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  or  4 , 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 any one of the  claims 1  to  5  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 any one of the  claims 1  to  5  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 any one of the  claims 1  to  5  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 any one of the  claims 6  to  8  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/mL. 
     
     
         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 any one of the preceding claims, 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 any one of the preceding claims, 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 any one of the preceding claims, 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 any one of the preceding claims, 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 . The process according to  claim 15  wherein the solution prepared in step (1.2) comprises only one stabilizer which is gentisic acid and the solution prepared in step (2.1) comprises only one stabilizer which is ascorbic acid. 
     
     
         19 . The process according to any one of  claims 15  to  18  wherein the solution prepared in step (1.2) comprises stabilizer/stabilizers in a total concentration of from 15 to 50 mg/mL, preferably from 20 to 40 mg/mL. 
     
     
         20 . The process according to any one of  claims 15  to  18  wherein the solution prepared in step (1.2) comprises only one stabilizer which is gentisic acid in a concentration of from 20 to 40 mg/mL, preferably from 25 to 35 mg/mL. 
     
     
         21 . The process according any one of  claims 15  to  20 , wherein the solution of step (1.2) further comprises a buffer, preferably an acetate buffer. 
     
     
         22 . The process according to any one of  claims 15  to  21 , wherein in step (1.3) the resulting mixture is heated to a temperature of from 70 to 99° C., preferably from 90 to 98° C., for from 2 to 59 min, preferably from 10 to 15 min. 
     
     
         23 . The process according to any one of  claims 15  to  22 , wherein the solution of step (2.1) further comprises diethylentriaminepentaacetic acid (DTPA) or a salt thereof. 
     
     
         24 . The process according to any one of  claims 15  to  23 , further comprising the process steps:
 (3) Filtering the solution obtained by step (2) through 0.2 μm: 
 (4) Dispensing the filtered solution obtained by step (3) into dose unit containers in a volume required to deliver the radioactive dose of from 5.0 to 10 MBq, preferably from 7.0 to 8.0 MBq, more preferably from 7.3 to 7.7 MBq, even more preferably from 7.4-7.5 MBq, preferably said volume is from 10 to 50 mL, more preferably from 15 to 30 mL, even more preferably from 20 to 25 mL. 
 
     
     
         25 . The process according to any one of  claims 15  to  24 , wherein the solution of step (1.1) comprises LuCl 3  and HCl. 
     
     
         26 . The process according to any one of  claims 15  to  25 , wherein the solution of step (1.2) comprises  177 Lu-DOTA-TATE or  177 Lu-DOTA-TOC, gentisic acid, acetic acid, and sodium acetate. 
     
     
         27 . The process according to any one of  claims 15  to  26 , wherein the solution of step (2.1) comprises DTPA, and ascorbic acid. 
     
     
         28 . The process according to any one of  claims 24  to  27 , wherein the dose unit containers in step (4) are stoppered vials, enclosed within a lead container. 
     
     
         29 . The pharmaceutical aqueous solution obtained by the process as defined by any one of  claims 15  to  28 .