COMPOSITIONS FOR RADIOLABELING DIETHYLENETRIAMINEPENTAACETIC ACID (DTPA)-DEXTRAN
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 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 in to 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 the 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 patent comfort, compromising the steps of:
(a) adding an aqueous Sodium Pertechnetate (Tc 99m ) 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 99m dose range from about 0.3 to 5.0 millicuries Tc 99m 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.