. Several alternative methods discuss the use of a microwave oven as the source of heat. Microwave heating methods are discussed in an article by Gagnon, Tallifer, Bavaria and Levilie, "Fast labeling of technetium-99m- sestamibi with microwave oven heating", J Nucl Med Technol 1991; 19; 90-3, and in an article by Hung, Wilson, Brown and Gibbons, "Rapid preparation and quality control method for technetium-99m-2 methoxy isobutyl isonitrile (technetium-99m sestamibi)", J Nucl Med 1991; 32; 2162-8. Another method, discussed in a letter by Wilson, Hung and Gibbons, "Simple procedure for microwaved technetium-99m sestamibi temperature reduction", J Nucl Med Technol 1992; 20; 180, focuses on a technique for the rapid cooling of a heated Technetium ^99m Tc-Sestamibi formulation.

Although microwave oven-based heating methods appear to overcome some of the obstacles presented in the preparation of a Technetium ^99m Tc formulation, such methods appear also to exhibit serious attendant drawbacks, such as vial breakage (as outlined in a letter by Hung and Gibbons, "Breakage of technetium-99m sestamibi

vial with the use of a microwave oven", J Nucl Med 1992; 33; 176-8). Other perceived problems with the microwave oven-based heating technique are set forth in an article by Wilson, Hung and Gibbons, "An alternative method for rapid preparation of ^99m Tc-sestamibi", Nucl Med Commun 1993; 14; 544-9. This latter article proposes an alternative heating method involving the use of an instant hot water machine as the source of heated water used for the preparation of Technetium ^99m Tc-Sestamibi formulation.

Other heating sources for raising the temperature of materials used in connection with life science reactions are known in the art. For example, an apparatus manufactured by MJ Research, Inc, Watertown, Massachussetts and sold as "The MiniCycler.TM. programmable thermal controller" utilizes a heating/cooling element driven by the thermoelectric effect to both heat and cool samples for various biotechnological reactions. The basic operating principle of a thermoelectric heating/cooling element is the Peltier Effect, in which heat is liberated or absorbed as a current passes through a junction of two dissimilar materials. Electrons passing across the junction absorb or give up an amount of energy equal to the transport energy and the energy difference between the dissimilar-materials conduction bands.

The materials to be heated or cooled in the programmable thermal controller apparatus are typically carried in microultracentrifuge tubes, also known as "Eppendorf Tubes", or in other suitable reaction tubes. The programmable thermal controller includes a sample block in which a plurality of wells are formed. Each tube carrying a sample therein is inserted into a well, and the appropriate heating and/or cooling program initiated. Each of the wells formed in the sample block corresponds in configuration to the exterior configuration of the container inserted therein. Use of the programmable thermal controller in connection with radioactive reactions appears to be contemplated.

In view of the foregoing it is believed advantageous to utilize a thermoelectric

(Peltier-effect) heating/cooling element to precisely control both heating and cooling of a Technetium ^99m Tc imaging formulation, thereby to make preparation of an

effective dosage of the imaging formulation rapidly available for use in emergency and other situations.

One example of a device which incorporates a Peltier heating element is disclosed in United States Patent No. 5,397,902, the entire disclosure of which is hereby incorporated by reference herein. The heating device disclosed in this patent incorporates a Peltier heating element in thermally connective contact with a mounting block having a number of raised mounting projections for mating engagement with a vial-holder device. The vial-holder device includes a depending annular wall member which defines a socket for receiving the mounting projection of the mounting block. Such a design, however, places the heating element solely below the vial containing the contents to be heated or cooled. This physical displacement by a relatively large heat sink between the heating element and the vial can inhibit the efficient heat transfer between the two such that significant temperature gradients may still exist at a time when the thermal cycling program assumes that a steady state temperature has been achieved within the vial. This means that the vial contents may not be heated to the desired temperature.

There is therefore a need in the art for a vial heating device which incorporates a Peltier heating device in a manner providing a more efficient and reliable heat- transmissive relationship with a vial having contents requiring heating and/or cooling.

Summary of the Invention

In view of the needs of the prior art, the present invention provides both an apparatus and a method for using a thermoelectric heating/cooling element both to apply heat to and/or remove heat from a vial having the components necessary to form a radiopharmaceutical formulation contained therein.

The present invention further provides a vial heater having a housing with a Peltier heating element positioned therein. A vial holder device positioned in direct thermal communication with the Peltier heating element includes an interior cylindrical surface defining an elongate cylindrical cavity formed from a radiation

shielding material. The cavity receives a vial containing a radiopharmaceutical. A lid is movably positionable in overlying registry with the holder device within the housing interior. A cap is affixed to the lid so as to be positionable in overlying radiation-shielding registry with the cavity of said holder device. At least one thermally conductive radiation surface extends from the Peltier heating element opposite to the holder device. λ fan unit provides a cooling current about the radiation surface and a controller unit governs the temperature of the holder device through operation of the Peltier heating element and fan.

In another aspect the invention is directed toward a radiation-shielding vial holder for receiving a vial storing the components necessary to form a radiopharmaceutical formulation therein and in which such components may be both heated and cooled. The vial holder includes a hollow outer conductive member formed from a thermally-conductive material such as aluminum or copper and an inner radiation shielding member formed from a radiation-shielding material, such as lead or tungsten. The inner shielding member is received within the outer conductive member. The inner shielding member desirably defines a cavity to receive the vial therein in an interference fit which provides sliding engagement between the inner shielding member and the vial.

The present invention still further provides a method for heat treating a vial containing a radiopharmaceutical, comprising the steps of providing a vial heater of the present invention, sliding a vial containing a radioactive mixture into the cavity defined by the interior cylindrical surface of vial holder device, and closing the lid of the vial heater. The holder device is heated to a desired temperature so as to heat the radiopharmaceutical contents of the vial to a desired temperature. The heating clement may further allow for the cooling of the radiopharmaceutical by cooling the holder device. Additionally, the holder device may be pre-heated prior to inserting the vial so as to reduce the heating time.

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Brief Description of the Drawings

Figures IA-B depict front elevational views of a vial heating apparatus of the present invention having, respectively, its lid in the closed position and in the open position to thereby allow access to the vial-holding device. 5

Figure 2 is a front elevational view of the vial heating apparatus of Figure 1 with a vial containing a radiopharmaceutical formulation received within the vial- holding device.

10 Figure 3 depicts a cross-sectional view of the vial heating apparatus of the present invention taken through the line 3-3 of Figure 1.

Figure 4 depicts a side perspective view of the vial heating apparatus of Figure 1. 15

Figure 5 depicts a bottom perspective view of the vial heating apparatus of the present invention.

Figure 6 depicts a time-temperature profile for operating the vial heater of the 20 present invention.

Detailed Description of the Preferred Embodiment

Figures 1 A-3 depict a vial heating apparatus 10 of the present invention. Vial heater 10 provides for the heating and cooling of a vial holding a radiopharmaceutical

25 compound. Typically, the vial will initially hold non-radioactive components in lyophilized form. A radiopharmaceutical formulation is produced by heating and thereafter cooling a mixture of the (lyophilized) non-radioactive components following reconstitution with a radioactive liquid. Vial heater 10 supports the vial V while the mixture of the non-radioactive components and the radioactive liquid is

30 being heated and cooled. The vial may carry the components necessary to produce any of a variety of radiopharmaceutical formulations, including, by way of illustration but not of limitation, the technetium-labeled radiopharmaceutical Technetium ^99m Tc-

mertiatideimaging agent manufactured by Mallinckrodt, and sold under the trademark MAG3 ^IM . Alternatively, the ^99m Tc-sestamibi radiopharmaceutical formulation manufactured by Bristol Myers Squibb and sold under the trademark CARDIOLITE™ may also be produced using the various aspects of the present invention. Another technetium product, invented by researchers at the University of Pennsylvania and known as TRODAT, may also be contained in the vial used in the present invention.

Vial heater 10 includes a body 12 and a lid 14 hingedly attached thereto. Body 12 defines a housing opening 16 and a housing interior 18 in fluid communication therewith. A vial holder 20 is positioned within housing interior 18. Vial holder 20 includes an open end 21 and defines a cavity 22 for receiving a vial with the radiopharmaceutical product to be processed. Lid 14 supports a cap 24 thereon and is positionable in sealing registry over opening 16. Cap 24 desirably includes a perimetrical cylindrical wall 26 extending between an open end 28 and a closed base end 30. Cylindrical wall 26 defines a cap cavity 32 for receiving any exposed portion of a vial therein so as to more fully shield the operator from the radiopharmaceutical contents. Lid 14 may be positioned between an open and closed position. In the open position of Figure IB, an operator will have access for inserting or withdrawing a vial from cavity 22. In the closed position, a vial may be heated and cooled while having a radiation shield provided thereabout.

Vial heater 10 includes an operator-engagable keyboard 36 with buttons or switches for operating vial heater 10. A display 38 is provided to allow the operator to scroll through selectable heating/cooling programs and to provide status information of the heating cycle to the operator.

Figure 2 depicts vial heater 10 with a vial 40 positioned within vial holder 20. Vial 40 is desirably a conventional vial as used for the storage and handling of radiopharmaceuticals and their non-radioactive components. Vial 40 includes a cylindrical glass body 42 supporting a puncturable cap 44 thereon. Body 42 defines a receptacle 45 for containing the radiopharmaceutical. Cap 44 is positioned over open

end 46 of body 44 and includes a resealable septum 48 for allowing the injection and withdrawal of a radioactive liquid into and out of receptacle 45. With particular reference to Figure 4, vial holder 20 provides a suitable interference fit with vial 40 so as to provide a sliding engagement therewith. The interference fit and sliding engagement between vial holder 20 and vial 40 helps ensure that vial 40 may not be dropped into cavity 22 and risk breakage. It is also desirable that cavity 22 be dimensioned so as to afford sliding engagement with a label provided on the outside of vial body 42.

Figure 3 provides more detail on the interior structure of vial heater 10.

Interior 18 accommodates a thermal unit 50. Thermal unit 50 includes vial holder 20, a Peltier heating unit 52, a radiator fin block 54, a cooling fan 56, a base member 55. Housing 12 defines side venting apertures 60 for allowing air blown from fan 56 over radiator fin block 54 to exit from interior 18. Additionally, a heater control unit 62 is provided for translating operator commands from the keyboard 36 along cable 65 to thermal unit 50. Heater control unit 62 incorporates the necessary hardware, software, and power supply, not shown, for allowing an operator to operate vial heater 10 as desired and to provide status information on the heating and cooling cycle, including e.g., temperature of the vial holder 20, elapsed time, location within the heating or cooling cycle, name or type of heating or cooling cycle, etc. Figure 3 also depicts that cylindrical wall 26 of cap 24 need not be coextensive with vial holder 20, As shown, the present invention contemplates that open end 21 of vial holder 20 may be sized and shaped to extend into cap cavity 32 so that wall 26 extends past open end 21 of vial holder 20 so as to contain radiation from the contents of vial 40.

With additional reference to Figure 4, thermal unit 50 is shown removed from housing 12. Holder device 20 includes a hollow outer conductive member, or shell, 70 formed from a thermally-conductive material such as, for purposes of illustration and not of limitation, aluminum or copper. Outer conductive member 70 includes a first open end 72, a closed second end 74 and an elongate cylindrical wall 76 extending therebetween. Closed second end 74 desirably further includes a radially- extending flange 78 having a major surface 79 for engaging Peltier heating unit 52

and providing improved heat transfer therewith. Cylindrical wall 76 includes an inner cylindrical surface 77 defining a first elongate cylindrical passageway 75, Holder device 20 also includes an inner shielding member 80 formed from a radiation- shielding material, such as, by way of illustration and not of limitation lead or tungsten. It is also contemplated that depleted uranium may be used to form inner shielding member 80. Inner shielding member 80 formed to be received within the outer conductive member in full contact with inner surface 77 thereof. Inner shielding member 80 includes an open first end 82, a closed second end 84, and an elongate cylindrical wall 86 extending therebetween. Cylindrical wall 86 includes an inner cylindrical surface 87 which defines an elongate open cavity 88 to receive a vial 40 therein in an interference fit which provides sliding engagement between the inner shielding member and the vial. The interference fit between cylindrical wall 86 and vial 40 ensures that vial 40 may not be dropped into cavity 88 and possibly damaged. Holder device 20 desirably includes an aluminum shell with a lead lining such that the lead lining comprises the interior cylindrical surface 87.

It is further contemplated that the present invention provides a vial holder capable of accommodating more than a singe vial in thermally-conductive engagement. For example, the vial holder may be formed to accommodate a 2x2 array of vials over the Peltier heating unit 52. In such a configuration, it is further contemplated that four individual vial holders of the present invention be provided as well as a single outer wall member about a four-space inner wall member.

The vial holder 20 is secured to the Peltier heating unit 52 by a layer 90 of adhesive material. Any adhesive that is thermally stable to temperatures on the order of approximately 12O.dcgrcc. C, such as an cpoxy material, is suitable for use as the adhesive.

Also adhered to Peltier heating unit 52 is an upstanding perimetrical wall 92 which surrounds holder device 20. Perimetrical wall 92 is provided to isolate the operating components of vial heater 10 from the work environment of the operator while inserting or removing a vial from holder device 20. Perimetrical wall 92 is

formed from three overlying square cut-out layers 92a, 92b, and 92c which together define a holder cavity 94 in which holder device 20 is positioned. Cut-out layers 92b and 92c are formed from a suitable plastic material which is able to withstand the operating temperatures of the vial heater. Layer 92a is desirably formed from a suitable foam or elastic material so as to provide sealing engagement with an interior rim 96 of housing 12.

Peltier heating unit 52 takes the form of four square-shaped Peltier heaters affixed to circuit-board 98 in a coplanar 2x2 matrix. Connector interface 95 accepts a plug 97 at the free end of cable 65 (seen in Figure 5) and provides electric power to each heater so as to control their temperature as well that of the vial holder 20. Circuit-board 98 is positioned on the planar surface 102 of base 100 of radiator fin block 54. Power for heating unit 10 is desirably provided by an on-board battery (not shown) or from a plug to a conventional electrical outlet (not shown).

Radiator fin block 54 includes a number of elongate substantially planar radiator fins 104 extending from base 100 in a direction opposite from holder device 20. Radiator fin block 54 may be formed of any suitable material having high thermal conductivity for assisting the cooling of holder device 20. End fins 104a and 104i are affixed to upwardly-extending flanges 55a and 55b of open planar base member 55.

Cooling fan 56 is affixed to open base member 55 adjacent to radiator block 54. Operation of cooling fan 56 is also determined by control unit 62 (although the actual connection between the two is not shown). When operating, fan 56 conducts outside air through inlet opening 108 of base member 55 and across radiator fins 104 to exit through vent apertures 60 of housing 12.

As shown in Figure 6, the bottom surface 12a of housing 12 defines access opening 110 for receiving thermal unit 50 into housing interior 18. Fastener holes 112 on surface 12a register with fastener holes 114 of base member 55 to allow thermal unit 50 to be held in place.

Having described the structure of the vial heater and holder device of the present invention, a method for heat treating a vial containing a radiopharmaceutical composition is also provided.

A vial containing non-radioactive active ingredients (which may preferably be lyophilized) and a radioactive isotope (eg. ^99m Tc) in liquid or solution form is itself placed in a vial holder device 20 of vial heater 10. The interference fit between the vial and the interior surface of holder device 20 ensures optimum thermal contact and desirably that the vial will simply not drop into the lead holder and break. Lid 14 is then closed. Under program control of heater control unit 62, the contents of the vial are heated and cooled using the thermal unit 50 in accordance with the time- temperature profile of Figure 7. As shown in Figure 7, vial heater 10 maybe operated so as to raise the temperature of the vial holder prior to introducing the vial therein, thus reducing the time required to prepare the radiopharmaceutical over devices of the prior art which provide a shielded vial to a heater. Moreover, the present invention contemplates that any appropriate time-temperature profile for heating and cooling of the mixture of the radioactive liquid and the non-radioactive components within the vial may be used, consistent with the particular radiopharmaceutical formulation being produced. The temperature of the contents of the vial will rise due to the activation of the Peltier heating unit 52. Likewise, the temperature of the contents of the vial will drop due to the combined activation of the Peltier heating unit 52 and the fan 62 blowing air over radiator fin block 54.

The radiopharmaceutical formulation of the desired radiochemical purity is thus produced within the vial once the time-temperature profile has been completed. Using the apparatus and method of the present invention, a radiopharmaceutical formulation exhibiting the desired labeling efficiency is thus prepared.

While the particular embodiment of the present invention has been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the teachings of the invention. The matter set forth in the foregoing description and accompanying drawings is offered by way of

illustration only and not as a limitation. The actual scope of the invention is intended to be defined in the following claims when viewed in their proper perspective based on the prior art.