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Stabalised 99mtc compositions

a radiopharmaceutical composition and composition technology, applied in the direction of radiation therapy, medical preparations, therapy, etc., can solve the problem of significant potential radiolysis problems

Active Publication Date: 2011-01-13
GE HEALTHCARE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0037]The non-radioactive kits may optionally further comprise additional components such as a transchelator, pH-adjusting agent or filler. A “transchelator” is a compound which reacts rapidly to form a weak complex with technetium, then is displaced by the ligand. This minimises the risk of formation of reduced hydrolysed technetium (RHT) due to rapid reduction of pertechnetate competing with technetium complexation. Suitable such transchelators are salts of organic acids with a biocompatible cation, especially “weak organic acids” having a pKa in the range 3 to 7. Suitable such weak organic acids are acetic acid, citric acid, tartaric acid, gluconic acid, glucoheptonic acid, benzoic acid, phenols or phosphonic. acids. Hence, suitable salts are acetates, citrates, tartrates, gluconates, glucoheptonates, benzoates, phenolates or phosphonates. Preferred such salts are tartrates, gluconates, glucoheptonates, benzoates, or phosphonates, most preferably phosphonates, most especially diphosphonates. A preferred such transchelator is a salt of gluconic acid, with a biocompatible cation, especially sodium gluconate. An additional preferred transchelator is 5-sulfosalicyclic acid or salt thereof with a biocompatible cation. Two or more transchelators may be used in combination, and the tetrofosmin kits of the present invention most preferably comprise a combination of sodium 5-sulfosalicyclate and sodium gluconate.
[0083]Example 6 shows that the Myoview30 kit of the present invention permits much more rapid preparation times for multiple 99mTc-tetrofosmin radiopharmaceutical preparations, with substantially reduced operator radiation dose. The amount of radioactivity used for the QC sample is the same for Myoview30 and Myoview™, but Myoview30 involves 70% less time and 75% less radioactivity. In addition, it is easier for the operator to place 4 QC chromatography strips behind a radiation shield than 16.

Problems solved by technology

Such high levels of radioactivity for extended periods pose significant potential radiolysis problems for the 99mTc radiopharmaceutical composition.

Method used

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  • Stabalised 99mtc compositions
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  • Stabalised 99mtc compositions

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Tetrofosmin

[0088]All reactions and manipulations were performed either in vacuo or under an oxygen-free nitrogen atmosphere. Solvents were dried, and degassed by nitrogen purge prior to use. α-Azo-isobutyronitrile (AIBN) and ethyl vinyl ether were obtained from BDH and Aldrich respectively. Bis(diphosphino)ethane was prepared according to the literature [Inorganic Synthesis, Vol 14, 10].

[0089]A Fischer pressure-bottle equipped with a Teflon™ stirring bar, was charged with ethyl vinyl ether (5 cm3, 52.3 mmol), bis(diphosphino)ethane (1 cm3, 10 mmol) and α-azo-isobutyronitrile (0.1 g, 0.61 mmol). The reaction mixture was then stirred and heated to 75° C. for 16 hours. After cooling back to room temperature, the viscous liquid was transferred to a 50 cm3 round-bottomed flask. Removal of volatile materials was performed by heating under vacuum. The involatile material obtained was pure by NMR. Yield: 3.0 g, 80%.

[0090]1H NMR (CDCl3): δ 1.12 (12H, dt J=1.16 Hz, 7.15 Hz; OCH2C...

example 2

Lyophilised Bulk Vial Kit Formulation and Preparation

[0092]An optimised formulation for a 30 ml bulk vial preparation is as follows:

Tetrofosmin0.69mg,Stannous chloride dihydrate90μg,Disodium sulfosalicylate0.96mg,Sodium-D-gluconate3.0mg,Ascorbic acid5.0mg,Sodium hydrogen carbonate11.0mg,pH on reconstitution with saline8.3 to 9.1.

[0093]This kit formulation is termed “Myoview30”.

[0094]Batches of 500 ml were prepared. Thus, approximately 90% of the total volume of Water for Injection (WFI) was added to a preparation vessel. The WFI was deoxygenated by purging with nitrogen. Tetrofosmin sulphosalicylate, stannous chloride dihydrate, Sodium D-gluconate, ascorbic acid and sodium hydrogen carbonate were dispensed, added and dissolved in consecutive order with constant mixing. The dispensing beakers were rinsed with deoxygenated WFI. The bulk solution was adjusted to 100% of the final volume with deoxygenated WFI during continuous mixing. The nitrogen purging was discontinued. A nitrogen bl...

example 3

Procedure for the Reconstitution of a Bulk Radioprotectant-Containing Kit

[0096]A Myoview30 kit 30 ml vial (from Example 2) was inserted into a suitable radioactive shielding container, and the rubber septum sanitised with an isopropyl alcohol swab. A sterile needle (the venting needle) was inserted through the rubber septum. 99mTc-pertechnetate generator eluate [10-30 cm3 volume; diluted with Sodium Chloride Injection, USP as appropriate which does not contain a bacteriostat; at a radioactive concentration of up to 10 GBq / cm3 and a total 99mTc radioactive content of up to 100 GBq (2.7 Ci)] was added using a shielded, sterile syringe. The venting needle was then removed. The reconstituted vial was mixed gently for 10 seconds to ensure complete dissolution of the lyophilised powder and then incubated at room temperature for 15 minutes.

[0097]The reconstituted Myoview30 was stored at 2-25° C., and the contents used within 12 hours of preparation. Withdrawn aliquots were also stored at 2...

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Abstract

The present invention relates to stabilised 99mTc radiopharmaceutical compositions of the ligand tetrofosmin, which include an ascorbic acid or ascorbate radioprotectant, in the absence of an antimicrobial preservative. The invention also provides lyophilised kits suitable for the bulk preparation of multiple unit patient doses of 99mTc-tetrofosmin metal complexes. Also disclosed are unit doses of 99mTc-tetrofosmin, together with processes for preparing such unit doses from the lyophilised bulk vial.

Description

FIELD OF THE INVENTION[0001]The present invention relates to stabilised 99mTc radiopharmaceutical compositions of 99mTc-tetrofosmin, which include an ascorbic acid or ascorbate radioprotectant, in the absence of an antimicrobial preservative. Lyophilised kits suitable for the bulk preparation of multiple unit patient doses of the 99mTc-tetrofosmin radiopharmaceutical composition are also disclosed, together with processes for preparing such unit doses from the lyophilised bulk vial.BACKGROUND TO THE INVENTION[0002]Diagnostic imaging radiopharmaceuticals based on the radioisotope technetium-99m (99mTc) are known for a variety of clinical diagnoses, including functional studies (eg. renal), and perfusion (especially heart and brain). The radioisotope 99mTc has a half-life of 6 hours, hence such 99mTc radiopharmaceuticals are usually prepared from so-called “kits”.[0003]These kits for the preparation of 99mTc radiopharmaceuticals permit the user to maintain stocks of non-radioactive, l...

Claims

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Application Information

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IPC IPC(8): A61K51/00A61P43/00A61K51/04
CPCA61K51/0497A61P43/00A61K51/02
Inventor HJELSTUEN, OLE KRISTIANMARTINUSSEN, GRETHE KARINSTENSRUD, GRY
Owner GE HEALTHCARE LTD
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