Process for preparing radioactive pharmaceutical preparation and apparatus for making the same

The present invention relates to an apparatus and a method for preparing a radiopharmaceutical.

Prior art

Technetium Tc⁹-⁵m - Sestamibi is a technetium-labeled radiopharmaceutical manufactured by Du Pont-Merck Pharmaceutical Company, Billerica, Massachusetts and available under the tradename Cardiolite^R. Technetium Tcm Sestamibi has basic uses as an imaging diagnosis for myocardium.

In the form of a preparation for use, technetium-labeled radiopharmaceutical diagnosticians are prepared by injecting a volume (of the order of about one to three milliliters) of pyrogen-free sodium pertechnetate Tcm prepared from into a vial containing lyophilisates of other non-radioactive ingredients / particularly suitable amounts of copper (2-methoxyisobutyl and sonic). -tetrafluoroborate, sodium citrate dihydrate, cysteine ​​hydrochloride monohydrate, mannitol and stannous chloride dihydrate). The vial itself is placed in a suitable radiation shielded capsule, usually formed in a lav-item. In this manual, the vial containing a mixture of sodium pertechnetate and lyophilized non-radioactive ingredients needs to be removed from the radiation shielding case and heated in a bath with boiling water for at least 10 minutes. After heating in a water bath, the vial is again placed in the case for a period of time. required for cooling, approximately fifteen minutes. A radioactive purity analysis is performed to confirm that the radiopharmaceutical prepared in this manner exhibits the desired potency prior to use.

These time constraints in the preparation of radiopharmaceuticals containing technetium Tcm-Sestamibi may limit their availability in cases such as emergencies. In order to shorten the preparation time and consequently increase the availability of diagnostic preparations containing technetium Tcm-estamibi, several alternative methods for its preparation have been proposed.

One way discussed in an article by Tallifer, Gagnon, Lambérť and Leví ÍTe, '' Lauel ing- -procedure .a.nd. . in-vitro stability of Tc-99m methoxy isobutyl isonitrile (MIBI): practical considerations, published in J.Nucl.Med. 1989 ;, 30; 865 (abs), demonstrates that a time as low as one minute of lasting can be sufficient to prepare a Tcm-Sestamibi technetium solution with satisfactory efficacy and radiochemical purity at a ninety percent surplus. However, the process still requires a significant proportion of the time (on the order of ten to twenty-five minutes) spent on heating the water used for the immersion bath to boil. The time gain achieved by reducing the actual immersion time is lost due to the still necessary time required to heat the immersion bath water.

Other proposed procedures for the preparation of diagnostic products containing technetium Tvm-Sestamibi have focused on the use of alternative heat sources. The use of a microwave oven as a heat source is mentioned in several alternative methods. The use of microwave heating is dealt with in the article by Gagnon, Tallifer, Bavaria and Leville, Fast labeling of technetium-99m-setamibi with microwave oven heating ”, J.Nuc1.Med.Techno1. 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 procedure is given in Wilson, Hung and Gibbons, Simple procedure for microwaved technetium-99m sestamibi temperature reduction, J.Nucl.Med.Techno1. 1992;

20; 180, which is directed to rapidly cooling a heated formulation containing the iumTCm-Sestamibi technet.

Although it has been shown that microwave-based processes overcome certain difficulties present in the preparation of a formulation containing technetium Tc⁹⁹m-Sestamibi, have also been shown to have serious concomitant defects such as rupture of the vial (as reported in Hung and Gibbons, Breakage of technetium 99m sestamibi vial with the use of a microwave oven ”, J. Nucl. Med. 1992; 33 ; 176-8). Other known problems associated with microwave-based processes are described in the work of Wilson, Hung and Gibbons, An alternative method for rapid preparation of⁹⁹Tc^m-sestamibi,

Nucl.Med.Commun. 1993; 14; 544-9. In the latter work, an alternative heating procedure is proposed, which includes? the use of equipment for the preparation of hot instant beverages as a source of hot water for the preparation of a preparation containing technetium Tcm-Sestamibi.

Other heat sources are known in the art for raising the temperature of materials in connection with the known materials.^_bbras't'i natural sciences. For example, an instrument manufactured by MJ Research, Inc. Watertown, Massachusetts and available as The MiniCycler^T·'¹programmable thermal controller uses a heating / cooling element based on the thermoelectric effect to heat and cool samples in various biotechnological reactions. Basic

The working principle of the thermoelectric heating / cooling element is also the Peltier cooling effect, in which heat is absorbed or generated according to the passage through the point of contact of two different materials. The electrons passing through the point of contact absorb or give off a quantity of energy equal to the transport energy and the energy difference between the conductivity bands of these different materials.

Materials for heating or cooling in said programmable heat controller are usually placed in microcentrifuge tubes, also known as Eppendorf tubes, or in other suitable reaction tubes. This programmable thermal controller includes a sample block containing a VbšaTeho^rTvikičamek Each sample tube is placed in a well and the appropriate heating and / or cooling program is initiated. All holes in the block for. The samples correspond to the dimensions of the external dimensions of the vessels inserted in them. - The use of a thermal regulator in connection with radioactive reactions can be assumed.

In view of the above, the use of a thermoelectric (Peltier effect) heating / cooling element is expected to precisely control both the heating and cooling of a diagnostic preparation containing technetium Tcm-Sestamibi, thus providing an effective dose of the diagnostic preparation readily available for use in emergencies and other cases. situations.

The essence of the invention

The present invention is directed to both an apparatus and a method of using a thermoelectric heating / cooling element for both heat supply and / or heat removal from a vial containing ingredients necessary for the manufacture of a radiopharmaceutical.

A first aspect of the invention is directed to a radiation shielded vial storage container containing ingredients necessary for the preparation of a radiopharmaceutical and in which those ingredients can be both heated and cooled. The container comprises a more hollow shielding element made of a radiation shielding material such as lead or tungsten and a vial holder contained in the outer shielding member. The outer shield member substantially completely surrounds the vial holder. The bottle holder is made of a material; which has a high thermal conductivity such as aluminum or copper. The vial holder contains a jacket part which. defines the throat. The neck defined by the jacket part has a size corresponding to a suitable assembly with a base protrusion in a heat transmissive relationship. A closure also made of a radiation shielding material can be placed in the neck defined by the housing part of the vial holder.

Another aspect of the invention is directed to an apparatus in which the ingredients necessary for the preparation of a radiopharmaceutical contained in a vial are both heated and cooled. This device comprises the above-mentioned container, a thermoelectric heating and cooling element and a thermally conductive pad connected to the heating and cooling element. The base block has a base protrusion of a size corresponding to a suitable assembly in a heat transmissive relationship with the neck defined by the housing part of the container vial holder.

Yet another aspect of the invention is directed to a method of rapidly preparing a radiopharmaceutical composition in a vial. The method includes the steps of inserting a vial containing the non-radioactive ingredients necessary to prepare a radiopharmaceutical into a vial holder. In some cases, these non-radioactive components may be in lyophilized form. The vial holder is located in the radiation shielding container and is substantially surrounded by it. The bottle holder is made of a material with high thermal conductivity and contains a jacket part that defines the neck. A radioactive liquid is added to the non-radioactive components contained in the vial, preferably after the vial has been placed in a radiation shielding container.^L'The bottle holder • is · placed · in the. ... ......

in transmissive contact with the base protrusion on the base block by assembling the housing part to the base protrusion so that the latter penetrates the housing part of the vial holder and is with it in

thermal contact. The base block itself is in thermal conductivity in contact with the thermoelectric heating and cooling element. Using this thermoelectric heating and cooling element, heat is supplied and removed from the mixture of radioactive liquid and (lyophilized) non-radioactive components in the vial, the vial being stored in the vial holder in the container. -.— for — tv.orb-v_r.adiopharmaceutical preparation in ----------- 1.

vial.

PfcMeJL ohvltkd na. drawings

The invention description which forms part of it can be better understood from the following detailed is made in accordance with the figures in the appendix to this application and where:

Giant. 1 is an exploded side sectional view of a container for preparing a radiopharmaceutical according to the first aspect of the invention, and FIG. 2A is a stylized schematic illustration of an apparatus for heating and cooling components necessary for preparing a radiopharmaceutical using a thermoelectric heating and cooling element. according to Fig. 1 it is in a full side section and in a fully assembled position;

Fig. 2B shows a plan view of the container shown in Fig. 2A and Fig. 2C shows a perpendicular projection of the lid of the container according to Figs. 2A and 2B in sectional lines 2C-2C of Fig. 2B.

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

Giant. i represents an exploded side section of the shielding radiation - r.

a general container designated by the reference numeral 10 according to the first aspect of the invention. As will be described below, a vial V containing various non-radioactive ingredients necessary for the preparation of a radiopharmaceutical preparation is inserted into the radiation J shielding container 10. In some cases, these non-radioactive components may be in lyophilized form. The radiopharmaceutical is formed by heating and then cooling a mixture of (lyophilized) non-radioactive components and a radioactive liquid. A vial V is stored in the radiation shielding container 10, and the mixture of non-radioactive components and radioactive liquid is heated and cooled. The supply and removal of heat from the mixture is carried out using the device schematically shown in Figure 2 and indicated by the reference numeral 80. Vial V may contain ingredients necessary for the manufacture of various radiopharmaceuticals, such as Technetium-labeled radiopharmaceutical diagnostics of the Technetium myocardium

TCm-Sestamibi manufactured by DuPont-Merck Pharmaceutical

Company, Billerica, Massachusetts and sold under the trademark Cardiolite^R. A radiopharmaceutical, also manufactured by DuPont-Merck Pharmaceutical Company 1 and sold under the trademark Neurolite, can also be prepared using various aspects of the present invention.^R.

The container 10 includes an outer shield member 12 best seen in Figure 2A. This outer shielding member 12 is a hollow cylindrical element made of a magnetic shielding shield such as lead or tungsten. Tungsten is preferred for structural rigidity and machinability. However, in cases where a highly radioactive liquid is used in the preparation of the formulation, the shielding member 12 of the container 10 may be made of a material such as depleted uranium.

The shield member 12 has internal threads 14 on the inner surface associated with the first-axial end 4. The inner surface of the cylindrical shield member 12 has a support cutout 16 generally ^-With the opposite axial to the support slot 16, the shield member 12 has a major part of its The support cutout 16 defines an arm 18. To increase the radiation shielding capacity, the container 10 has an inner shielding member 20 concentrically located on the shielding member 12. The inner shield member 20, which is preferably made of lead, is tightly seated in the outer shield member 12. The inner shield member 12 is seated on the upper surface of the support slot 16 and in position is secured by a snap ring 22. The snap ring 22 is seated in a groove 24 formed in the inner surface of the member 12 generally associated with the threads 14 of that surface.

The open first axial end of the outer shield member 12 is closed by a lid 28. The lid 28 is generally disc-shaped and has an annular bead 30 on the bottom surface. The outer surface of the annular bead 30 is provided with threads 32 by which the lid 28 can be secured by engagement with threads 14 on the outer shield member 12. The lid 28 has an opening 34 which it extends centrally and axially in it. Access to the opening 34 and thus to the interior of the shield member 12 is provided through the closure 36 as required. The closure 36 slides in a dovetail channel 38 formed in the lid 28. The closure 36 is provided with an inlet opening 40.

The reverse side of the closure 36 is provided with a groove 42. The groove 42 is intersected by a spring stop 44 which is closed in an opening 46 formed in the disc portion of the lid 28. The stop 44 restricts the sliding movement of the closure 36 through the channel 38. 36 is preferably made of tungsten.

In the closed position (shown in solid lines in Fig. 2B), the opening 40 of the closure 36 is laterally offset from the opening 34 on the lid 28. However, the closure 36 may slide in the channel 38 to a position (shown in broken lines in Fig. 2B). the opening 40 of the closure 36 overlaps with the opening 34 in the lid 28. In this position, a portion of the closure 36 extends beyond the lid 28 as shown in Fig. 2B.

The bottle holder 54 is seated and substantially surrounded by an outer shield member 22. The bottle holder 54 is integrally fabricated or pressed from a high thermal conductivity material such as aluminum or copper. Structurally, the holder 5.4 .mu.m consists of a base part 56, from which a cup-shaped sleeve 58 extends upwards. The sleeve 58 is dimensioned such that the vial V is properly seated therein. Preferably, the inner surface of the sleeve 58 is electroplated with nickel to prevent corrosion in the event of a vial rupture. A shell portion 60 extends from the lower surface of the base portion 56. The upper portion 62 of the inner surface of the shell portion 60 is generally cylindrical.

- Jll, ** hr —-. + _ shape. However, the lower portion 64 of the inner surface of the shell portion 60 is extended outwardly and has the shape of a truncated cone for a reason which will be fully explained herein. The vial holder 54 is attached to the outer shield member 12 near the inner arm 18 by a layer 68 of adhesive material. A suitable adhesive for this purpose is any thermally stable adhesive, on the order of about 120 ° C, such as epoxide-based adhesives.

To ensure that the vial V seated and held in the sleeve 58 of the vial holder 54 is substantially completely surrounded by the radiation shielding material, an insert 72 is mounted in the upper cylindrical portion 62 of the inner surface of the shell portion 60. The insert 72 is also made of tungsten although another suitable radiation shielding material may alternatively be used. The attachment of the sleeve 72 to the housing portion 60 is provided by a layer 74 of adhesive. For the adhesive layer 74, it is preferred to use the same epoxide-based material that forms the adhesive layer 68.

^to · · A

An insert 76 is defined by an insert 72 located in the inner volume of the shell portion 60 and bounded by its outer surface and the truncated cone-shaped lower portion 64 of the shell portion 60, the neck 76 of which will be described. The neck 76 has a predetermined axial direction 78.

The radiation shielding container 10 shown in Fig. 1 includes as part of a device which serves both to supply heat and to remove it from the vial V in which the radiopharmaceutical is prepared. The heating and cooling device which forms the second aspect of the invention is generally indicated in Fig. 2A by reference numeral 80. In addition to the container 10, the heating and cooling device 80 also includes a base block 84 and a thermoelectric heating device.

cooling element 94_; which is connected by a thermally-conductive contact with the base block 84. <

The base block 84 is a generally planar member having a base portion 86. A base protrusion 88 extends upwardly from the base portion 86 to a predetermined height 90. The height 90 is slightly less than or substantially equal to the axial dimension 78 of the neck 76 defined by the housing portion 60 of the holder. 54 vials. The neck 6 and the base protrusion 88 are shaped relative to each other and are sized to ensure that the protrusion 88 fits snugly into the neck 76 in thermal transmission contact. To increase the tightness of the seated vial holder 54 on the protrusion 88, the outer surface of the protrusion is chamfered to match the configuration of the bottom portion 64 of the shell portion 60 of the vial holder 54. The downwardly expanding shape of the lower portion 64 of the housing portion 60 facilitates assembly and separation of the housing portion 60 on and from the protrusion 88. The backing block 84 is preferably a machined method of a highly thermally conductive material such as aluminum. '

The thermoelectric heating and cooling element 94 is connected by a thermally conductive connection to the backing block 84 as schematically shown by a connecting line 96. The element 94 is made of a suitable thermally conductive material such as aluminum. *

The thermoelectric element 94 supplies and dissipates heat from the pad 84 and the vial holder 54 to the seat block when controlled by a microcomputer-based controller 98. In practice, the regulator 98 serves to set the potential difference at the contact of the various materials forming the element 94. Thermoelectric heating and cooling, d.LcJ_p.rv.e.k_.94: -a, .p.od.10-žn.í__b. lok 84 can be structurally integrated into a single unit in a manner demonstrated on a commercially available thermoelectric heating and cooling device, such as the aforementioned device manufactured by MJ Research, Inc.

Water.tow.n, Massachusetts and sold ... as. The .MiniCyc 1 is a programmable thermal controller.

After describing the structure of both the container 10 (Figs. 1 and 2A, 2B,

2C) of such a heating and cooling device 80 (FIG. 2A), according to yet another aspect of the invention, there is provided a method of preparing a radiopharmaceutical composition in a vial V.

The method includes the step of inserting a vial V containing the non-radioactive ingredients necessary to prepare a series of pharmaceutical preparations into the vial holder 54. As noted, these non-radioactive components may in some cases be lyophilized. The vial and vial holder 54 themselves are located in and substantially surrounded by the radiation shielding container 10.

Preferably, a radioactive liquid is then added to the vials contained in the vial holder in the vial located in the vial holder. This step is performed by withdrawing a predetermined volume of radioactive liquid from the radionucleotide generator using a compressed syringe.^—The patent is disclosed in U.S. Patent No. 5,109,060 (Evers), issued April 28, 1992, assigned to the assignee of the present invention. The cap 36 of the lid 28 is moved in the channel 38 to expose the opening 34 in the lid, the syringe is inserted inside the shield 12 and the radioactive liquid is injected through the septum into the vial V. The addition of radioactive liquid serves to reconstitute the non-radioactive components presence in the vial in the lyophilized state. Although not advantageous, it is necessary. note that it is within the scope of this invention to spray. radioactive liquid into the vial beforehand. by fitting it into the vial holder 54.

Then, the vial holder 54 is brought into closely related contact with the base protrusion 88 of the base

Also, block 84 by assembling the housing portion 60 of the holder 54 onto the protrusion 88 so that the protrusion 88 penetrates the housing portion and is in thermally conductive contact with the housing portion 60 of the vial holder 54.

Using a thermoelectric heating and cooling element 94, heat is supplied or removed to the vial containing the mixture of radioactive liquid and non-radioactive components as needed while the vial is seated in the vial holder 54 within the radiation shielding container 10. Thus, a radiopharmaceutical is prepared in the vial. Any suitable time temperature profile can be used to heat the mixture of radioactive liquid and non - radioactive components in the vial and. cools, corresponding to the preparation of the particular radiopharmaceutical.

According to various aspects of the present invention, due to the ability of -F control and the inherent accuracy of the thermoelectric heating and cooling element, a radiopharmaceutical can be rapidly prepared that satisfies the labeling efficiency and chemical purity range. In addition, the use of a radiation shielding container 10 in accordance with the present invention allows the manufacture of a series of pharmaceuticals with worker exposure to radiation as low as reasonably practicable (ALARA).

Example

The use and practice of various aspects of the present invention will become apparent from the following example of the preparation of a technetium-labeled radiopharmaceutical manufactured

DuPont-Merck Pharmaceutical Company 1, Billerica, Mass., And sold under the trademark Cardio1ite^R.

A vial containing the lyophilized form of the non-radioactive active ingredients (in particular the appropriate amounts of (2-methoxyisobutyl isonitrile)) of methyl fluoroborate, sodium citrate dihydrate, cysteine ​​hydrochloride monohydrate, mannitol and stannous chloride dihydrate / is removed. places the vial in the outer shield member 12 in the vial holder 54. Using a sterile shielded syringe, take 1 to 3 ml of additive-free, sterile pyrogen-free sodium pertechnetate (Tcm) (925-5550 Mbq, 15-150 mC) from the nuclide generator. The liquid containing sodium pertechnetate Tcm is aseptically added to the vial. The needle is not withdrawn and the same volume escapes from the vial from above the solution to maintain atmospheric pressure. The contents of the vial are vortexed for several minutes.

The vial holder 54 located in the outer shield 10 is seated on the base protrusion 88 of the base block 84. The housing portion 60 of the vial holder 54 is seated on the protrusion 88 so that the protrusion 88 is in thermally conductive contact. with the sheath portion 60 of the vial holder 54. The programmable control heats and cools the contents of the vial using a thermoelectric element with the following time and temperature profile:

1) Within 1 minute, the temperature of block 64 rises from room temperature (about 20 ⁰C) at 119 ° C.

2) The block temperature is maintained at 119 ° C for four minutes.

3) Within two to three minutes, the temperature of block 64 decreases from 119 ° C to 10 ° C ⁰ C a

4) the block temperature is maintained at 10 ° C for one minute.

Using the device and method of the invention, radiopharmaceuticals prepare a formulation of the desired purity and labeling efficiency. The total preparation time is of the order of ten minutes, in contrast to the preparation time of twenty-five minutes required when using a boiling water bath according to the prior art.

Those skilled in the art will appreciate various modifications of the invention that utilize the above. These modifications are to be considered as modifications within the scope of the invention as defined by the appended claims.