Composition Containing a Somatostatin Analogue for Radiopharmaceutical Use

Abstract

The present invention relates to a somatostatin analogue composition for radiopharmaceutical use, in particular for diagnostic or therapeutic use. More specifically the somatostatin analogue is a receptor-selective somatostatin peptide antagonist.

Claims

1. A receptor-selective somatostatin peptide antagonist composition comprising: a DOTA-peptide of formula (I), ##STR00003## or a salt thereof; an antioxidant; and a bulking agent.

2. The composition of claim 1, further comprising: a buffering agent and a surfactant.

3. The composition of claim 1, wherein the weight ratio of the antioxidant over the DOTA-peptide is at least 20.

4. The composition of claim 1, wherein: the antioxidant ascorbic acid or a salt thereof; the bulking agent arginine or histidine, and the surfactant is a polysorbate.

5. The composition of claim 1, wherein the composition is in a lyophilized form.

6. The composition of claim 5, wherein the DOTA-peptide is in a salt form and is present in the range of 0.10% to 3.00% by weight relative to the total weight of the composition.

7. (canceled)

8. The composition of claim 5, wherein the antioxidant is ascorbic acid and is present in the range of 40% to 70% by weight relative to the total weight of the composition.

9. (canceled)

10. The composition of claim 5, wherein the bulking agent is a basic amino acid and is present in the range of 25% to 55% by weight relative to the total weight of the composition.

11. (canceled)

12. The composition of claim 5, wherein the surfactant is polysorbate 80 and is present in the range of 0.01% to 0.10% by weight relative to the total weight of the composition.

13. The composition of claim 5, comprising: DOTA-peptide acetate salt in the range of 0.10% to 3.00% by weight; ascorbic acid in the range of 40% to 70% by weight; arginine in the range of 25% to 55% by weight; and a polysorbate in the range of 0.01% to 0.10% by weight; wherein the DOTA-peptide acetate salt, ascorbic acid, disaccharide and polysorbate, taken together, represent at least 98% of the total weight of the composition.

14. The composition of claim 1, wherein the composition is in a liquid aqueous form.

15. The composition of claim 14, comprising: ascorbic acid; arginine; a polysorbate; and water for injection; and wherein the DOTA-peptide is in a salt form.

16. The composition of claim 14, wherein the DOTA-peptide is in a salt form and is present at a concentration of 0.1 to 2.0 mg/mL.

17. The composition of claim 1, wherein the composition is a radiolabeled composition.

18. The composition according to claim 17, wherein the composition comprises: ascorbic acid and a salt thereof; arginine; a polysorbate; DTPA; and water for injection; and wherein the DOTA-peptide is .sup.177Lu.sup.3+ radiolabeled.

19. A kit comprising a suitable container containing the composition of claim 1.

20. The kit of claim 19, comprising: a first vial containing the composition, wherein the composition is in a lyophilized form; and a second vial containing a sterile stabilizing solution comprising an antioxidant.

21. The kit of claim 20, wherein the sterile stabilizing solution comprises water for injection, sodium ascorbate, MPA and polysorbate 80.

22. The method of claim 23, wherein the tumor is selected from: neuroendocrine tumors (NETs) and tumors of prostate, breast, lung or lymphoma cancer.

23. A method for treating SSTR2 receptor positive tumors comprising administering to a mammal in need of such treatment an efficient quantity of the composition of claim 17.

Description

FIGURES

[0245] FIG. 1 schematically represents the process for preparing a radiolabeled composition (III) according to the invention. A lyophilized composition (I) according to the invention is reconstituted with water for injection to provide the liquid composition (II). Then, a radionuclide solution is added to the thereby obtained liquid composition (II), followed by the addition of a stabilizing solution, to provide the radiolabeled composition (III).

[0246] FIG. 2 schematically represents the process for preparing a preferred embodiment of the radiolabeled composition (III) according to the invention. A lyophilized composition (I) according to the invention is reconstituted with water for injection to provide the liquid composition (II). Then, a .sup.177Lu solution is added to the thereby obtained liquid composition (II), followed by a stabilizing solution, to provide the radiolabeled composition (III).

EXPERIMENTAL PART

Example 1: Preparation of a Lyophilized Composition (I)

[0247] 71 g of arginine, 100 g of ascorbic acid and 0.1 g of polysorbate 80 were added in a flask containing 900 mL of water for injection (WFI). After dissolution, water for injection was added up to 1 L. 500 mg of pure DOTA-peptide (INN: satoreotide tetraxetan) were weighed and dissolved in 200 mL of the solution previously prepared. The mixture was stirred until complete homogenization and solubilisation of the DOTA-peptide. The solution thus obtained was dispensed in vials (about 10 mg of DOTA-peptide per vial) and lyophilized according to an adequate freeze-drying cycle to get the lyophilized composition (I).

Example 2: Preparation of a Liquid Composition (II)

[0248] A lyophilized composition (I) prepared in a vial in example 1 was reconstituted with 10 mL of water for injection in order to reach a liquid composition (II) with a concentration of DOTA-peptide of about 1 mg/mL. The pH of the solution was between 4.0 and 4.5.

Example 3: Preparation of a Stabilizing Composition

[0249] A solution was prepared by dissolving 61.87 g of sodium ascorbate (equivalent to 55.00 g of ascorbic acid), 0.05 g of DTPA (pentetic acid) and 0.15 g of polysorbate 80 in 500 mL of water for injection. This solution was sterilized by steam sterilization.

Example 4: Preparation of a Radiolabeled Composition (III)

[0250] The liquid composition (II) prepared according to Example 2 was radiolabeled with a diluted lutetium-177 chloride aqueous solution in hydrochloric acid.

[0251] Radiolabeling was achieved by preheating the lutetium-177 chloride solution for at least 15 min at 80° C., followed by the addition of the liquid composition (II) of example 2 and immediate heating for 10 min at 80° C. Radiolabeling was performed at a concentration of 0.25 mg/mL of DOTA-peptide.

[0252] The mixture was then diluted with the stabilizing composition of example 3 to yield a stock solution of .sup.177Lu-DOTA-peptide at a concentration of about 1 GBq/mL, which can be divided into individual unit doses for patient administration.

Example 5: Stability Study of the Lyophilized Compositions

[0253] Pharmaceutical lyophilized compositions 1 to 6 according to the invention have been prepared according to the process described in example 1, using a total amount of 4 mL of WFI as solvent (then removed via lyophilization) per vial. The amount of the API per vial (i.e. DOTA-peptide in base form) given in Table 1 below is expressed in mg. The percentage of surfactant is given by weight relative to the total weight of dry material.

[0254] The stability of these lyophilized compositions (I) has been studied under the different conditions: 40° C./75% RH (RH: relative humidity), 25° C./60% RH, and 5° C. A stability study measures the evolution over time of the amount of API and the evolution over time of the amount of impurities. When the initial amount of API is maintained over time and the amount of impurities does not significantly increase, a pharmaceutical composition is said stable.

TABLE-US-00001 TABLE 1 Lyophilized API bulking compositions (mg) antioxidant agent surfactant 1 10 ascorbic acid arginine — 400 mg 284 mg 2 10 ascorbic acid arginine polysorbate 80 400 mg 284 mg + 0.4 mg trehalose 100 mg 3 10 ascorbic acid arginine polysorbate 80 400 mg 284 mg + 0.4 mg trehalose 200 mg 4 10 ascorbic acid arginine polysorbate 80 400 mg 284 mg 0.4 mg 5 10 ascorbic acid dextran 40 polysorbate 80 121 mg + 284 mg 0.4 mg sodium ascorbate 314 mg 6 10 ascorbic acid arginine polysorbate 80 121 mg + 284 mg + 0.4 mg sodium trehalose ascorbate 100 mg 314 mg 7 10 ascorbic acid arginine — 800 mg 458 mg 8 10 ascorbic acid dextran 40 — 152 mg + 400 mg sodium ascorbate 391 mg

[0255] The stability data at these different conditions and after 2 weeks (2W), 1 month (1M), 2 months (2M), 3 months (3M), 5 months (5M), 6 months (6M) or 12 months (12M) are summarized in Tables 2-4 below. The percentage of impurities is the sum of the percentages of all impurities detected by UPLC (Ultra Performance Liquid Chromatography) and with a percentage over 0.1% (limit of detection). The water content was determined using a coulometer.

TABLE-US-00002 TABLE 2 conditions 40° C./75% RH composition 1 composition 2 T0 2 W 1 M 2 M 3 M T0 2 W 1 M 2 M 3 M Water content (%) 0.99 — — — — 1.00 1.04 1.11 1.22 — API content 9.97 10.11 9.99 10.05 10.33 10.18 10.22 10.26 10.29 — (mg/vial) Impurities (%) 1.24 1.15 1.15 1.13 1.24 1.22 1.20 1.15 1.13 — composition 3 composition 4 T0 2 W 1 M 2 M 3 M T0 2 W 1 M 2 M 3 M Water content (%) 1.35 1.09 1.15 1.09 — 0.87 0.93 1.08 1.08 1.05 API content 10.18 10.30 10.23 10.39 — 10.26 10.52 10.47 10.51 10.77 (mg/vial) Impurities (%) 1.25 1.16 1.15 1.13 — 1.36 1.20 1.16 1.13 1.21 composition 5 composition 6 T0 2 W 1 M 2 M 3 M T0 2 W 1 M 2 M 3 M Water content (%) 2.63 2.45 2.48 2.57 — 2.42 2.34 2.62 2.34 — API content 10.21 10.45 10.16 10.29 — 9.84 10.22 10.43 10.18 — (mg/vial) Impurities (%) 1.44 1.25 1.22 1.64 — 1.45 1.30 1.23 1.63 — composition 7 composition 8 T0 2 W 1 M 2 M 3 M T0 2 W 1 M 2 M 3 M Water content (%) 1.8 — — — 3.9 5.2 — — — — API content 9.4 — 8.8 9.0 8.6 9.1 — 9.6 9.3 — (mg/vial) Impurities (%) 0.9 — 1.2 1.8 2.2 0.6 — 1.2 2.3 —

TABLE-US-00003 TABLE 3 conditions 25° C./60% RH composition 1 composition 2 composition 3 compositor 4 T0 1 M 2 M 3 M 6 M T0 1 M 2 M 3 M T0 1 M 2 M 3 M T0 1 M 2 M 3 M 6 M Water content (%) 0.99 — — — 1.02 1.00 2.42 0.94 — 1.35 1.07 1.13 — 0.87 0.90 0.92 0.90 0.98 API content 9.97 — 9.96 10.40 10.26 10.18 9.84 10.31 — 10.18 10.23 10.47 — 10.26 10.29 10.50 10.82 10.78 (mg/vial) Impurities (%) 1.24 — 1.11 1.19 1.25 1.22 1.45 1.10 — 1.25 1.14 1.10 — 1.36 1.18 1.11 1.17 1.07 composition 5 composition 6 composition 7 composition 8 T0 1 M 2 M 3 M T0 1 M 2 M 3 M T0 1 M 2 M 3 M 5 M T0 1 M 2 M 3 M Water content (%) 2.63 2.65 2.12 — 2.42 2.39 2.29 — 1.8 — — 4.0 2.3 5.2 — — — API content 10.21 — 10.23 — 9.84 — 10.19 — 9.4 8.9 9.1 8.8 9.2 9.1 9.7 9.4 — (mg/vial) Impurities (%) 1.44 — 1.13 — 1.45 — 1.13 — 0.9 0.7 0.9 1.0 1.2 0.6 0.9 1.0 —

TABLE-US-00004 TABLE 4 conditions 5° C. composition 1 composition 2 composition 3 composition 4 T0 1 M 3 M 6 M T0 1 M 3 M T0 1 M 3 M T0 1 M 3 M 6 M 12 M Water content (%) 0.99 — — 0.94 1.00 0.84 — 1.35 1.09 — 0.87 0.82 0.90 0.85 0.75 API content 9.97 — 10.34 10.33 10.18 — — 10.18 — — 10.26 — 10.82 10.82 10.52 (mg/vial) Impurities (%) 1.24 — 1.23 1.08 1.22 — — 1.25 — — 1.36 — 1.33 1.26 1.06 composition 5 composition 6 composition 7 composition 8 T0 1 M 3 M T0 1 M 3 M T0 1 M 3 M 5 M T0 1 M 3 M Water content (%) 2.63 2.51 — 2.42 2.56 — 1.8 3.2 1.7 1.7 5.2 4.7 5.1 API content 10.21 — — 9.84 — — 9.4 8.9 8.8 9.5 9.1 9.8 9.5 (mg/vial) Impurities (%) 1.44 — — 1.45 — — 0.9 0.7 1.0 1.1 0.6 0.9 0.9

Example 6: Stability Study of the Radiolabeled Composition

[0256] A pharmaceutical radiolabeled composition 7 according to the invention has been prepared according to the process described in example 4.

[0257] After dilution with the stabilizing solution, the radiolabeled composition 7 contained 20 μg/mL of DOTA-peptide (0.6 GBq/mL), 100 mg/mL of ascorbic acid, 0.6 mg/mL of arginine, 0.03% by weight of polysorbate 80, and 0.05 mg/mL of DTPA. The percentage of surfactant is given by weight relative to the total weight of dry material.

[0258] The stability of the radiolabeled composition 7 has been studied at room temperature. The total mass content of impurities and the mass contents of the 2 main impurities (A and B), at the end of preparation (TO), after 1 day (1D), 2 days (2D), 4 days (4D), and 7 days (7D) were obtained by HPLC and are summarized in Table 5 below:

TABLE-US-00005 TABLE 5 T0 1 D 2 D 4 D 7 D Total impurity (%) 2.0 2.5 3.5 4.0 6.1 Impurity A (%) < < 0.3 0.3 0.6 Impurity B (%) < 0.5 1.1 1.5 2.7 <: not detected or % below the limit of qualification