Apparatus and method for the preparation of a radiopharmaceutical formulation

PUBLICATION LITERATURE

Apparatus and process for the preparation of a composition for radiation treatment

The present invention relates to apparatus and a method for the rapid preparation of a composition for radiation treatment.

Technetium Tcm Sestamibi is a technetium-labeled radioactive formulation manufactured by DuPont-Merck Pharmaceutical Company, Billerica, Massachusetts and marketed under the trademark Cardiolite®. Technique Tcm-Sestamibi is primarily used as a myocardial imaging agent.

The technetium-labeled preparation is prepared as a radiopharmaceutical for use in a syringe, wherein an amount (about one to three millimeters of custom) of non-pyrogenic pertechnetate Tcm solution is obtained from the nuclide generator in a vial containing other non-radioactive constituents in lyophilized form. (2-methoxyisobutylisonitrile) copper tetrafluoroborate, sodium citrate dihydrate, cysteine ​​hydrochloride monohydrate, mannitol and tin (-) chloride dihydrate]. The vial itself is embedded in a suitable radiation shield, typically a cylindrical sheath member provided with a protective cap. The label instructions require that after injection the vial containing the mixture of sodium pertechnetate and lyophilized non-radioactive ingredients be removed from the radiation barrier and heated in a hot water bath for at least 10 minutes. After heating in a hot water bath, the vial is returned to the radiation barrier for a cooling period of about 15 minutes. Radiochemical purity analysis is performed to ensure that the resulting radiopharmaceutical has the desired radioactive efficacy prior to use.

These time constraints may limit the usefulness in the preparation of a Technécium Tcm-Sestamibi radiotherapy formulation, for example in urgent cases. In order to reduce the preparation time and consequently increase the usability of the Technécium Tcm-Sestamibi imaging agent, several alternative methods for its preparation have been developed.

One of the procedures described by Tallifer, Gagnon Lamber and Leville in The Labeling Process and In Vitro Stability of Tcm Methoxy Isobutyl Isonitrile (MIBI), Practical Aspects, published in J. Nucl Med 1989; 30; 865 (abs), a

Article -2 illustrates that reflux time is as short as possible, one (1) minute may be sufficient to provide Technécium Tcm-Sestamibi solution with acceptable radioactive efficiency and ninety percent radio-chemical purity. However, this process still requires a considerable amount of time (ten to twenty-five minutes from order) to heat the boiling water. Thus, the time gained from reducing the current dive time will be lost, since it is still necessary to boil water for the submersible.

Another process for the preparation of the Technécium Tcm-Sestamibi formulation has been focused on the use of alternative heat sources. Many alternative methods discuss using a microwave oven as a heat source. Microwave Warming Process described in Gagnon, Tallifer, Bavaria, and Leville, J., Rapid Labeling of Technetium-99m-sestamibi by Heating in a Microwave. Nucl Med Technoi, 19, 1991; 90-3; and another article by Hung, Wilson, Brown, and Gibbson on Rapid Production and Quality Control of Technetium-99m-2-Methoxyisobutylisonitrile (Technetium-99m-Sestamibi), J. Nucl Med, 1991; 32; 2162-8. Another procedure can be found in Wilson, Hung, and Gibbons, A Simple Method for Reducing Temperature of Microwave Technetium-99msestamibi, J. Nucl Med 1992; 20; 180, the process of rapidly cooling the heated Technécium Tcm-Sestamibi formulation is in focus.

Although microwave-based heating processes appear to overcome many of the obstacles that are present in the preparation of the Technécium Tcm-Sestamibi formulation, processes that also appear to have serious disadvantages, such as breaking the vial (as outlined below) Vial fracture of a technetium-99m-Sestamibi formulation using a microwave oven (Hung and Gibbons, J. Nucl Med 1992; 33; 176-8). Other noticeable problems with the microwave oven heating process are disclosed in an article by Wilson, Hung, and Gibbson, "An Alternative Method for the Quick Preparation of the Tcm-Sestamibi Preparation," Nucl Med Commun 1993; 14; 544-9. The latter article proposes an alternative heating process which includes an instant hot water generator as a hot water source used to make the Technécium Tcm-Sestamibi preparation.

-3 Other heating sources for raising the temperature of materials used in life science reactions have long been known. For example, a device manufactured by MJ Research, Inc. of Watertown, Massachusetts, commercially known as the MiniCycIer ™ Programmable Temperature Controller, utilizes a heating / cooling unit that operates on a thermoelectric effect and is capable of heating and cooling a variety of biotech reactions. The basic operating principle of a thermal electric heating / cooling unit is the Peltier cooling effect, in which heat is removed or produced as a current passes through the connection of two different materials. As the electrons pass through the junction, they take away or release a portion of energy equal to transporting energy and the energy difference between the conducting bands of different materials.

The materials to be heated and cooled are typically introduced into the programmable thermoregulator into microultracentrifuge tubes, also known as Eppendorf tubes, or into other suitable reaction tubes. The programmable thermostat includes a pattern block in which a plurality of boreholes are formed. Each tube carries a sample into it, is inserted into the borehole, and the appropriate heating and / or cooling program is started. Each borehole is configured in the sample block to conform to the shape of the outer shell of the container into which it is inserted. The use of a programmable thermoregulator seems to be a consideration for radioactive reactions.

In view of the foregoing, it is advantageous to use a heat-electric (Peltier effect) heating / cooling unit to precisely control the heating and cooling of the Technécium Tcm-Sestamibi imaging agent composition, thereby making rapid delivery of the effective imaging agent in emergency and other situations.

The present invention relates both to apparatus and to a process for the use of a thermoelectric heating / cooling unit suitable for both heat generation and heat extraction from a vial containing the components necessary for the preparation of a radiation treatment composition.

The object of the present invention is to provide a vial containing a radiation protection container containing the ingredients necessary for the preparation of a radiation treatment composition in which said ingredients are both heated and cooled. This invention is further developed by: a hollow outer made of a radiation protection material. protective sheet section; and a vial holder which is received and substantially surrounded by a hollow outer shield portion. The vial holder is made of a material with good thermal conductivity. The vial holder has a collar portion that defines the socket. The socket is dimensioned so that it can receive the protrusion of the base in a heat transfer connection.

According to a preferred embodiment of the radiation protection container according to the invention there is further provided a plug made of a radiation protection material located inside the collar part.

The present invention is further based on an apparatus in which the ingredients necessary for the preparation of a radiation treatment composition within the vial are both heated and cooled. According to the invention, the apparatus comprises: a thermoelectric heating and cooling unit; a pedestal unit having a pedestal projection. The pedestal unit is thermally conductive in communication with the thermal electric cooling and heating unit. A radiation shielding container for receiving a vial containing the ingredients needed to form the radiation treatment composition. The container comprises: a hollow outer shield part made of radiation shielding material; and a vial holder, which is received and substantially surrounded by a hollow outer shield portion. The vial holder is made of a material with good thermal conductivity. The vial holder has a collar portion that defines the socket. The socket is dimensioned so that it can receive the protrusion of the base in a heat transfer connection.

In accordance with a preferred embodiment of the invention, the device further comprises a plug made of a radiation shield material disposed within the collar portion.

In a further aspect of the present invention, there is provided a process for preparing a radiotherapy composition within a vial, wherein the process of the present invention comprises the steps of: inserting a vial for preparing a radiotherapy composition containing non-radioactive ingredients. The vial holder is substantially enclosed within the radiation shield. The vial holder is made of a material with good thermal conductivity and has a collar portion that defines the socket. Radioactive liquid is added to the non-radioactive ingredients in the vial. Place the vial holder in a heat transfer connection with the pedestal protrusion on the pedestal assembly, securing the vial holder shoulder portion so that the pedestal protrusion extends, and

-5heat transfer in connection with the vial holder shoulder. The soles! unit itself is thermally conductive in communication with the thermal electric heating and cooling unit. We use a thermoelectric heating and cooling unit for both heat transfer and heat extraction from a mixture of radioactive liquid and non-radioactive ingredients within the vial. During this time, the vial is kept inside the vial holder within the radiation shield. In this way, a radiopharmaceutical is prepared within the vial.

The invention will now be described in more detail with reference to the accompanying drawings, in which an exemplary embodiment of the proposed apparatus is shown. In the drawing it is

First Figure 1A is an exploded sectional view of a radiation shielding container for use in the preparation of a radiopharmaceutical as a first aspect of the invention;

2A. FIG. 2A is a stylized schematic diagram of an apparatus for heating or cooling components for making a radiation treatment composition using the thermoelectric heating and cooling unit, the apparatus comprising the radiation shield of FIG. Fig. 2 is a fragmentary sectional view, fully fitted; the

2B. 2A. FIG

2C. 2A. 2B and 2B. FIGS. 2B is a cross-sectional view taken along lines 2C-2C of FIG. 2B.

In the following detailed description, like reference numerals refer to like elements in the figures.

Figure 1 is an exploded sectional view of a radiation shield, generally designated 10, according to a first aspect of the present invention. The radiation shield container 10 of the present invention receives a V-vial containing non-radioactive ingredients necessary for the preparation of a radiation-treating composition. In some cases, the non-radioactive ingredients may be in lyophilized form. The radiation treatment composition is first heated and then cooled with a mixture of the (lyophilized) non-radioactive ingredient and the radioactive liquid. The radiation shield 10 holds the V vial while the mixture of non-radioactive ingredients and radioactive liquid is heated and cooled. The heat transfer and heat removal from the mixture is accomplished using the apparatus designated 80 in Figure 2. The AV vial may contain ingredients for the preparation of any formulation for radiation treatment, such as the Technecium TcmSestamibi myocardinal imaging agent commercially available under the trademark Cardiolite® from DuPont-Merck Pharmaceutical Company, Billerica, Massachusetts. The radiotherapy composition, which may be prepared using various aspects of the present invention, is also manufactured by DuPont-Merck Pharmaceutical Company and is marketed under the trademark Neurolite®.

The radiation shield 10 includes an outer shield 12 which is shown in FIG. 2a. can be clearly seen. The outer protective part 12 is a hollow cylindrical part made of a radiation shielding material such as lead and tungsten. In terms of structural strength and processing, tungsten is preferred. However, in some cases, when very strong radioactive liquids are used in the preparation of the composition, the protective portion 12 of the radiation shield 10 may be made, for example, from depleted uranium.

The protective part 12 has an internal thread 14 formed around its inner surface, close to the first axial end. The outer tubular guard 12 has an inner surface, generally close to its opposite axial end, with a cut-out stand 16 formed therein. The presence of the scaffold 16 results in a reduced diameter thickness of the protective layer 12 through a major portion of its axial length. The stand 16 is undercut to form the shoulder portion 18 therein. In order to increase the radiation shielding capacity of the radiation shield container 10, an inner shield layer 20 is concentricly arranged inside the outer shield portion 12. The inner protective layer 20, preferably made of lead, is tightly arranged inside the outer protective part 12. The inner protective part 12 sits on the upper surface of a lower stand where it is held in place by a retaining ring 22. The retaining ring 22 is received by the groove 24 which is formed on the inner surface of the outer protective part 12, generally adjacent to the threads 14 provided thereon.

-ΊΑ. the open first axial end of the outer protective part 12 is closed by a protective cap 28. The protective cap 28 is generally a plate-like portion having a circular rim 30 defined by the lower surface. The outer surface of the flange 30 is threaded in the same way as the flange 32, whereby the protective cap 28 engages the threads 14 on the outer protective part 12. An opening 34 extends centrally and axially through the cap 28. Access to the opening 34 and thus to the inside of the outer guard 12 is optionally provided by the lockable plug connector 36. The plug connector 36 slides in the dovetail channel 38 formed in the cap 28. The connector 36 has an access end 40 therein.

The bottom of the plug connector 36 has a groove 42. The groove 42 receives the spring-loaded retaining pin 44 which is received by the plate-like portion of the cap 28 with a bore 46. The retaining pin 44 restricts the sliding movement of the plug connector 36 within the channel 38 and thereby retains the plug connector 36 on the cap 28. The connector 36 is preferably made of tungsten.

When in the closed position (shown in solid line in Figure 2b), the opening 40 of the plug connector 36 is laterally offset from the opening 34 of the protective cap 28. However, the plug connector 36 may slide inside the channel 38 to a position (dashed in Fig. 2b) where the opening 40 in the plug connector 36 is exactly aligned with the opening 28 in the cap. In this position, a portion of the plug connector 36 extends beyond the cap 28 as shown in FIG. 2b. FIG.

The vial holder 54 is received and extensively surrounded by the outer protective part 12. The vial holder 54 is made in one unit by machine or extrusion of a material with high thermal conductivity, such as aluminum or copper. Structurally, the vial holder 54 includes a base portion 56 from which the receptacle portion 58 extends in a cup-like manner. The receiving portion 58 is dimensioned so as to receive the V-vial tightly. Preferably, the inner surface of the receiving portion 58 is galvanized with nickel to protect it from corrosion in case the vial is flowing. The upper portion 62 of the inner surface of the collar portion 60 is generally cylindrical. However, the lower surface 64 of the inner surface of the collar portion 60 expands outwardly and has a frustoconical shape. The vial holder 54 is secured to the outer protective part 12 by a layer of adhesive 68 near the inside of the shoulder 18. Any adhesive that can be used for approx. 120 It is heat resistant up to ° C, such as epoxy resin.

In order to ensure that the vial V, which is received and held by the receiving portion 58 of the vial holder 54, is securely hugged with the radiation shielding material, a plug 72 engages the upper cylindrical portion 62 of the inner surface of the collar portion 60. The 72 connector is also made of tungsten, although it may be made of other suitable radiation shielding material. The plug connector 72 is connected to the collar portion 60 by an adhesive layer 74. The same epoxy material which forms the adhesive layer 68 can also be used advantageously for the adhesive layer 74.

With the plug 72 in place, the internal volume is delimited by the outer surface of the plug 72 and the truncated cone portion 64 of the inner surface of the collar portion 60, determined by the plug socket, for the reasons described. The socket 76 has a predetermined axial size 78.

The radiation shield 10, shown in Figure 1, includes an element of the device for both heating and heat removal of the vial in which the composition for radiation treatment is manufactured. The heating and cooling device, which is the second aspect of the invention, is designated by the reference numeral 80 in FIG. 2A. In addition to the radiation shield container 10, the heating and cooling device 80 also includes a support block 84 and a thermoelectric heating and cooling unit 94 which is thermally coupled to the support block 84.

The support block 84 is generally a flat member having a base member 86. The pedestal protrusion 88 extends upwardly from the base 86 to a predetermined distance 90. The distance 90 is slightly less than or completely greater than the axial size 78 of the socket 76 defined by the collar 60 of the vial holder 54. Each of the socket 76 and the base projection 88 are sized and configured so that the socket 76 can directly receive the base projection 88 in a heat transfer connection. In order to enhance the direct fit of the vial holder 54 to the protrusion of the base 88, the outer surface of the protrusion 88 of the base 88 has a conical shape corresponding to the lower part 64 of the collar portion 60 of the vial holder. The tapered design of the lower portion 64 of the collar portion 60 facilitates mounting and disassembly of the collar portion 60 from the pedestal projection 88. Preferably, the support block 84 is made by machine from a material of high thermal conductivity, such as aluminum.

-9Α 94 The thermoelectric heater and cooling unit is connected in a heat conductive connection to the support block 84, as shown schematically, with the connection lead 96. The thermoelectric heating and cooling unit 94 is made of a suitable heat conducting material, for example aluminum. The thermoelectric heating and cooling unit 94 generates and withdraws heat from the holding block 84 and the vial holder 54 mounted thereon, controlled by a microcomputer controller 98. In practice, the controller 98 adjusts the potential difference through the junction of the various materials forming the heat and cooling unit 94. Physically, the thermoelectric heater and cooling unit 94 and the support block 84 may be combined into a single unit, thereby presenting a commercially available thermoelectric heater and cooling unit, such as that described above by MJ Research, Inc. Manufactured by Watertown, Massachusetts and marketed as a MiniCycler ™ programmable thermostat.

1, 2A, 2B and 2C, and the heating and cooling unit 80 is shown in Figure 2A, and accordingly, a further aspect of the present invention is illustrated, wherein the radiation-treating composition is shown in FIG. is made inside a vial.

The method includes the step of inserting a vial V into the foil holder 54, which contains non-radioactive ingredients necessary for the preparation of the radiopharmaceutical. As noted, these non-radioactive ingredients may be, for example, in lyophilized form. The AV vial and vial holder 54 are substantially enclosed within the radiation shield 10.

Preferably, within the V vial, within the vial holder 54, a radioactive liquid is subsequently added to the components in the V vial. This step is done by withdrawing a predetermined amount of radioactive liquid from the radionuclide generator using a radiation-protected syringe. A suitable radionuclide generator is described in U.S. Patent No. 5,109,160,160 (Evers), issued April 28, 1992, which is hereby assigned to the assignee of the present invention. The plug 36 slides into the cap 28 in the cap 38 to open the opening in the cap 34, places the syringe inside the radiation shield 12 and injects radioactive liquid through the septum of the vial. The addition of the radioactive liquid serves to prepare the non-radioactive components when stored in a lyophilized form in the vial. Although not advantageous, it should be noted that it is within the scope of the present invention to inject the injected radioactive liquid into the V vial before inserting the V vial into the vial holder 54.

Next, the vial holder 54 is inserted into a direct nest contact with the pedestal protrusion 88 on the support blocks 84 by retaining a portion of the collar 60 of the vial holder 54 so that the protrusion of the pedestal 88 extends and receives thermal conductive engagement with the collar portion 60 of the vial holder 54.

Using the thermoelectric heating and cooling unit 94, it selectively generates or withdraws heat from the mixture of radioactive liquid and non-radioactive components within the vial while the vial holder 54 holds the vial within the radiation shield container 10. This is how the radiopharmaceutical is prepared inside the vial. Any suitable time-temperature profile by which the heating and cooling of the mixture of radioactive liquid and non-radioactive components within the V-vial can be accomplished is the same as the preparation of the particular radiation treatment composition.

In accordance with various aspects of the present invention, due to the controllability and related accuracy of the thermoelectric heating and cooling, a radiation treatment composition having acceptable radioactive efficiency and radioactive chemical purity can be rapidly prepared. Furthermore, it is noted that the radiation shield 10 of the present invention utilizes radiation as low as possible to reach exposed personnel during the preparation of a radiation treatment composition. (Alarm).

Example

The practice and use of the various aspects of the present invention will be more readily understood by reference to the following preparation of a technetium-labeled radiopharmaceutical, manufactured by DuPont-Merck Pharmaceutical Company, Billerica, Massachusetts and marketed under the trademark Cardiolite ®.

One vial contains the non-radioactive constituents of the lyophilized form [mainly, sufficient amounts of (2-methoxyisobutylisonitrile) copper tetrafluoroborate, sodium citrate dihydrate, cysteine ​​hydrochloride monohydrate, mannitol and tin (') chloride -dihydrate] which is inserted into the

- 11 54 in a vial holder in the outer radiation shield 12. Using a sterile radiation shielded syringe, one to three ml of additive-free, sterile, non-pyrogenic pertechnetate Tcm [9255550Mbq, (15-150mC)] fluid is obtained from the nuclide generator. Sodium pertechnetate Tcm was aseptically added to the vial. Without retracting the needle, an equal volume of internal air is removed from the vial to maintain atmospheric pressure. Stir the contents of the vial for a few minutes.

The vial holder 54 is contained in the outer radiation shield 10 which is mounted on the projection 88 of the support block 84. The collar portion 60 of the vial holder 54 receives the protrusion 88 of the pedestal 88 so that the protrusion of the pedestal 88 extends and receives it in thermal conductivity with the collar portion 60 of the vial holder 54. By program control, the contents of the V vial are heated and cooled by the thermoelectric unit according to the following time-temperature profile:

1) Within one minute, the temperature of block 64 rises from ambient temperature (about 20 ° C) to 119 ° C;

2) The block was kept at 119 ° C for four minutes;

3) Within two or three minutes, the temperature of block 64 drops from 119 ° C to 10 ° C; and

4) The block was kept at 10 ° C for one minute.

Using the apparatus and method of the present invention, a composition suitable for radiation treatment of the desired purity and radioactivity shown is obtained. The total preparation time is 10 minutes, as opposed to the 25 minutes required for prior art heating water baths.

Those skilled in the art can make many adjustments to the benefits of the teachings of the present invention. Such modifications may be made within the scope of the present invention as defined by the following claims: