Radiopharmaceutical compositions of radioactive halogenated benzylguanidine

Abstract

The present disclosure concerns radiopharmaceutical compositions of radioactive halogenated benzylguanidine (such as radioiodinated MIBG) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In a preferred embodiment, the composition has at least 97% of radiochemical purity for at least 4 days. Advantageously, the compositions of the present disclosure may be devoid of parabens, which are carcinogenic and yet are used in known radioactive MIBG compositions. The present disclosure also provides processes of preparing a radioactive halogenated benzylguanidine composition. The compositions of the present disclosure can be used in diagnosis and treatment of various diseases.

What is claimed: 
     
         1 . A radiopharmaceutical composition comprising:
 radiohalogenated benzylguanidine selected from  131 I-benzylguanidine or a pharmaceutically acceptable salt, hydrate or solvate thereof; and,   radioprotectants comprising benzyl alcohol and niacinamide,   wherein the benzyl alcohol and niacinamide are present in a ratio of about 1:0.8 to 1:32,   wherein the radioactivity concentration of the composition is about 20 mCi/mL to about 1 Ci/mL,   wherein the composition has a radiochemical purity of at least 99% at the time immediately following its preparation from its constituent ingredients, and   wherein the composition is free of paraben.   
     
     
         2 . The radiopharmaceutical composition of  claim 1 , wherein the radiohalogenated benzylguanidine is  131 I-benzylguanidine. 
     
     
         3 . The radiopharmaceutical composition of  claim 1 , wherein the radiohalogenated benzylguanidine is present in a concentration from 0.10 mg/ml to 10 mg/ml. 
     
     
         4 . The radiopharmaceutical composition of  claim 1 , wherein the benzyl alcohol is present in a concentration from 0.9% (v/v) to 2.0% (v/v). 
     
     
         5 . The radiopharmaceutical composition of  claim 1 , wherein the niacinamide is present in a concentration from 0.5 g to 10 g/100 ml. 
     
     
         6 . The radiopharmaceutical composition of  claim 1 , wherein the benzyl alcohol and niacinamide are present in the composition in a ratio of from 1:1 to 1:5. 
     
     
         7 . The radiopharmaceutical composition of  claim 6 , wherein the benzyl alcohol and niacinamide are present in the composition in a ratio of from 1:1 to 1:3. 
     
     
         8 . The radiopharmaceutical composition of  claim 7 , wherein the benzyl alcohol and niacinamide are present in the composition in a ratio of about 1:1. 
     
     
         9 . The radiopharmaceutical composition of  claim 1 , wherein the benzyl alcohol and niacinamide are present in the composition in a ratio of about 1:1.8. 
     
     
         10 . The radiopharmaceutical composition of  claim 1 , wherein the composition has a radiochemical purity of at least 97% following four days of storage at 5±3° C. after its preparation from its constituent ingredients. 
     
     
         11 . The radiopharmaceutical composition of  claim 1 , wherein the composition has a radiochemical purity of at least 95% at two days following its preparation when stored at any temperature from 78±3° C. to 25±3° C. 
     
     
         12 . The radiopharmaceutical composition of  claim 1 , wherein the composition has a radiochemical purity of at least 95% at two days following its preparation when stored at a temperature of 5±3° C. 
     
     
         13 . The radiopharmaceutical composition of  claim 1 , wherein the composition has a pH from 3.0 to 7.0. 
     
     
         14 . The radiopharmaceutical composition of  claim 13 , wherein the pH is 5.0±0.1. 
     
     
         15 . The radiopharmaceutical composition of  claim 1 , wherein the radioprotectants consist of benzyl alcohol and niacinamide. 
     
     
         16 . The radiopharmaceutical composition of  claim 1 , wherein the radioprotectants do not include gentisic acid. 
     
     
         17 . The radiopharmaceutical composition of  claim 1 , wherein the composition further comprises a buffer comprising sodium acetate and sodium chloride. 
     
     
         18 . The radiopharmaceutical composition of  claim 1 , wherein the composition is prepared by a method comprising the steps of:
 (i) combining benzyl alcohol with water to form a combination;   (ii) adding niacinamide to the combination of step (i), and mixing;   (iii) adjusting the pH of the combination from 3.0 to 7.0; and   (iv) adding  131 I-benzylguanidine to the pH-adjusted combination of step (iii).   
     
     
         19 . The radiopharmaceutical composition of  claim 18 , wherein the step (ii) of the method further comprises the addition of sodium acetate and sodium chloride. 
     
     
         20 . The radiopharmaceutical composition of  claim 1 , wherein the composition is a lyophilized powder, solution, suspension or emulsion. 
     
     
         21 . The radiopharmaceutical composition of  claim 1 , wherein the composition is provided in a container selected from the group consisting of a vial, an ampoule, a prefilled syringe, and a capsule. 
     
     
         22 . A radiopharmaceutical composition comprising:
 radiohalogenated benzylguanidine selected from  131 I-benzylguanidine or a pharmaceutically acceptable salt, hydrate or solvate thereof; and,   radioprotectants comprising benzyl alcohol and niacinamide,   wherein the benzyl alcohol and niacinamide are present in a ratio of about 1:0.8 to 1:32,   wherein the radioactivity concentration of the composition is about 20 mCi/mL to about 1 Ci/mL,   wherein the composition has a radiochemical purity of at least 99% at the time immediately following its preparation from its constituent ingredients, and   wherein the composition has a pH from 3.0 to 7.0.   
     
     
         23 . The radiopharmaceutical composition of  claim 22 , wherein the benzyl alcohol is present in a concentration from 0.9% (v/v) to 2.0% (v/v). 
     
     
         24 . The radiopharmaceutical composition of  claim 22 , wherein the niacinamide is present in a concentration from 0.5 g to 10 g/100 ml. 
     
     
         25 . The radiopharmaceutical composition of  claim 22 , wherein the composition has a radiochemical purity of at least 97% following four days of storage at 5±3° C. after its preparation from its constituent ingredients. 
     
     
         26 . A radiopharmaceutical composition comprising:
 radiohalogenated benzylguanidine selected from  131 I-benzylguanidine or a pharmaceutically acceptable salt, hydrate or solvate thereof; and,   radioprotectants comprising benzyl alcohol and niacinamide,   wherein the benzyl alcohol and niacinamide are present in a ratio of about 1:0.8 to 1:32, and, benzyl alcohol is present in a concentration from 0.9% (v/v) to 2.0% (v/v),   wherein the radioactivity concentration of the composition is about 20 mCi/mL to about 1 Ci/mL, and   wherein the composition has a radiochemical purity of at least 99% at the time immediately following its preparation from its constituent ingredients.   
     
     
         27 . The radiopharmaceutical composition of  claim 26 , wherein the niacinamide is present in a concentration from 0.5 g to 10 g/100 ml. 
     
     
         28 . The radiopharmaceutical composition of  claim 26 , wherein the composition has a radiochemical purity of at least 97% following four days of storage at 5±3° C. after its preparation from its constituent ingredients. 
     
     
         29 . A method for the detection or localization in a subject of primary or metastatic pheochromocytoma, neuroblastoma, paraganglioma, neuroendocrine tumor of gastroenteropancreatic tract, medullary thyroid carcinoma, or a disease resulting from myocardial ischemia and cardiomyopathy, the method comprising administering to the subject the radiopharmaceutical composition of  claim 1 , and, performing scintigraphic imaging in order to detect or localize the primary or metastatic pheochromocytoma, neuroblastoma, paraganglioma, neuroendocrine tumor of gastroenteropancreatic tract, medullary thyroid carcinoma, or a disease resulting from myocardial ischemia and cardiomyopathy in the subject. 
     
     
         30 . A method for diagnosing or treating in a subject pheochromocytoma, neuroblastoma, paraganglioma, or neuroendocrine tumor of the gastroenteropancreatic tract, the method comprising administering to the subject the radiopharmaceutical composition of  claim 1 .