Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1998-03-24
2002-01-01
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C534S014000, C206S223000, C424S001110, C424S009100
Reexamination Certificate
active
06334995
ABSTRACT:
FIELD OF INVENTION
The present invention to a technetium-99m radiolabelled diethylene triamine pentaacetic acid diester kit for the diagnosis of renal disorders.
BACKGROUND
For accurate evaluation of degree of renal disorder estimation rate of transfer of some specified substances such as technetium-99m diethylene triamine pentaacetic acid and iodine-131 orthoiodo-hippurate from blood to urine are to be determined. These compounds can be eliminated from blood either by glomerular filtration or by renal tubular secretion.
Technetium-99m diethylene triamine pentaacetic acid which is widely available and used for above said estimation, but since it is cleared by glomerular filtration, the extraction efficiency is only 20%. Therefore, while using this reagent, a low target to background ratio is produced and in many cases non-diagnostic images are obtained with patients having impaired renal function.
Orthoiodo-hippurate labeled either with iodine-131 or with iodine-123 which is also used for the above said estimation, is eliminated mainly by renal tubular secretion and therefore, has a very high extraction efficiency (87%). This compound is extremely useful for patients with poor renal function. However, iodine-131 not only impairs a high radiation dose to patients but shows a poor spatial resolution; this is due to its non-optimal energy characteristics. On the other hand, iodine-123 has an ideal energy but is very expensive and not available widely. These problems led to the search for an agent which will have similar renal property of orthoiodo-hippurate but labeled with a radionucleide of optimal energy characteristics such as technetium-99m.
After a decade of research in this area, a compound technetium-99m mercaptoacetylglycylglycylglycine was offered for clinical use. However, this compound deviated considerably from the nearly optimal renal properties of iodine-131 orthoiodo-hippurate in the following way:
1. Renal extraction of technetiurn-99m mercaptoacetylglycylglycylglycine was only 53% compared to that of iodine-131 orthoiodo-hippurate which was 79%.
2. High protein binding (77%) of technetium-99m mercaptoacetylglycylglycylglylcine compared to a moderate value (32%) of iodine-131 orthoiodo-hippurate.
3. Technetium-99m mercaptoacetylglycylglycylglycine is prohibitively expensive and not available in this country.
4. Technetium-99m mercaptoacetylglycylglycylglycine kit needs considerable skill to reconstitute or otherwise it may produce variable results.
5. Unwanted accumulation in hepatobiliary system is observed for technetium-99m mercaptoacetylglycylglycylglycine unlike that of iodine-13 1 orthoiodo-hippurate.
To solve these difficulties we developed a new compound, viz., technetium-99m diethylene triamine pentaacetic acid diester and a process for the preparation of this compound.
OBJECTS OF INVENTION
It is accordingly an object of the invention to provide such a new compound and process for its preparation that obviates such prior difficulties, and a novel diagnostic kit using such new compound.
SUMMARY OF INVENTION
Accordingly, the present invention provides a technetium-99m radiolabelled diethylene triamine pentaacetic acid diester kit for the diagnosis of renal disorders wherein technetium-99m diethylene triamine pentaacetic acid dimethyl ester has Rf value=zero in silica gel/acetone TLC Thin layer chromatography system and Rf value=1 in silica gel/acetonitrile water (1:1) TLC system and technicium-99m diethylene triamine pentaacetic acid dimethyl ester movement is of the order of half of the distance as compared to the standard compound, technicium-99m dithelene triamine pentaacetic acid, on conducting paper electrophoresis.
The invention further provides a process for the preparation of a technetium-99m radiolabelled diethylene triamine pentaacetic acid diester kit for the diagnosis of renal disorders which comprises:
(a) Adding appropriate amount of stannous ion to a dilute aqueous solution of diethylene triamine pentaacetic acid diester prepared by known methods
(b) Keeping the resultant solution obtained in step (a) in an evacuated rubber sealed injection vial flushed with nitrogen;
(c) lyophilizing the said kit and storing the lyophilized product as obtained in step (b) at 4° C.;
(d) radiolabelling the said lyophilised product obtained with Tc-99by allowing the kit to attain the room temperature before addition of 99m TcO
4
(e) shaking the kit vigorously to obtain the radiolabelled product available for use within a period of one hour.
In an embodiment of the invention, diethylene triamine pentaacetic acid diester used is prepared by
[a] esterifying dianhydride of diethylene triamine pentaacetic acid by conventional methods,
[b] evaporating the resulting semi-solid mass,
[c] titrating with an organic solvent to get the crude diester, and
[d] preparing the crude diester by recrystallisation from alcohol.
In another embodiment of the invention, esterification is effected by heating dianhydride of diethylene triamine pentaacetic acid with an alcohol in the presence of a solvent.
In a further embodiment of the present invention, the solvent used is selected from pyridine, piperidine, picoline and the like.
In yet another embodiment of the invention, the solvent used for tritration is selected from petroleum ether, benzene; toluene and the like.
In yet another modification of the present invention, the alcohol used for crystallization is selected from methanol, ethanol, propanol, isopropanol and the like. Further, in the preparation of the techetium-99m radiolabelled diethylene triamine pentaacetic acid diester kit for the diagnosis of renal disorders, stannousions are introduced by dissolving stannous chloride in dihydrate in HCI diluted nitrogen purged water.
REFERENCES:
patent: 5275801 (1994-01-01), Niedballa et al.
patent: 5676923 (1997-10-01), Platzek et al.
patent: 5808091 (1998-09-01), Linder et al.
patent: 5859214 (1999-01-01), Gries et al.
patent: 6027710 (2000-02-01), Higashi et al.
Dewanjee et al, vol. 132, p. 711-716, Pharmacodynamics of Stannous Chelates Administered with 99mTc-Labeled Chelates, 1979.
Banerjee Some Nath
Chatterjee Mita
Sen Karabi
Council of Scientific & Industrial Research
Jones Dameron L.
Rines and Rines
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