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, wherein said composition comprises: a NODAGA-peptide of formula (I), ##STR00003## or a salt thereof; an antioxidant; and a bulking agent, wherein the bulking agent is a disaccharide.

2. The composition according to claim 1, wherein said composition further comprises a surfactant.

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

4. The composition according to claim 2, wherein: the antioxidant is selected from ascorbic acid or a salt thereof, methionine, gentisic acid or a salt thereof, retinol, cysteine, N-acetyl cysteine, propyl gallate, and any combination thereof, and the surfactant is a polysorbate.

5. The composition according to claim 1, wherein said composition is in a lyophilized form.

6. The composition according to claim 5, wherein the NODAGA-peptide is in a salt form in the range of 0.02% to 0.20% by weight relative to the total weight of the composition;

7. The composition according to claim 5, wherein the antioxidant is present in the range of 4% to 15% by weight relative to the total weight of the composition.

8. (canceled)

9. The composition according to claim 5, wherein the bulking agent is present in the range of 80% to 96% by weight relative to the total weight of the composition.

10. (canceled)

11. The composition according to claim 5, wherein the composition further comprises a surfactant in the range of 0.01% to 0.36% by weight relative to the total weight of the composition.

12. The composition according to claim 11, wherein the surfactant is a polysorbate.

13. The composition according to claim 12, wherein said composition comprises: NODAGA-peptide acetate salt and in the range of 0.02% to 0.20% by weight; ascorbic acid or methionine in the range of 4% and 15% by weight; the disaccharide in the range of 80% to 96% by weight; and the polysorbate in the range of 0.10% to 0.36% by weight; wherein NODAGA-peptide acetate salt, ascorbic acid or methionine, the disaccharide and the polysorbate, taken together, represent 98% of the total weight of the composition.

14. (canceled)

15. The composition according to claim 1, wherein said composition is in a liquid aqueous form.

16. The composition according to claim 15, wherein said composition comprises: ascorbic acid or methionine; the disaccharide; a polysorbate; and a buffer solution; and wherein the NODAGA-peptide is in a salt form.

17. The composition according to 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 according to claim 1, wherein said composition is a radiolabeled composition.

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

20. A kit for the preparation of a radiopharmaceutical composition, said kit comprising a first vial containing the composition according to claim 1.

21. The kit according to claim 20, said kit comprising: the first vial containing a lyophilized composition, and a second vial containing a sterile reconstitution solution comprising a buffer solution.

22. The method of claim 23, the radiolabeled composition according to SSTR2 receptor positive tumor is selected from the group consisting of neuroendocrine tumor (NET) and tumors associated with prostate cancer, breast cancer, lung cancer or lymphoma.

23. A method for imaging a SSTR2 receptor positive tumor within a mammal, said method comprising: administering a detectable quantity of the radiolabeled composition according to claim 18 to the mammal; allowing sufficient time for the radiolabeled composition to become associated with said SSTR2 receptor, and detecting said radiolabeled composition associated with said SSTR2 receptor, by submitting said human to external imaging, by radioactive scanning or by magnetic resonance imaging.

Description

FIGURES

[0283] 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).

[0284] 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)

[0285] 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 g 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)

[0286] 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 g/mL.

Example 3: Preparation of a Radiolabeled Composition (III)

[0287] 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

[0288] 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 g. The percentage of surfactant is given by weight relative to the total weight of dry material.

[0289] 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 (g) antioxidant agent surfactant 1 50 ascorbic trehalose acid 5 mg 30 mg 2 50 methionine trehalose 5 mg 30 mg 3 100 ascorbic trehalose acid 5 mg 30 mg 4 50 ascorbic trehalose acid 5 mg 50 mg 5 50 methionine trehalose 5 mg 50 mg 6 50 ascorbic trehalose poloxamer 188 acid 5 mg 50 mg 0.1 mg 7 50 ascorbic trehalose polysorbate 80 acid 5 mg 50 mg 0.1 mg 8 50 methionine trehalose poloxamer 188 5 mg 50 mg 0.1 mg 9 50 ascorbic trehalose polysorbate 80 acid 5 mg 100 mg 0.1 mg 10 50 ascorbic trehalose polysorbate 80 acid 8 mg 100 mg 0.1 mg

[0290] 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 T0 2 W 1 M 2 M 3 M Water content (%) 1.5 3.4 3.9 3.9 4.4 API content (g/vial) 49.0 49.6 48.7 48.9 48.8 Impurities (%) 2.2 1.9 2.1 1.9 2.0 composition 2 T0 2 W 1 M 2 M 3 M Water content (%) 0.1 1.9 3.3 2.6 3.0 API content (g/vial) 47.0 48.2 47.1 46.3 45.9 Impurities (%) 2.8 2.9 3.7 4.2 4.5 composition 3 T0 2 W 1 M 2 M 3 M Water content (%) 1.5 3.4 3.8 4.0 4.1 API content (g/vial) 99.9 100.1 100.5 94.5 98.5 Impurities (%) 2.2 1.5 1.6 1.6 1.9 composition 4 T0 2 W 1 M 2 M 3 M 6 M Water content (%) 1.0 2.4 2.7 3.0 3.0 2.5 API content (g/vial) 48.2 48.9 50.0 48.5 48.5 46.8 Impurities (%) 2.5 1.7 1.5 1.8 1.8 2.9 composition 5 T0 2 W 1 M 2 M 3 M Water content (%) 0.1 1.7 2.0 2.2 2.3 API content (g/vial) 46.1 48.3 49.4 48.6 48.9 Impurities (%) 2.7 1.8 1.8 1.8 2.3 composition 7 T0 2 W 1 M 3 M 6 M Water content (%) 1.1 2.5 2.9 2.6 API content (g/vial) 57.3* 47.9 48.0 46.6 46.8 Impurities (%) 2.3 2.5 2.5 2.7 3.9 composition 9 T0 2 W 1 M 2 M Water content (%) 0.5 1.2 API content (g/vial) 46.6 46.3 47.1 45.4 Impurities (%) 2.0 2.3 3.0 2.6 composition 10 T0 2 W 1 M 2 M Water content (%) 0.8 1.4 API content (g/vial) 46.0 46.0 46.1 45.4 Impurities (%) 2.2 2.2 3.8 2.9 *calibration curve without surfactant

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

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