Stable, concentrated radionuclide complex solutions

Abstract

The present invention relates to radionuclide complex solutions of high concentration and of high chemical stability, that allows their use as drug product for diagnostic and/or therapeutic purposes. The stability of the drug product is achieved by at least one stabilizer against radiolytic degradation. The use of two stabilizers introduced during the manufacturing process at different stages was found to be of particular advantage.

1 . A pharmaceutical aqueous solution comprising:
 (a) a complex formed by
 (ai) the radionuclide  177 Lu (Lutetium-177), and 
 (aii) a somatostatin receptor binding peptide linked to the chelating agent DOTA; and 
   (b) at least two different stabilizers against radiolytic degradation;   wherein
 said radionuclide is present in a concentration that it provides a volumetric radioactivity of from 250 to 500 MBq/mL; and 
 said stabilizers are present in a total concentration of from 0.2 to 20.0 mg/mL. 
   
     
     
         2 . The pharmaceutical aqueous solution according to  claim 1 ,
 wherein said component (b) comprises the stabilizers:   (bi) gentisic acid or a salt thereof; and   (bii) ascorbic acid or a salt thereof.   
     
     
         3 . The pharmaceutical aqueous solution according to  claim 2 ,
 wherein   (bi) gentisic acid is present in a concentration of from 0.5 to 2 mg/mL, preferably from 0.5 to 1 mg/mL; and   (bii) ascorbic acid is present in a concentration of from 2.0 to 5.0 mg/mL.   
     
     
         4 . The pharmaceutical aqueous solution according to  claim 3 , further comprising:
 (c) diethylentriaminepentaacetic acid (DTPA) or a salt thereof in a concentration of from 0.01 to 0.10 mg/mL.   
     
     
         5 . The pharmaceutical aqueous solution according to  claim 3 , further comprising:
 (d) an acetate buffer composed of:   (di) acetic acid in a concentration of from 0.3 to 0.7 mg/mL; and   (dii) sodium acetate in a concentration from 0.4 to 0.9 mg/mL;   preferably said acetate buffer provides for a pH of from 4.5 to 6.0, preferably from 5.0 to 5.5.   
     
     
         6 . The pharmaceutical aqueous solution according to  claim 1 , wherein at least one of the stabilizers is present during the complex formation of components (ai) and (aii) and at least one of the stabilizers is added after the complex formation of components (ai) and (aii). 
     
     
         7 . The pharmaceutical aqueous solution according to  claim 1 , wherein at least gentisic acid is present during the complex formation of components (ai) and (aii) and at least ascorbic acid is added after the complex formation of components (ai) and (aii). 
     
     
         8 . The pharmaceutical aqueous solution according to  claim 1 , wherein the only stabilizer present during the complex formation of components (ai) and (aii) is gentisic acid and the only stabilizer added after the complex formation of components (ai) and (aii) is ascorbic acid. 
     
     
         9 . The pharmaceutical aqueous solution according to  claim 6 , wherein that/those stabilizer/stabilizers which is/are present during the complex formation of components (ai) and (aii) is/are present during the complex formulation in a total concentration of from 15 to 50 mg/mL, preferably from 20 to 40 mg/m L. 
     
     
         10 . The pharmaceutical aqueous solution according to  claim 9  wherein the only stabilizer present during the complex formation of components (ai) and (aii) is gentisic acid and is present during the complex formation in a concentration of from 20 to 40 mg/mL, preferably from 25 to 35 mg/mL. 
     
     
         11 . The pharmaceutical aqueous solution according to  claim 1 , which has a shelf life of at least 72 h when stored at ≤25° C., in particular at least at least 72 h when stored at 25° C. 
     
     
         12 . The pharmaceutical aqueous solution according to  claim 1 , for which the radiochemical purity (determined by HPLC) is maintained at ≥95% for at least 72 h when stored at 25° C. 
     
     
         13 . The pharmaceutical aqueous solution according to  claim 1 , wherein said solution is produced at commercial manufacturing scale, in particular is produced at a batch size of at least 20 GBq, at least 50 GBq, at least 70 GBq. 
     
     
         14 . The pharmaceutical aqueous solution according to  claim 1 , which is ready-to-use. 
     
     
         15 . A process for manufacturing the pharmaceutical aqueous solution as defined in any one of the preceding claims, comprising the process steps:
 (1) Forming a complex of the radionuclide  177 Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA by
 (1.1) preparing an aqueous solution comprising the radionuclide; 
 (1.2) preparing an aqueous solution comprising the a somatostatin receptor binding peptide linked to the chelating agent, and at least one stabilizer against radiolytic degradation; and 
 (1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; 
   (2) Diluting the complex solution obtained by step (1) by
 (2.1) preparing an aqueous dilution solution optionally comprising at least one stabilizer against radiolytic degradation; and 
 (2.2.) mixing the complex solution obtained by step (1) with the dilution solution obtained by the step (2.1) to obtain the final solution; 
   wherein if the solution prepared under (1.2) comprises only one stabilizer, then the solution prepared under (2.1) comprise at least one stabilizer.   
     
     
         16 . The process according to  claim 15  wherein the solution prepared in step (1.2) comprises at least one stabilizer and the solution prepared in step (2.1) comprises at least one stabilizer. 
     
     
         17 . The process according to  claim 15  wherein the solution prepared in step (1.2) comprises at least the stabilizer gentisic acid and the solution prepared in step (2.1) comprises at least the stabilizer ascorbic acid. 
     
     
         18 - 28 . (canceled) 
     
     
         29 . The pharmaceutical aqueous solution obtained by the process as defined by  claim 15 . 
     
     
         30 . A pharmaceutical aqueous solution comprising:
 (a) a complex formed by
 (ai) the radionuclide  177 Lu (Lutetium-177), and 
 (aii) a somatostatin receptor binding peptide linked to the chelating agent DOTA; and 
   (b) at least two different stabilizers against radiolytic degradation comprising
 (bi) a first stabilizer; and 
 (bii) a second stabilizer; 
   wherein
 said radionuclide is present in a concentration that it provides a volumetric radioactivity of from 250 to 500 MBq/mL; and 
 the first stabilizer is present in a concentration of from 0.5 to 2 mg/mL and the concentration ratio between the first and second stabilizers is between 1:3 to 1:7; and 
 the pharmaceutical aqueous solution has less than 2% ethanol. 
   
     
     
         31 . The pharmaceutical aqueous solution of  claim 30 , wherein the radiochemical purity (determined by HPLC) of the solution is maintained at 95% for at least 72 h when stored at about 25° C.