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 99mTc-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 99mTc-pertechnetate, resulting in radiolabeled 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 practioners for adjusting its potency.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]NoneSTATEMENT REGARDING FEDERALLY SPONSORED RESEARCH[0002]Not applicable.BACKGROUND[0003]The present disclosure relates to the field of oncology and more particularly to the radiolabeling of a cancer detection agent.[0004]Sentinel node biopsy is rapidly gaining acceptance as a common practice for melanoma and breast cancer diagnosis (Vera, D. R. et al. (2001) J. Nucl. Med. 42, 951-959). This technique has not been standardized; it typically involves the use of a 99mTc-colloid and a blue dye. The radioisotope, 99mTechnetium, that is used in the colloid imaging agent and in the current invention, has several desirable properties: its ready availability, relatively low cost, excellent imaging quality, and its short half-life of 6 hours. This radiotracer is employed preoperatively to ascertain the location of the sentinel node and, then, it is used intraoperatively to pinpoint the dissection of the sentinel node(s). The blue dye, which is cle...

AI Technical Summary

Benefits of technology

[0007]The present disclosure provides a composition containing a dextran conjugated with a bifunctional chelating agent, such as, DTPA, with ease of use as an “instant” kit involving a single lyophilized vial and a liquid diluent vial, having high radiochemical purity upon radiolabeling. The present disclosure also provides long-term storage stability, as well as sufficient reconstituted stability to facilitate its pharmaceutical or clinical use for ease of manipulation and administration as a diagnostic imaging agent.

[0009]The high radiochemical purity of 99mTc-DTPA-dextran was achieved by decreasing the pH to between about 2 and 4, screening for non-competing constituents and identifying the ideal transchelator, Glycine (which also serves as a pH buffer), and utilizing the following facts: (1) the distribution of competing ligands for 99mTc is determined by association rate constants, and (2) the dissociation rate constants for 99mTc from its DTPA-dextran complex is very slow and pH-dependent. Hence, the high efficiency of radiolabeling DTPA-dextran is enhanced by the transient binding to Glycine under highly acidic conditions, Glycine transferring the radioisotope to DTPA-dextran that more avidly binds it and the retention of the Technetium-99m (due to its slow dissociation rate constant) after the pH of this “instant” kit is shifted to mildly acidic conditions by its diluent.

[0010]The present disclosure further provides a phosphate buffered saline diluent, enabling patient comfort by shifting pH from harsh acidic conditions (i.e., pH between about 3 and 4), which would cause pain on injection, to moderately acidic conditions (i.e., pH>˜5), which would be well tolerated (M. Stranz and E. S. Kastango (2002) Int. J. Pharm. Compound. 6(3), 216-220).

[0011]The present disclosure further provides a reducing agent, such as, for example, L-ascorbic acid, which further stabilizes a radiolabeled DTPA-dextran preparation containing excess stannous or stannic ions, preventing the formation of Sn-colloids or other radiochemical impurities, such as, Sn4+. The present disclosure yet prevents the oxidative degradation of the drug substance and its constituents and the autoradiolysis of the radiolabeled drug product by containing L-ascorbic acid in the formulation.

[0012]Furthermore, the present disclosure further provides a stable and esthetically pleasing environment for the DTPA-dextran in an amorphous disaccharide lyophilization cake, allowing for quick reconstitution with Sodium 99mTc-pertechnetate and addition with a buffered saline diluent to produce a clear, non-particulate liquid for ease of use. The present disclosure also provides an inert gaseous headspace by backfilling the lyophilized vials with pharmaceutical-grade nitrogen gas, further stabilizing the stannous ions to provide an excess capacity over the storage lifetime of this invention for reducing Sodium 99mTc-pertechnetate (or, 99mTcO4−).

[0013]The present method, then, is an improved method for generating high radiochemical purity 99mTc(III) (and possibly, 99mTc(IV)) complexes of DTPA-dextran with a single, lyophilized vial that is further reconstituted with pH-buffered Diluent to shift final solution pH, resulting in a solution that is stable for at least 6 hours and that facilitates patient comfort (Russell, C. D. (1980) J. Nucl. Med. 21, 354-360; Russell, C. D. and Speiser, A. G. (1982) Int. J. Appl. Radiat. Isot. 33, 903-906). The formulation of the lyophilized cold kit for DTPA-dextran is an “instant” kit, stabilizing the stannous chloride necessary to reduce Sodium 99mTc-pertechnetate in a solid white lyophilized cake under a nitrogen environment, which has long-term storage stability. This kit generates high radiochemical purity by the Sn2+ reduction of 99mTc-pertechnetate under highly acidic conditions, while maintaining the 99mTechnetium-DTPA-dextran complex in greater than 90% radiochemical yield following dilution with a phosphate-buffered saline solution to shift the reconstituted solution pH toward neutrality.

Problems solved by technology

(1989) J. Nucl. Med. 30, 1235-1239), the heptadentate DTPA binds with decreased thermodynamic stability, which makes it more susceptible to competition for binding 99mTc ions, possibly resulting in decreased radiochemical purity.

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