GB1565865A

GB1565865A - Process for the manufacture of a technetium-997 labelled diagnostic agent for bone scanning

Info

Publication number: GB1565865A
Application number: GB695877A
Authority: GB
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1976-02-19
Filing date: 1977-02-18
Publication date: 1980-04-23
Also published as: DE2606561B2; IT1074322B; LU76794A1; CH626253A5; DE2606561C3; AT357271B; FR2341306A1; DK71277A; ATA111077A; IE44699B1; FR2341306B1; DE2606561A1; BE851656A; NL7701532A; IE44699L

Abstract

A labelling unit for the purpose of labelling with the eluate from a technetium-99m generator is produced. 0.7 to 1.3 parts by weight of tin(II) chloride and 4.8 to 9.5 parts by weight of sodium pyrophosphate are dissolved in 500 to 2000 parts by weight of water. The solution is adjusted to a pH between 3 and 9 and frozen. The water is subsequently stripped off with fusion under a partial pressure of water vapour from 1 to 5 torr, and the residue is dried under 10<-2> to 10<-3> torr. The labelling unit is suitable for the preparation of a bone diagnosis agent.

Description

(54) PROCESS FOR THE MANUFACTURE OF A TECHNETIUM-99M LABELLED DIAGNOSTIC AGENT FOR BONE SCANNING (71) We, HOECHST AKTIEN GESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt/Main 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the follow mg statement: This invention relates to a process for the manufacture of a technetium-99m labelled diagnostic agent.

Technetium-99m is being used to an increasing extent for diagnostic applications because of its short half-life and its radiation properties, which are particularly useful in nuclear-medical methods of examination.

In order to avoid transport and storage losses, it is preferably obtained in a corresponding nuclide generator (for example according to German Offenlegungsschrift No. 2,236,565). Technetium-99m is present in the eluate of the corresponding generator in the form of pertechnetate, and may be in a physiological saline solution. In this chemical form, it may be used for scintigraphy of the brain and the thyroid, and for examining circulatory parameters. For examination of other organs, however, a suitable organo-specific carrier substance, for example, particles of different size for liver and lung diagnosis, pyrophosphate or a diphosphonate for visualizing the skeleton, or a complex compound for kidney scintigraphy, must be labelled with technetium99m.

In order to obtain a technetium-99m label, the pertechnetate is reduced and reacted with the carrier substance. Tin (II) salts are generally used as the reducing agent, as they are able to reduce the pertechnetate in a neutral medium. A technetium-99m labelled carrier substance, however, is stable for a short time only when in solution, so is preferably prepared just prior to use. To facilitate this, it has been proposed to provide a so-called "labelling unit" which, for example, consists of a vial containing the appropriate organospecific carrier substance and the tin (II) salt, the vial being closed by a pierceable stopper. Since tin (II) salts are sensitive to oxidation, the solution is lyophilized and the contents of the vial are protected by an inert gas, for example, nitrogen, thus ensuring the storability of the contents for a prolonged period. In order to prepare the diagnostic agent which, as mentioned above, is stable for a short time only in dissolved form, the eluate of a technetium99m generator is introduced into the vial by means of a syringe prior to use.

Technetium-99m labelled pyro- and polyphosphates and diphosphonates are suitable for bone scintigraphy, as mentioned above, (G. Subramanian and J. G. McAffee, Radiology, 99, pp. 192-196; U.S. Patent Specification No. 3,735,001; German Offenlegungsschriften Nos. 2, 327,870; 2,344,802; 2,424,496; 2,424,453, and may be produced using the above labelling units. However, it has been observed by means of tests in man and animals that the concentration of technetium-99m in the liver and especially the spleen was considerably increased after prolonged storage of the labelling unit, resulting in the liver and spleen being subjected to a greater dose of radiation than is desirable.

Furthermore, the diagnostic evidence of diseases of the skeleton become difficult to interpret in general. and especially in the neighbourhood of the liver and the spleen due to the concentration of radio-activity there.

The present invention provides a process for the manufacture of a composition comprising a tin(II) salt and a pyrophosphate suitable for being labelled with the eluate of a technetium-99m generator, which comprises dissolving from 0.7 to 1.3 parts by weight of a tin(II) salt, calculated on the anhydrous salt, the salt generally being a tin(II) halide and preferably tin(II) chloride, and from 4.8 to 9.5 parts by weight of an alkali metal pyrophosphate, calculated on the anhydrous pyrophosphate, preferably sodium pyrophosphate, in 500 to 2000 parts by weight of water adjusting the solution to a pH of from 3 to 9, preferably 6 to 7, freezing it, subsequently removing the water, while melting the frozen solution, at a steam partial pressure of from 1 to 5, preferably 2 to 4, mm Hg, and drying the residue at from 10-2 to 10-3 mm Hg.

It is advantageous to contact the tin(II)/ pyrophosphate solution with metallic tin, generally purified on the surface, and preferably in the form of tin granules, which ensures the reduction of any small amounts of tin(IV) salts present. (Tetravalent tin is undesirable because it is thought that together with bivalent tin, it forms mixed hydroxide microparticles which may also be labelled with technetium-99m and which, as is known, are concentrated in the liver, the spleen and the bone marrow.) The product obtained after drying is preferably dispensed into vessels, for example, beaded rim vials, under sterile conditions and under an inert gas atmosphere, for example, a nitrogen atmosphere, and the vials are tightly closed. The labelling unit prepared thus stores well.

In order to obtain the diagnostic agent for bone scanning, the eluate of a technetium99m generator is added to the vial under sterile conditions shortly before administration. Even after a prolonged storage of the labelling unit, the diagnostic agent for bone scanning obtained thus enables the bones to be visualised well without substantially straining other organs by radiation.

The following Example illustrates the invention.

Example 18 g of Na4P,O . 10 H,0 are dissolved in 1500 ml of sterile bidistilled water. 1.8 g of SnCl . 2H,O are added, and the solution is adjusted td a pH of from 6 to 7 by means of 1 N HCI. Subsequently, the solution is stirred for about 20 minutes over some tin granules which have been previously purified on the surface. The solution is then sterile-filtered using a 0.2 Rm membrane filter, charged into 12 ml beaded rim vials in portions of 1 ml each. and frozen in liquid nitrogen. Without melting the contents, the vials are immediately placed in a lyophilization apparatus. the storage surface of which is cooled to -10 C. Subsequently. a pressure of 2 to 4 mm Hg is established, and the storage surface is warmed to +20"C, whereby the water is removed with melting of the contents of the vials. The residue is dried at 10-2 to 10-3 mm Hg. The vials are filled with sterile nitrogen and closed under sterile conditions.

To prepare the diagnostic agent for bone scanning, from 1 to 10 ml of technetium99m pertechnetate solution, advantageously in a 0.9% NaCI solution, are added in form of the eluate of a technetium-99m generator to the vial by means of a syringe.

WHAT WE CLAIM IS: 1. A process for the manufacture of a composition comprising a tin(II) salt and a pyrophosphate suitable for being labelled with the eluate of a technetium-99m generator, which comprises dissolving from 0.7 to 1.3 parts by weight of a tin(II) salt, calculated on the anhydrous salt, and from 4.8 to 9.5 parts by weight of an alkali metal pyrophosphate, calculated on the anhydrous pyrophosphate, in 500 to 2000 parts by weight of water, adjusting the solution to a pH of from 3 to 9, freezing it, subsequently removing the water, while melting the frozen solution, at a steam partial pressure of from 1 to 5 mm Hg, and drying the residue at from l0- to 10-3 mm Hg.

2. A process as claimed in claim 1, wherein the tin(II) salt is a tin halide.

3. A process as claimed in claim 2, wherein the tin(II) halide is tin(II) chloride.

4. A process as claimed in any one of claims 1 to 3, wherein the alkali metal pyrophosphate is sodium pyrophosphate.

5. A process as claimed in any one of claims 1 to 4, wherein the pH is adjusted to 6 to 7.

6. A process as claimed in any one of claims 1 to 5, wherein the steam partial pressure is from 2 to 4 mm Hg.

7. A process as claimed in any one of claims 1 to 6, wherein the tin(II) salt/ pyrophosphate solution is contacted with metallic tin.

8. A process as claimed in claim 1, carried out substantially as described in the Example herein.

9. A process as claimed in any one of claims 1 to 8. wherein the dried product is dispensed into vessels under sterile conditions and under an inert atmosphere, and the filled vessels are sealed.

10. A process as claimed in claim 9, carried out substantially as described in the Example herein.

11. A composition comprising a tin(II) salt and a pyrophosphate suitable for being labelled with the eluate of a technetium-99m generator, whenever prepared by a process as claimed in any one of claims 1 to 10.

12. A method of producing a diagnostic agent for bone scanning. which comprises adding the eluate of a technetium-99m generator to a composition as claimed in

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Claims

**WARNING** start of CLMS field may overlap end of DESC **.

a technetium-99m generator, which comprises dissolving from 0.7 to 1.3 parts by weight of a tin(II) salt, calculated on the anhydrous salt, the salt generally being a tin(II) halide and preferably tin(II) chloride, and from 4.8 to 9.5 parts by weight of an alkali metal pyrophosphate, calculated on the anhydrous pyrophosphate, preferably sodium pyrophosphate, in 500 to 2000 parts by weight of water adjusting the solution to a pH of from 3 to 9, preferably 6 to 7, freezing it, subsequently removing the water, while melting the frozen solution, at a steam partial pressure of from 1 to 5, preferably 2 to 4, mm Hg, and drying the residue at from 10-2 to 10-3 mm Hg.

It is advantageous to contact the tin(II)/ pyrophosphate solution with metallic tin, generally purified on the surface, and preferably in the form of tin granules, which ensures the reduction of any small amounts of tin(IV) salts present. (Tetravalent tin is undesirable because it is thought that together with bivalent tin, it forms mixed hydroxide microparticles which may also be labelled with technetium-99m and which, as is known, are concentrated in the liver, the spleen and the bone marrow.) The product obtained after drying is preferably dispensed into vessels, for example, beaded rim vials, under sterile conditions and under an inert gas atmosphere, for example, a nitrogen atmosphere, and the vials are tightly closed. The labelling unit prepared thus stores well.

In order to obtain the diagnostic agent for bone scanning, the eluate of a technetium99m generator is added to the vial under sterile conditions shortly before administration. Even after a prolonged storage of the labelling unit, the diagnostic agent for bone scanning obtained thus enables the bones to be visualised well without substantially straining other organs by radiation.

The following Example illustrates the invention.

Example

18 g of Na4P,O . 10 H,0 are dissolved in 1500 ml of sterile bidistilled water. 1.8 g of SnCl . 2H,O are added, and the solution is adjusted td a pH of from 6 to 7 by means of 1 N HCI. Subsequently, the solution is stirred for about 20 minutes over some tin granules which have been previously purified on the surface. The solution is then sterile-filtered using a 0.2 Rm membrane filter, charged into 12 ml beaded rim vials in portions of 1 ml each. and frozen in liquid nitrogen. Without melting the contents, the vials are immediately placed in a lyophilization apparatus. the storage surface of which is cooled to -10 C. Subsequently. a pressure of 2 to 4 mm Hg is established, and the storage surface is warmed to +20"C, whereby the water is removed with melting of the contents of the vials. The residue is dried at 10-2 to 10-3 mm Hg. The vials are filled with sterile nitrogen and closed under sterile conditions.

To prepare the diagnostic agent for bone scanning, from 1 to 10 ml of technetium99m pertechnetate solution, advantageously in a 0.9% NaCI solution, are added in form of the eluate of a technetium-99m generator to the vial by means of a syringe.

WHAT WE CLAIM IS: 1. A process for the manufacture of a composition comprising a tin(II) salt and a pyrophosphate suitable for being labelled with the eluate of a technetium-99m generator, which comprises dissolving from 0.7 to 1.3 parts by weight of a tin(II) salt, calculated on the anhydrous salt, and from 4.8 to 9.5 parts by weight of an alkali metal pyrophosphate, calculated on the anhydrous pyrophosphate, in 500 to 2000 parts by weight of water, adjusting the solution to a pH of from 3 to 9, freezing it, subsequently removing the water, while melting the frozen solution, at a steam partial pressure of from 1 to 5 mm Hg, and drying the residue at from l0- to 10-3 mm Hg.
2. A process as claimed in claim 1, wherein the tin(II) salt is a tin halide.
3. A process as claimed in claim 2, wherein the tin(II) halide is tin(II) chloride.
4. A process as claimed in any one of claims 1 to 3, wherein the alkali metal pyrophosphate is sodium pyrophosphate.
5. A process as claimed in any one of claims 1 to 4, wherein the pH is adjusted to 6 to 7.
6. A process as claimed in any one of claims 1 to 5, wherein the steam partial pressure is from 2 to 4 mm Hg.
7. A process as claimed in any one of claims 1 to 6, wherein the tin(II) salt/ pyrophosphate solution is contacted with metallic tin.
8. A process as claimed in claim 1, carried out substantially as described in the Example herein.
9. A process as claimed in any one of claims 1 to 8. wherein the dried product is dispensed into vessels under sterile conditions and under an inert atmosphere, and the filled vessels are sealed.
10. A process as claimed in claim 9, carried out substantially as described in the Example herein.
11. A composition comprising a tin(II) salt and a pyrophosphate suitable for being labelled with the eluate of a technetium-99m generator, whenever prepared by a process as claimed in any one of claims 1 to 10.
12. A method of producing a diagnostic agent for bone scanning. which comprises adding the eluate of a technetium-99m generator to a composition as claimed in

claim 11.
13. A diagnostic agent for bone scanning, whenever prepared by a process as claimed in claim 12.