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|Title:||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 .sup.99mTc-pertechnetate, Ascorbic Acid to reduce stannic ions to stannous ions to maintain a reducing environment, .alpha.,.alpha.-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 .sup.99mTc-pertechnetate, resulting in radiolabeled .sup.99mTc-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 practitioners for adjusting its potency.|
|Inventor(s):||Magneson; Gerald Ross (Needham, MA), Orahood; Richard Cushman (Delaware, OH)|
|Assignee:||Navidea Biopharmaceuticals, Inc. (Dublin, OH)|
|Filing Date:||May 01, 2012|
|Claims:||1. 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/mL; 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/mL; (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/mL; (e) adding a DTPA-dextran with a concentration of up to 0.50 mg/mL; (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%; (i) removing the majority of the water content of the product, decreasing the residual moisture to about less than 1% water content by lyophilization; (j) backfilling the lyophilized product with an inert gas to about 11.5 p.s.i. prior to stoppering the vials; (k) crimping the lyophilized product vials with aluminum seals; and (l) storing the crimped-sealed lyophilized product vials at either 2.degree. to 8.degree. C. or 25.degree.. |
2. The method of claim 1, wherein the non-reducing disaccharide is .alpha.,.alpha.-Trehalose Dihydrate.
3. The method of claim 1, wherein the pH buffer is Glycine.
4. The method of claim 1, wherein the non-sulfhydryl anti-oxidant is L(+)-Ascorbic Acid Sodium salt.
5. The method of claim 1, wherein the stannous salt is Stannous Chloride Dihydrate.
6. The method of claim 1, wherein the DTPA-dextran contains multiple DTPA groups conjugated to dextran in the molar ratio range of about 2:1 to 12:1.
7. The method of claim 1, wherein the DTPA-dextran contains dextran in the average molecular weight range of about 5,000 to 20,000 Daltons.
8. The method of claim 1, wherein the DTPA-mannosyl-dextran containing a molar ratio range of about 2:1 to 12:1 conjugated mannose groups to DTPA-dextran.