METHOD FORFORMINGAVIALHOLDERDEVICE FORAVIAL

HEATERAPPARATUS Field of the Invention

The present invention is directed to the field of equipment used for radiopharmaceutical preparation. More specifically, the present invention is directed to method for preparing a vial holder for a vial heater apparatus.

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 ^99m 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,. ^99m 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.

One example of a heating device 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 vial holder having a thermally-conductive inner container for receiving the vial and a radiation-shielding liner constructed about the inner container. Also, the Peltier heating element is 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, displaces 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 more efficient vial heater apparatus incorporating a vial holding device which provides a radiation-shielding liner about the contained vial and which provides an outer thermally-conductive shell for engaging a heating element. A method of forming this improved vial holding device is thus required.

Summary of the Invention

The present invention is directed toward method of forming 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 method for forming a holder device for a vial containing a radiopharmaceutical including the steps of: providing a first piece of material; forming a first elongate passageway into the first piece of material;

filling the first elongate passageway with a second material which, when solid, is able to shield radiation; allowing the second material to solidify; and forming a second elongate passageway in the second material from the allowing step such that the solidified material defines an open first end, a closed second end, and an elongate cylindrical interior surface extending therebetween so as to define an elongate cavity for receiving the vial. It is contemplated that the elongate cavity for receiving the vial may be sized to receive the vial in sliding engagement whether the vial has a label affixed thereto or not.

The present invention contemplates that the second material may be either molten, such as molten lead, or merely soft and pliable so as to conform to the first passageway of the first material. The first material desirably provides high thermal conductivity and takes the form of a hollow cylinder.

Brief Description of the Drawings

Figures IA-B depict front elevational views of a vial heating apparatus incorporating a vial holder 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.

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- holdiηg device.

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

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

Figure 5 depicts a bottom perspective view of the vial heating apparatus of Figure 1.

Figure 6 depicts a time-temperature profile for operating the vial heater of Figure 1.

Detailed Description of the Preferred Embodiment

Figures IA- 3 depict a vial heating apparatus 10. Vial heater 10 provides for the heating and cooling of a vial holding a radiopharmaceutical 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 nonradioactive components and the radioactive liquid is 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™. Alternatively, the ^99ra 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 vial heater apparatus. 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 vial heater apparatus.

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 ofvial 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 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.

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.degree. C, such as an epoxy 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.

A method of forming a lead-lined interior surface of holder device 20 for a vial containing a radiopharmaceutical is contemplated by the present invention. Initially, a first piece of material, the workpiece, is provided. Typically, the workpiece is made from a material having a high coefficient of thermal conductivity, such as aluminum or copper. The workpiece may be provided in any shape from which outer conductive member 70 may eventually be machined.

Then, elongate passageway 75 is formed into the workpiece. Generally, passageway 75 is formed by drilling into the workpiece so as to form interior cylindrical surface 77. It is also contemplated that passageway 75 may have other shapes as may be desired and that surface 77 may be further provided with notches therein for accepting the radiation shielding material of inner shielding member 80. Eventually, the workpiece will be given the form of outer shell 70 having open first end 82, closed second end 84, and elongate cylindrical wall 86 extending therebetween.

First passageway 75 may then be filled with a second material which, when solid, is able to shield radiation. The second material may be poured into passageway 75 in molten form or otherwise compressed into place when the second material is in a soft pliable form. Lead, for example, may be provided in either form according to the present invention. The second material is allowed to solidify to a point at which it

may be further formed. Other materials contemplated to be used to fill passageway 75 include, but are not limited to, tungsten and depleted uranium. For example, tungsten could be provided in a soft form so as to be molded into the desired shape within passageway 75.

The method further includes the step of forming a second elongate passageway in the second material such that the solidified material defines the open first end 82, closed second end 84, and the elongate cylindrical interior surface 87 of wall 88 extending therebetween so as to define cavity 88 for receiving the vial in sliding engagement. Alternatively, interior surface 87 defining cavity 88 may be dimensioned with an interference fit so as to sϊidmgly engage a label affixed to the outside surface of the vial.

It is contemplated by this method of the present invention, therefore, that when the second material is provided in molten form into passageway 75 that it will be allowed to solidify prior to forming cavity 88. Alternatively, when the second material is provided in a soft and pliable form, the material may be considered to have been allowed to solidify sufficiently before it had been provided so as to allow cavity 88 to be formed while compressing the material into passageway 75. Therefore, the steps of allowing the material to solidify and forming cavity 88 may be performed in either order according to the present invention, depending in which form the second material is provided into passageway 75.

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.