Compositions for radiolabeling diethylenetriaminepentaacetic acid (dtpa)-dextran

Abstract

The subject invention relates to the compositions for radiolabeling Diethylenetriaminepentaacetic Acid (DTPA)-dextran with Technetium-99m and for stabilizing the DTPA-dextran Cold Kit. The composition contains Stannous Chloride ions to reduce 99m Tc-pertechnetate, Ascorbic Acid to reduce stannic ions to stannous ions to maintain a reducing environment, α,α-Trehalose to add bulk and to stabilize the lyophilized composition without interfering with the radiochemical yield, and Glycine to transchelate Technetium-99m under highly acidic conditions to facilitate radiolabeling DTPA-dextran with high radiochemical purity. In addition, the invention pertains to methods for making and using the compositions. The reconstitution of the lyophilized composition by 99m Tc-pertechnetate, resulting in radiolabeled 99m Tc-DTPA-dextran in a composition between pH 3 to 4. This invention contains a Diluent vial, which when used will shift the pH to a moderately acidic pH, which would provide less pain on injection and ease-of-use to clinical practioners for adjusting its potency.

1 . A composition for radiolabeling diethylenetriaminepentaacetic Acid (DTPA)-dextran with Technetium-99m, compromising:
 (a) a DTPA-dextran with a concentration of up to 0.50 mg/vial;   (b) a sugar selected from the group of non-reducing disaccharides with a concentration up to 2% (w/v);   (c) a non-sulfhydryl anti-oxidant wherein the concentration is in the range of about 0.5 mg/vial;   (d) a stannous salt wherein the concentration of the dihydrate form of the stannous salt is up to 75 micrograms/vial;   (e) a pH buffer selected from a group of pH buffers in the concentration range of up to about 0.5 mg/vial; and   (f) a water for injection (WFI), wherein the water is degassed and deaerated with an inert gas.   
     
     
         2 . The composition of  claim 1 , wherein the DTPA-dextran contains multiple DTPA groups conjugated to dextran in the molar range of about 2:1 to 12:1. 
     
     
         3 . The composition of  claim 1 , wherein the DTPA-dextran contains dextran in the average molecular weight range of about 5,000 to 20,000 Daltons. 
     
     
         4 . The composition of  claim 1 , wherein the DTPA-dextran is DTPA-mannosyl-dextran containing a molar ratio range of about 2:1 to 12:1 conjugated Mannose groups to DTPA-dextran. 
     
     
         5 . The composition of  claim 1 , wherein the non-reducing disaccharide is α,α-Trehalose Dihydrate. 
     
     
         6 . The composition of  claim 1 , wherein the non-sulfhydryl anti-oxidant is L(+)-Ascorbic Acid Sodium salt. 
     
     
         7 . The composition of  claim 1 , wherein the stannous salt is Stannous Chloride Dihydrate. 
     
     
         8 . The composition of  claim 1 , wherein the pH buffer and transchelator is Glycine. 
     
     
         9 . The composition of  claim 1 , wherein the inert gas used to deaerated WFI is nitrogen. 
     
     
         10 . A method for stabilizing a DTPA-dextran cold kit for long-term storage, compromising the steps of:
 (a) adding an aqueous composition, compromising;
 (i) a sugar selected from the group of non-reducing disaccharides with a concentration up to 2% (w/v); 
 (ii) a pH buffer selected from a group of pH buffers in the concentration range of up to about 0.5 mg/vial; 
    to a vessel containing about 90% of its target volume of degassed and deaerated water for injection;   (b) adding a non-sulfhydryl anti-oxidant wherein the concentration is in the range of about 0.5 mg/vial;   (c) adjusting the solution pH to a target pH of 3.2±0.2 with 6 N hydrochloric acid, while maintaining an inert gas sparge;   (d) adding a stannous salt wherein the concentration of the dihydrate form of the stannous salt is up to 75 micrograms/vial;   (e) adding a DTPA-dextran with a concentration of up to 0.50 mg/vial;   (f) adjusting the solution pH to a target pH of 3.2±0.2 with 6 N hydrochloric acid, while maintaining an inert gas sparge;   (g) adjusting the volume of the formulation to 100% of its target volume with degassed and deaerated water for injection;   (h) filtering the aqueous composition through a 0.22 micron filter and filling the aqueous composition into glass vials with 1.0 mL±10% and placing stoppers in the neck of the vials;   (i) removing the majority of the water content of the product, decreasing the residual moisture to about less than 1% water content by lyophilization in step a;   (j) backfilling the lyophilized product with an inert gas to about 11.5 p.s.i. prior to stoppering the vials in step b   (k) crimping the lyophilized product vials with aluminum seals in step c; and   (l) storing the crimped-sealed lyophilized product vials in step d at either 2° to 8° C., or 25° C.   
     
     
         11 . The method of  claim 10 , wherein the non-reducing disaccharide is α,α-Trehalose Dihydrate. 
     
     
         12 . The method of  claim 10 , wherein the pH buffer and transchelator is Glycine. 
     
     
         13 . The method of  claim 10 , wherein the non-sulfhydryl anti-oxidant is L(+)-Ascorbic Acid Sodium salt. 
     
     
         14 . The method of  claim 10 , wherein the stannous salt is Stannous Chloride Dihydrate. 
     
     
         15 . The method of  claim 10 , wherein the DTPA-dextran contains multiple DTPA groups conjugated to dextran in a molar ratio range of about 2:1 to 12:1. 
     
     
         16 . The method of  claim 10 , wherein the DTPA-dextran contains dextran in the average molecular weight range of about 5,000 to 20,000 Daltons. 
     
     
         17 . The method of  claim 10 , wherein the DTPA-mannosyl-dextran containing a molar ratio range of about 2:1 to 12:1 conjugated mannose groups to DTPA-dextran. 
     
     
         18 . A method for radiolabeling a DTPA-dextran cold kit with a Sodium  99m Tc-Pertechnetate solution and a diluent for use as a diagnostic radiopharmaceutical and for adjusting the final solution pH for patient comfort, compromising the steps of:
 (a) adding an aqueous Sodium Pertechnetate (Tc 99 m) composition, compromising;
 (i) greater than about 100 Curies of Sodium Pertechnetate/mmol DTPA-dextran in a volume of 0.7 mL; 
 (ii) allowing for a Tc 99 m dose range from about 0.3 to 5.0 millicuries Tc 99 m in a 0.2 mL dose in a final volume of 1.0 mL; 
   (b) adding an aqueous buffered saline diluent composition in a volume of 0.3 ml, compromising;
 (i) 0.5% (w/v) Sodium Chloride, USP; 
 (ii) 0.107% Sodium Phosphate Heptahydrate; 
 (iii) 0.036% Potassium Phosphate; 
 (iv) 0.4% Phenol; 
 (v) adding water for injection (wfi) to q.s. to a final volume; and 
 (vi) adding concentrated Sodium Hydroxide or Hydrochloric Acid, as needed to adjust ph to about ph 7.0.