US 3787565 A
Description (OCR text may contain errors)
United States Patent METHOD OF PRODUCING A DIAGNOSTIC PREPA- RATION ON THE BASIS OF AN IRON COMPLEX LABELLED WITH 99m Tc Jean-Paul Nouel, Boisguillaume, and- Henry Emile Edouard Renault, Paris, France, assignors to US. Philips Corporation, New York, N.Y.
No Drawing. Filed May 24, 1971, Ser. No. 146,543
Claims priority, applifistiopglgrance, May 22, 1970,
Int. Cl. A61k 27/04 US. Cl. 424-1 4 Claims ABSTRACT OF THE DISCLOSURE A method of producing a technetium labelled iron complex in which a solution of a technetium compound is reacted with ferrous ascorbate, the resultant solution is made alkaline and the solution is then agitated in the presence of air until a violet color appears.
The present invention relates to a method of producing a diagnostic preparation on the basis of an iron complex labelled with 99m Tc, with preparation is of importance for various scintigraphic examinations and especially for examinations of the brain and the kidneys.
Technetium is in great request for use in medicine owing to its short half-life (6 hours) its u-ray energy (140 kev.) and the absence of emission of SI-rays. As a result, the radiation doses administered to the patients may be reduced, whilst the injected activity and hence the statistical accuracy of the counts is increased and the duration of the examination may be reduced.
Furthermore technetium is frequently used for various examinations (thyroid, brain, liver, kidneys, spleen) in combination with various carriers.
The wide range of application of radioactive technetium is of great importance, because it enables the store of other radioactive elements to be restricted.
In addition, the radioactive technetium may simply be obtained at any desired instant by means of an elution process using, for example, the generator system described in French patent specification No. 1,518,130, in the form of sodium pertechnetate in an isotonic saline solution which may be mixed with the carrier required for the respective examination.
The use of a preparation on the basis of a technetiumlabelled iron complex for various scintigraphic analyses, in particular of the brain and the kidneys, is known and has often been described in the literature. According to a method of production described in Am. J. Rontg. (101), 1967, pp. 152-156, a pertechnetate solution is added to a solution of ascorbic acid and ferric chloride, after which the pH is first adjusted to 1.5 and then to about 7.4. Since the labelling efficiency is comparatively small, the technetium which has not been bound to the resulting complex is removed by means of an anion resin. The actual preparation is very difficult and requires a large number of operations, which consume much time and give rise to sterility problems. Especially the sterility problems are troublesome. All the operations, such as producing the solution of ascorbic acid, the solution of ferric chloride, adding the pertechnetate solution to the solution of ascorbic acid and ferric chloride, adjusting the pH to 1.5 and then to 7.4 and removing the unbound technetium, must be performed under strictly sterile conditions. This often cannot be realized, so that the ultimate product must again be sterilized.
These objections also apply to a method described in Medical Radio Isotope Scintigraphy Symposium, Salzburg, August 1968, vol. II, p. 627, in which ferrous sulphate is used instead of ferric chloride, although in this method the necessary operations are simplified to some extent.
We have now found a new method of producing a 99m Tc-labelled iron complex which does not suft'ffer from the above disadvantages.
The method according to the invention is characterized in that there is added to powdered ferrous ascorbate a solution of a technetium cmopund, after which if required, the resulting solution is made alkaline to a pH between 7 and 8, and finally the reaction mixture is agitated. Immediately before use the powdered ferro-ascorbate may be dissolved in an aqueous medium such, for example, as a physiological saline solution.
The reaction mixture is agitated in the presence of air, until a violet color appears. This treatment takes a few minutes. The violet color corresponds to the formation of a technetium-labelled ion complex.
The resulting product is ready for use and may be injected into the patient to be examined. The product is stable for several hours.
More particularly, it has been found that satisfactory results are obtained by using freeze-dried ferrous ascorbate in the method according to the invention.
The freeze-dried ferrous ascorbate has the further advantage that it remains stable for a prolonged period of time.
The technetium compound used in the method according 'to the invention preferably is sodium pertechnetate. The adjustment of the pH of the reaction mixture preferably is eifected by means of a trihydroxymethylaminomethane solution (sometimes referred to as Tris or THAM) which previously has been buffered to a pH of about 8 by the addition of hydrochloric acid.
In a preferred embodiment of the method according to the invention, the starting product is a powdered mixture of ferrous ascorbate and a basic substance. The amount of basic substance is such that after the solution of the technetium compound has been added the reaction mixture has a pH of from 7 to 8. The basic substance preferably has a buffer capacity at pH values between 7 and 8.
In this preferred embodiment of the method according to the invention, the adjustment of the pH after the addition of the technetium compound is not necessary.
As has been mentioned hereinbefore, the method according to the invention eliminates the afore-described disadvantages. A further advantage of the method according to the invention consists in an increase in the labelling efliciency. The method according to the invention results in a labelling efiiciency of from to 97%.
The invention also relates to a kit to be marketed as a unit which is suitable for use in the method according to the invention, which kit comprises at least one bottle of sterilized powdered ferrous ascorbate and at least one bottle of sterilized alkaline substance.
Obviously instead of bottles other hermetically sealed containers, such as ampoules, may be used in the kit according to the invention.
It should be mentioned that the solution of a radioactive technetium compound required in the method according to the invention cannot be supplied as such to the user owing to the radioactive disintegration of 99m Tc and hence this solution is not included in the kit according to the invention.
The required radioactive solution must be prepared in situ by means of elution of radioactive technetium generator.
The invention further relates to a new preparation for use in the method according to the invention, which preparation is characterized in that it comprises a pow- EXAMPLE I To 33 mg. of ferrous ascorbate there is added 2 ml. of a solution of TcO Na; to the resulting solution there is added 0.8 ml. of a solution of Tris (0.2 M) and the mixture is agitated in the presence of air, until a violet color is produced. The labelling efliciency, which has been determined by means of anion resins and by thinlayer chromatography, is 95%.
EXAMPLE II To 40 mg. of ferrous ascorbate there is added 5 ml. of a TcO Na solution in 1 ml. of a solution of Tris (1.5 M) buttered to a pH of 8 by means of hydrochloric acid.
The solution is agitated in air until a violet color is produced. The efliciency is about 95 What we claims is: Y
1. A method of producing a diagnostic preparation on the basis of an iron complex labelled with 99m Tc, said method comprising adding to powdered ferrous ascorbate a solution of a technetium compound, adjusting the solution to a pH between 7 and 8 if necessary and agitating the reaction mixture in the presence of air until a violet color is produced.
2. A method as claimed in claim 1, wherein freezedried ferrous ascorbate is used as the starting material.
3. A method as claimed in claim 1, wherein the solution is rendered alkaline by means of trihydroxymethylaminomethane which is buffered to a pH of about 8 by the addition of hydrochloric acid.
4. A method as claimed in claim 1, wherein a powdered mixture of ferrous ascorbate and an alkaline substance is used as the starting material.
References Cited UNITED STATES PATENTS 3,466,361 9/1969 Richards 424-1 BENJAMIN R. PADGE'IT, Primary Examiner UJS. Cl. X.R.
23-230 B; 250l06 T; 252301.1 R