1. Field of the Invention
The present invention relates to imaging agents. More particularly, the invention relates to imaging agents for imaging the myocardium in patients with suspected coronary artery diseases using rest and stress techniques.
2. Reported Developments
U.S. Pat. No. 4,705,849 discloses boronic acid adducts of technetium-99 m dioxime complexes for imaging the myocardium, hepatobiliary system, brain and blood pool in humans and other mammalian species. One of these complexes is used in a kit for imaging the myocardium, and sold under the trademark CARDIOTEC.RTM..
The kit comprises a 5 ml reaction vial which contains a sterile, nonpyrogenic, lyophilized formulation of: 2.0 mg cyclohexanedione dioxime;
2.0 mg methyl boronic acid; PA1 2.0 mg pentetic acid; PA1 9.0 mg citric acid; PA1 100.0 mg sodium chloride; PA1 50.0 mg gamma cyclodextrin; and PA1 0.058 mg (maximum) total tin expressed as stannous PA1 chloride (SnCl.sub.2), 0.020 mg (minimum) stannous PA1 chloride (SnCl.sub.2). PA1 1 to 3 mg cyclohexanedione dioxime; PA1 1 to 3 mg methyl boronic acid; PA1 1 to 3 mg pentetic acid; PA1 8 to 10 mg citric acid; PA1 5 to 10 mg sodium chloride; PA1 30 to 50 mg hydroxypropyl gamma cyclodextrin; and PA1 0.030 to 0.060 mg stannous chloride (SnCl.sub.2). PA1 1 to 3 ml pertechnetate Tc-99 m having 370 to 3,700 MBq (10-100 mCi) in physiological saline or derived from generator sources. PA1 1 to 3 mg cyclohexanedione dioxime; PA1 1 to 3 mg methyl boronic acid; PA1 1 to 3 mg pentetic acid; PA1 8 to 10 mg citric acid; PA1 5 to 10 mg sodium chloride; PA1 30 to 50 mg hydroxypropyl gamma cyclodextrin; and PA1 0.030 to 0.060 mg stannous chloride (SnCl.sub.2). PA1 1 to 5 ml pertechnetate Tc-99 m having 370 to 3,700 MBq (10-100 mCi) in physiological saline or from generator sources; PA1 wherein X is an anion; PA1 wherein n is 3 to 6 and PA1 wherein
To the 5 ml reaction vial, containing the lyophilized formulation, 1 ml sodium pertechnetate Tc-99 m injection is added containing 370 to 3,700 MBq (10-100 mCi) to obtain a solution which is then heated at 100.degree. C. for 15 minutes to obtain the diagnostic agent Technetium Tc-99 m Teboroxime.
The diagnostic agent has been used by health care professionals over several years and it has been found useful in distinguishing normal from abnormal myocardium in patients with suspected coronary artery diseases using rest and stress techniques.
The CARDIOTEC.RTM. kit contains a package insert instructing the diagnosticians to visually inspect the reconstituted formulation subsequent to the addition of the pertechnetate Tc-99 m into the reaction vial and the heating step. The formulation is to be used only if the solution is clear to slightly opalescent and free of particulate matter and discoloration.
The occurrence of particulate matter formation and discoloration of the diagnostic agent necessitated an investigation for finding a cause thereof. During the course of the investigation the solution was filtered to remove the particulate matter, which appeared to be successful. However, upon further investigation it was found that the problem of particulate matter formation and discoloration cannot be eliminated by filtration. Although immediately after filtration the solution is clear, the turbidity and discoloration reappear after a period of time necessitating re-filtration or discarding of the solution.
Thus, the additional step of filtration in producing the diagnostic agent was impractical, as it was cumbersome and inconvenient to the diagnosticians mainly for the reasons that: diagnostic facilities are not ordinarily equipped with such filtration devices having adequate radioactive shielding and the necessity to perform the filtration procedure immediately before use as it was not effective over the shelf-life of the reconstituted product.
Applicants in conducting extensive studies with the boronic acid adducts of technetium-99 m dioxime complexes disclosed in U.S. Pat. No. 4,705,849, which patent is incorporated herein by reference in its entirety, found a solution to the problems of particulate matter formation and discoloration.
Accordingly, the object of the present invention is to provide improved solutions of boronic acid adducts of technetium-99 m dioxime complexes for mycocardial infusion, in which no particulate matter is formed or discoloration occurs upon the injection of pertechnetate Tc-99 m into the reaction vial containing the lyophilized ingredients or during the shelf-life of the so-produced diagnostic agent formulation.
USPTO Backgrounds
USPTO Backgrounds