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 NODAGA-peptide of formula (I), ##STR00003## or a salt thereof; an antioxidant; and a bulking agent.

2. The composition of claim 1, further comprising a surfactant.

3. The composition of claim 1, wherein the weight ratio of the antioxidant over the NODAGA-peptide is at least 50.

4. The composition of claim 1, wherein: the antioxidant is selected from ascorbic acid or a salt thereof and methionine; the bulking agent is a disaccharide; 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 NODAGA-peptide is in a salt form and is present in the range of 0.02% to 0.20% by weight relative to the total weight of the composition, the antioxidant is present in the range of 4% to 15% by weight relative to the total weight of the composition: the bulking agent is present in the range of 80% to 96% by weight relative to the total weight of the composition; and/or the surfactant is present in the range of 0.01% to 0.36% by weight relative to the total weight of the composition.

7. (canceled)

8. The composition of claim 6, wherein the antioxidant is ascorbic acid.

9. (canceled)

10. The composition of claim 6, wherein the bulking agent is a disaccharide.

11. (canceled)

12. The composition of claim 6, claim 11, wherein the surfactant is a polysorbate.

13. The composition of claim 5, comprising: NODAGA-peptide acetate salt in the range of 0.02% to 0.20% by weight; ascorbic acid in the range of 4% to 15% by weight; a disaccharide in the range of 80% to 96% by weight; and a polysorbate in the range of 0.10% to 0.36% by weight; wherein the NODAGA-peptide acetate salt, ascorbic acid, disaccharide and polysorbate, taken together, represent 98% of the total weight of the lyophilized composition.

14. The composition of claim 5, further comprising a buffering agent.

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

16. The composition of claim 15, comprising: ascorbic acid; a disaccharide; a polysorbate; and a buffer solution; and wherein the NODAGA-peptide is in a salt form.

17. The composition of claim 15, wherein the NODAGA-peptide is in a salt form and is present at a concentration of 0.02 to 0.12 mg/mL.

18. The composition of claim 1, wherein the composition is a radiolabelled composition.

19. The composition of claim 18, wherein the composition comprises: ascorbic acid; a disaccharide; a polysorbate; and a buffer solution; and the NODAGA-peptide is .sup.68Ga.sup.3+ radiolabeled.

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

21. The kit of claim 20, comprising: a first vial containing the composition, wherein the composition is in a lyophilized form; and a second vial containing a sterile reconstitution solution comprising a buffer solution.

22. A method for imaging a tumor in a mammal, comprising administering the radiolabeled composition of claim 18 to the mammal.

23. The method of claim 18, wherein the tumor is a SSTR2 receptor positive tumor and the method further comprises: tumors within human body, said method comprising: allowing sufficient time for the radiolabeled composition to become associated with one or more SSTR2 receptors; and detecting the radiolabeled composition associated with the one or more SSTR2 receptors by submitting the mammal to external imaging, by radioactive scanning or by magnetic resonance imaging, in order to allow detection and localization of the tumors therein.

Description

FIGURES

[0290] FIG. 1 schematically represents the process for preparing a radiolabeled composition (III) according to the invention. Two options are presented to obtain the liquid composition (II): either from a lyophilized composition (I) or from a lyophilized composition (I′) as defined above. In the first option, a lyophilized composition (I) according to the invention is reconstituted with a buffer solution to provide the liquid composition (II). In the second option, a lyophilized composition (I′) according to the invention is reconstituted with water to provide the liquid composition (II). A radionuclide solution is then added to the thereby obtained liquid composition (II) to provide the radiolabeled composition (III).

[0291] FIG. 2 schematically represents the process for preparing a preferred embodiment of the radiolabeled composition (III) according to the invention. Two options are presented to obtain the liquid composition (II): either from a lyophilized composition (I) or from a lyophilized composition (I′) as defined above. In the first option, a lyophilized composition (I) according to the invention is reconstituted with an acetate buffer to provide the liquid composition (II). In the second option, a lyophilized composition (I′) according to the invention is reconstituted with water to provide the liquid composition (II). A .sup.68Ga.sup.3+ solution is then added to the thereby obtained liquid composition (II) to provide the radiolabeled composition (III).

Experimental Part Example 1: Preparation of a Lyophilized Composition (I)

[0292] 500 g of trehalose and 50 g of ascorbic acid were added in a vessel containing 7 L of water for injection (WFI). After dissolution, 1 g of polysorbate 80 then NODAGA-peptide (INN: satoreotide trizoxetan) acetate salt (mass equivalent to 500 mg of pure NODAGA-peptide) were successively added. The mixture was stirred until complete homogenization and solubilisation of the NODAGA-peptide. Further approximately 3 L of WFI were then added. The solution thus obtained was dispensed in vials (1 mL of solution, i.e. 50 μg of pure NODAGA-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)

[0293] A lyophilized composition (I) prepared in a vial in example 1 was reconstituted with 1M sodium acetate buffer solution (pH 5) to obtain liquid composition (II) with a concentration of NODAGA-peptide of about 50 μg/mL.

Example 3: Preparation of a Radiolabeled Composition (III)

[0294] To the liquid composition (II) prepared according to example 2 were added 5 mL of an eluate from .sup.68Ge/.sup.68Ga generator for radiolabeling to obtain radiolabeled composition (III).

Example 4: Stability Study of Lyophilized Compositions

[0295] Pharmaceutical lyophilized compositions 1 to 10 have been prepared according to the process described in example 1. The amount of the API per vial (i.e. NODAGA-peptide in base form) given in Table 1 below is expressed in μg. The percentage of surfactant is given by weight relative to the total weight of dry material.

[0296] 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 (μg) antioxidant agent surfactant 1 50 ascorbic trehalose — acid 30 mg 5 mg 2 50 methionine trehalose — 5 mg 30 mg 3 100 ascorbic trehalose — acid 30 mg 5 mg 4 50 ascorbic trehalose — acid 50 mg 5 mg 5 50 methionine trehalose — 5 mg 50 mg 6 50 ascorbic trehalose poloxamer 188 acid 50 mg 0.1 mg 5 mg 7 50 ascorbic trehalose polysorbate 80 acid 50 mg 0.1 mg 5 mg 8 50 methionine trehalose poloxamer 188 5 mg 50 mg 0.1 mg 9 50 ascorbic trehalose polysorbate 80 acid 100 mg 0.1 mg 5 mg 10 50 ascorbic trehalose polysorbate 80 acid 100 mg 0.1 mg 8 mg

[0297] The stability data at these different conditions and after 2 weeks (2 W), 1 month (1M), 2 months (2M), 3 months (3M), 6 months (6M), 9 months (9M), 12 months (12M), 18 months (18M) or 24 months (24M) 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 composition 3 T0 2 W 1 M 2 M 3 M T0 2 W 1 M 2 M 3 M T0 Water content (%) 1.5 3.4 3.9 3.9 4.4 0.1 1.9 3.3 2.6 3.0 1.5 API content 49.0 49.6 48.7 48.9 48.8 47.0 48.2 47.1 46.3 45.9 99.9 (μg/vial) Impurities (%) 2.2 1.9 2.1 1.9 2.0 2.8 2.9 3.7 4.2 4.5 2.2 composition 3 composition 4 2 W 1 M 2 M 3 M T0 2 W 1 M 2 M 3 M 6 M Water content (%) 3.4 3.8 4.0 4.1 1.0 2.4 2.7 3.0 3.0 2.5 API content 100.1 100.5 94.5 98.5 48.2 48.9 50.0 48.5 48.5 46.8 (μg/vial) Impurities (%) 1.5 1.6 1.6 1.9 2.5 1.7 1.5 1.8 1.8 2.9 composition 5 composition 7 composition 9 composition 10 T0 2 W 1 M 2 M 3 M T0 2 W 1 M 3 M 6 M T0 2 W 1 M 2 M T0 2 W 1 M 2 M Water content (%) 0.1 1.7 2.0 2.2 2.3 1.1 2.5 2.9 — 2.6 0.5 1.2 — — 0.8 1.4 — — API content 46.1 48.3 49.4 48.6 48.9 57.3* 47.9 48.0 46.6 46.8 46.6 46.3 47.1 45.4 46.0 46.0 46.1 45.4 (μg/vial) Impurities (%) 2.7 1.8 1.8 1.8 2.3 2.3 2.5 2.5 2.7 3.9 2.0 2.3 3.0 2.6 2.2 2.2 3.8 2.9 *calibration curve without surfactant

TABLE-US-00003 TABLE 3 conditions 25° C./60% RH composition 1 composition 2 composition 3 composition 4 composition 5 T0 1 M 2 M T0 1 M 2 M T0 1 M 2 M T0 1 M 2 M 6 M T0 1 M 2 M Water content (%) 1.5 2.9 3.4 0.1 1.6 2.0 1.5 3.1 3.5 1.0 2.1 2.4 2.2 0.1 1.3 1.6 API content 49.0 48.3 48.4 47.0 47.2 46.6 99.9 98.9 94.4 48.2 48.3 48.6 47.7 46.1 47.8 47.3 (μg/vial) Impurities (%) 2.2 2.1 1.8 2.8 2.6 2.7 2.2 1.4 1.2 2.5 1.7 1.4 2.3 2.7 1.8 1.8 composition 6 composition 7 composition 8 composition 9 composition 10 T0 1 M 2 M T0 1 M 2 M 6 M 9 M 12 M T0 1 M 2 M T0 1 M 2 M T0 1 M 2 M Water content (%) 1.1 2.1 — 1.1 2.1 2.4 2.1 — 2.4 0.1 1.2 — 0.5 — — 0.8 — — API content 56.2* 48.6 — 57.3* 48.9 47.3 47.4 49.0 48.6 56.4* 48.3 — 46.6 46.4 — 46.0 45.8 — (μg/vial) Impurities (%) 2.1 1.7 — 2.3 1.6 2.7 2.4 1.8 2.0 2.6 1.9 — 2.0 4.9 — 2.2 6.2 — *calibration curve without surfactant

TABLE-US-00004 TABLE 4 conditions 5° C. composition 1 composition 2 composition 3 composition 4 composition 5 T0 1 M 2 M T0 1 M 2 M T0 1 M 2 M T0 1 M 2 M 6 M T0 1 M 2 M Water content (%) 1.5 1.9 2.1 0.1 0.5 0.7 1.5 2.0 2.1 1.0 1.2 1.4 1.1 0.1 0.4 0.5 API content 49.0 48.0 47.7 47.0 46.9 45.4 99.9 98.5 93.3 48.2 47.7 47.6 47.4 46.1 45.7 46.5 (μg/vial) Impurities (%) 2.2 1.8 1.9 2.8 2.1 2.4 2.2 1.4 1.2 2.5 1.5 1.7 2.4 2.7 1.8 1.6 composition 6 composition 7 composition 8 composition 9 composition 10 T0 1 M 2 M T 0 1 M 2 M 6 M 9 M 12 M 18 M 24 M T0 1 M T0 1 M T0 1 M Water content (%) 1.1 1.2 — 1.1 1.3 1.4 1.0 1.2 1.5 1.8 1.9 0.1 0.3 0.5 — 0.8 — API content 56.2* 47.7 — 57.3* 48.6 48.0 47.4 49.2 49.1 51.0 52.8 56.4* 49.0 46.6 46.4 46.0 46.1 (μg/vial) Impurities (%) 2.1 1.8 — 2.3 1.9 2.3 2.5 1.6 2.0 1.8 1.9 2.6 1.8 2.0 3.8 2.2 4.1 *calibration curve without surfactant