Preparations of meta-iodobenzylguanidine and precursors thereof

Abstract

The present disclosure provides purified forms of iobenguane and preparations of a precursor to iobenguane, such as a polymer, the polymer comprising a monomer of formula (I) or a pharmaceutically acceptable salt thereof, the preparation comprising leachable tin at a level of 0 ppm to 850 ppm.

1 . A preparation comprising a polymer, the polymer comprising a monomer of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein leachable tin is present in the preparation at a level within a range of about 0 ppm to about 150 ppm. 
       
     
     
         2 . The preparation of  claim 1 , wherein the pharmaceutically acceptable salt is the HOAc salt. 
     
     
         3 . The preparation of  claim 1 , which preparation is enclosed in a container under inert gas. 
     
     
         4 . The preparation of  claim 3 , wherein the inert gas is nitrogen. 
     
     
         5 . The preparation of  claim 1 , wherein the level of leachable tin is within a range of about 0 ppm to about 120 ppm. 
     
     
         6 . The preparation of  claim 1 , wherein the level of leachable tin is within a range of about 0 ppm to about 50 ppm. 
     
     
         7 . The preparation of  claim 1 , wherein the polymer comprising monomer of formula (I), or the pharmaceutically acceptable salt thereof, makes up at least 98% of the preparation. 
     
     
         8 . The preparation of  claim 1 , the preparation comprising less than 1.5 wt % water relative to the wt % of the preparation. 
     
     
         9 . The preparation of  claim 1 , the preparation comprising less than 1.0 wt % water relative to the wt % of the preparation. 
     
     
         10 . The preparation of  claim 1 , the preparation comprising less than 0.5 wt % organic solvent relative to the wt % of the preparation. 
     
     
         11 . The preparation of  claim 1 , the polymer comprising less than about 0.5 wt % of a monomer of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The preparation of  claim 1 , the polymer comprising less than about 0.5 wt % of a monomer of formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . A kit comprising a preparation, the preparation comprising a polymer comprising a monomer of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein leachable tin is present in the preparation at a level within a range of about 0 ppm to about 150 ppm, and the kit further comprising a container that stores the polymer comprising monomer of formula (I) under inert gas. 
       
     
     
         14 . The kit of  claim 13 , comprising any one of the preparations of  claims 2 - 12 . 
     
     
         15 . The kit of  claim 13 , wherein the purified polymer comprising monomer of formula (I), or salt thereof, is least 98 wt % pure, for at least six months at −20° C. 
     
     
         16 . The kit of  claim 13 , wherein the kit maintains leachable tin content at a level of less than 150 ppm for at least six months at −20° C. 
     
     
         17 . The kit of  claim 13 , wherein the kit maintains leachable tin content at a level of less than 20 ppm for at least nine months at −20° C. 
     
     
         18 . The kit of  claim 13 , comprising less than 1.5 wt % water relative to the wt % of the preparation. 
     
     
         19 . The kit of  claim 13 , comprising less than 1.0 wt % water relative to the wt % of the preparation. 
     
     
         20 . A pharmaceutical composition comprising:
 (a) a compound of formula (VI):   
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein R 1  is a radioisotopic label, and 
         the compound of formula (VI) is formed by contacting a radioisotope of a halogen ion with a preparation of a polymer comprising monomer of formula (I): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm; and 
         (b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
       
     
     
         21 . The pharmaceutical composition of  claim 20 , comprising the preparation of  claim 2 . 
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein the radioisotope of a halogen ion is fluoride, bromide, iodide or astatine. 
     
     
         23 . The pharmaceutical composition of  claim 20 , wherein the radioisotope of a halogen ion is  123 I,  124 I,  125 I or  131 I. 
     
     
         24 . The pharmaceutical composition of  claim 20 , wherein the radioisotope of a halogen ion is  211 At. 
     
     
         25 . A pharmaceutical composition comprising:
 (a) meta-iodobenzylguanidine (MIBG):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein MIBG is formed by contacting an iodide salt with a preparation of a polymer comprising monomer of formula (I): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm; and 
         (b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
       
     
     
         26 . The pharmaceutical composition of  claim 25 , comprising the preparation of  claim 2 . 
     
     
         27 . The pharmaceutical composition of  claim 25 , wherein not more than about 0.5 wt % meta-iodobenzylamine (MIBA): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, is present in the composition. 
       
     
     
         28 . The pharmaceutical composition of  claim 25 , wherein not more than about 0.5 wt % meta-iodobenzylbiguanidine (MIBBG): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, is present in the composition. 
       
     
     
         29 . The pharmaceutical composition of  claim 25 , wherein not more than about 0.5 wt % meta-hydroxybenzylguanidine (MHBG): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, is present in the composition. 
       
     
     
         30 . The pharmaceutical composition of  claim 25 , wherein not more than about 0.5 wt % meta-iodobenzylamine (MIBA), meta-iodobenzylbiguanidine (MIBBG), and/or meta-hydroxybenzylguanidine (MHBG): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts of any thereof, is present in the composition. 
       
     
     
         31 . A pharmaceutical composition comprising:
 a compound of formula (VI):   
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle; 
         wherein R 1  is a radioisotopic label; 
         the pharmaceutical composition comprising leachable tin at a level of 0 ppm to 150 ppm. 
       
     
     
         32 . A pharmaceutical composition comprising:
 meta-iodobenzylguanidine (MIBG):   
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle; 
         the pharmaceutical composition comprising leachable tin at a level of 0 ppm to 150 ppm. 
       
     
     
         33 . A method for preparing a purified composition of a polymer comprising monomer of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the method comprising the steps of: 
         solvent-treating a preparation comprising the polymer or pharmaceutically acceptable salt thereof, by contacting the preparation with a solvent, and then removing substantially all of the solvent so that a solvent-depleted material comprising the polymer, or pharmaceutically acceptable salt thereof, is generated; and 
         subjecting the solvent-depleted material to vacuum, and to a temperature within a range of about 30° C. to about 50° C., 
         the subjecting being performed under conditions and for a time sufficient so that not more than about 150 ppm of leachable tin is present and, therefore, a purified composition of the polymer, or pharmaceutically acceptable salt thereof, has been produced. 
       
     
     
         34 . The method of  claim 33 , wherein the solvent is or comprises an alcohol. 
     
     
         35 . The method of  claim 34 , wherein the alcohol is or comprises ethanol. 
     
     
         36 . The method of  claim 33 , wherein the step of solvent-treating the preparation comprises first and second solvent-treating steps, performed with first and second solvents, wherein the first solvent is an aqueous alcohol and the second solvent is an anhydrous alcohol. 
     
     
         37 . The method of  claim 36 , wherein the first solvent is aqueous alcohol and the second solvent is anhydrous ethanol. 
     
     
         38 . The method of  claim 33 , the purified composition comprising less than 1.5 wt % water relative to the wt % of the composition. 
     
     
         39 . The method of  claim 33 , the purified composition comprising less than 1.0 wt % water relative to the wt % of the composition. 
     
     
         40 . The method of  claim 33 , further comprising a step of: storing the purified composition under an inert gas. 
     
     
         41 . A method for preparing meta-iodobenzylguanidine (MIBG): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the method comprising steps of: 
         contacting an iodide salt with a preparation comprising a polymer comprising monomer of formula (I): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the preparation being substantially free of leachable tin such that leachable tin is present in the preparation at a level below 150 ppm. 
       
     
     
         42 . The method of  claim 41 , wherein the step of contacting comprises contacting with a preparation as set forth in  claim 2 . 
     
     
         43 . The method of  claim 41 , wherein the iodide salt is sodium 1-131 iodide. 
     
     
         44 . A method comprising administering to a subject a pharmaceutical composition comprising:
 (a) meta-iodobenzylguanidine (MIBG):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein MIBG is formed by contacting an iodide salt with a preparation of a polymer comprising monomer of formula (I): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm; 
         (b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
       
     
     
         45 . The method of  claim 44 , wherein the pharmaceutical composition comprises leachable tin at a level of 0 ppm to 150 ppm upon administration.