Reconstitutable teverelix-TFA composition

Abstract

The present invention relates to a reconstitutable teverelix-TFA composition having a predefined molar ratio of teverelix to trifluoroacetate which is below the molar ratio required for microcrystal formation. Said composition remains stable during storage e.g. at a temperature around 2-8° C. Upon reconstitution a fixed amount of trifluoroacetate can be added to said composition thereby effectively and simply achieving an exact and desired molar ratio in order to obtain a fluid, milky microcrystalline aqueous teverelix-TFA suspension.

Claims

1. A stable reconstitutable teverelix-TFA composition having a molar ratio of teverelix (Ac-D-Nal-D-pClPhe-D-Pal-Ser-Tyr-D-Hci-Leu-Lys(iPr)-Pro-D-Ala-NH2) to trifluoroacetate below the molar ratio required for microcrystal formation, wherein the composition comprises between 1.3 mol trifluoroacetate and 1.6 mol trifluoroacetate per mol teverelix, wherein the reconstitutable composition is a powder, wherein water is present in the reconstitutable teverelix-TFA composition in an amount between 0.3% and 5% by weight based on the total weight of the reconstitutable teverelix-TFA composition, and wherein the composition forms a gel without any insoluble teverelix in the form of microcrystals.

2. The reconstitutable composition according to claim 1, wherein water is present in the reconstitutable teverelix-TFA composition in an amount between 1% by weight and 2% by weight.

3. The reconstitutable composition according to claim 1, wherein the powder of the reconstitutable composition is obtained by lyophilization or spray-drying and/or a cake obtained by lyophilization.

4. A method of preparing the reconstitutable teverelix-TFA composition according to claim 1, wherein said method comprises mixing teverelix and trifluoroacetate at a molar ratio below the molar ratio required for microcrystal formation thereby providing an aqueous teverelix-TFA solution, wherein the composition comprises between 1.3 mol trifluoroacetate and 1.6 mol trifluoroacetate per mol teverelix, drying the aqueous teverelix-TFA solution, and wherein the aqueous teverelix-TFA solution is dried to an extent such that the provided reconstitutable teverelix-TFA composition comprises water in an amount between 0.3% and 5% by weight based on the total weight of the reconstitutable teverelix-TFA composition.

5. The method according to claim 4, wherein the molar ratio of teverelix to trifluoroacetate (TFA) is above 1:1.3 and below 1:1.6 in the aqueous teverelix-TFA solution such that for each mole teverelix in the composition the composition comprises above 1.3 mol trifluoroacetate and below 1.6 mol trifluoroacetate.

6. The method according to claim 4, wherein said method comprises the step of analysing the molar ratio in the aqueous teverelix-TFA solution prior to drying, and optionally adjusting the molar ratio of teverelix to trifluoroacetate (TFA) to a specific predefined molar ratio such that the composition comprises between 1.3 mol TFA and 1.6 mol TFA per mol teverelix, before said solution is dried.

7. A method of reconstituting the reconstitutable teverelix-TFA composition according to claim 4, wherein said method comprises adding an aqueous reconstitution solution to the reconstitutable teverelix-TFA composition and adjusting the molar ratio of teverelix to trifluoroacetate by adding trifluoroacetate for each teverelix in the composition, wherein the composition comprises at least 1.6 mol TFA.

8. The method according to claim 7, wherein the aqueous reconstitution solution comprises trifluoroacetate in an amount sufficient to provide a molar ratio of teverelix to trifluoroacetate of at least 1:1.6.

9. A package filled with the reconstitutable teverelix-TFA composition according to claim 1.

10. The package according to claim 9, wherein the package is a syringe suitable for providing a subcutaneous and/or intramuscularly injection.

11. A kit comprising a first package as defined in claim 9, and a second package filled with a aqueous reconstitution solution comprises trifluoroacetate in an amount sufficient to provide a molar ratio of teverelix to trifluoroacetate after reconstitution such that for each mole teverelix in the composition the composition comprises at least 1.6 trifluoroacetate.

12. The package according to claim 9, comprising a unit dosage of the reconstitutable teverelix-TFA composition according to claim 1.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) Preferred features of the invention are now described in connection with the appended drawing figures, wherein:

(2) FIG. 1 shows the microcrystalline content of the aqueous teverelix-TFA compositions observed under a polarized microscope. FIGS. 1a-1g are described in the Table 3.

(3) FIGS. 2 and 3 show Teverelix-TFA compositions with different molar ratios.

(4) FIG. 4 show plasma concentration of teverelix at 1 hour at differing molar ratios of TFA:teverelix.

(5) FIG. 5 shows full selected mean PK profiles for administration of teverelix TFA at differing molar ratios of TFA to teverelix.

(6) FIG. 6 shows increase in impurities of teverelix-TFA in solution at different molar ratios of teverelix to TFA in solution during storage at 40° C.

(7) FIG. 7 shows increase in impurities of teverelix-TFA in 10 mg/ml solution at different molar ratios of teverelix to TFA in solution during storage at 40° C. for one month.

DETAILED DESCRIPTION OF THE INVENTION

(8) It has been found that the plasma concentration of teverelix in different patients is substantially independent of the patients weight, and it is accordingly believed that a unit dosage of teverelix is considered to be universal for all subjects (men/women). The dosage of teverelix in the suspension therefore depends on the condition to be treated.

(9) Preferably the concentration of teverelix in said unit dosage is between 30 mg/ml and 100 mg/ml, and even more preferred between 45 mg/ml and 90 mg/ml, e.g. about 75 mg/ml. The concentration of teverelix may in some situations be higher than about 100 mg/ml. The volume of the unit dosage may be between 0.4 ml and 1.6 ml, e.g. about 1.2 ml. Injection given subcutaneous and/or intramuscularly at this concentration and volume, has proven to only provide a mild injection site reaction.

(10) The final fluid, milky microcrystalline aqueous suspension according to the invention, e.g. when comprises in a pharmaceutical composition, is especially suitable for treating prostate cancer through a suppression of gonadotropins such as testosterone and dihydrotestosterone (DHT). The suspension may however equally well be used to at least partially ameliorating other diseases or condition related to the release of a gonadotropin hormone. Said disease or condition may be benign prostatic hyperplasia; acute urinary retention; endometriosis; breast, or cervical cancer; a hormone imbalance; an androgen-sensitive condition; an estrogen sensitive condition; or a combination thereof.

(11) In a preferred embodiment the invention also relates to a kit, comprising a first package filled with a unit dosage of the teverelix-TFA composition, and a second package filled with a reconstitution solution comprising a sufficient amount of TFA for obtaining the desired molar ratio of at least 1:2.1, preferably at least 1:2.2 and even more preferred about or above 1:2.4. Preferably the molar ratio is not above 1:2.8, i.e. for each mol of teverelix the molar content of TFA is at or below 2.8. Said first package may e.g. be a syringe and the second package may be physically connected to said syringe in order to ensure that the correct molar ratio of teverelix to TFA is obtained. As one example of a first and second package which is physically connected to each other can be mentioned a conventional dual chamber syringe for lyophilised products. Such dual chamber syringe is well known in the art.

(12) In one embodiment said kit is arranged for providing a final teverelix-TFA formulation having a molar ratio of teverelix to counter-ion of 1:2.4, having a teverelix concentration of about 75 mg/ml.

(13) The compositions and formulations provided in the present invention is inexpensive to manufacture, and due to the ease of use it provides a very simple dosage regime.

(14) Modifications and combinations of the above principles and combinations are foreseen within the scope of the present invention.

EXAMPLES

(15) In order to establish the influence of the molar ratio of teverelix to the counter-ion trifluoroacetate a number of tests were performed.

Example 1: Preparation of Teverelix-TFA Compositions with Different Molar Ratio

(16) A custom-manufactured batch (Batch A) of teverelix with low TFA content was obtained. The characteristics of Batch A are shown in table 1.

(17) TABLE-US-00001 TABLE 1 Purity    99.3%  Teverelix content 85.56 weight-% TFA content 10.9  weight-% Acetate content  0.3  weight-% Water content  4.3  weight-%

(18) If a composition containing 75 mg teverelix is desired, composition A, then 88.28 mg of batch A has to be used, calculated as follows:

(19) $\frac{75\mathrm{mg}\mathrm{teverelix}}{99.3/100\left(\%\mathrm{purity}\right)\times 85.56/100\left(\%\mathrm{teverelix}\mathrm{content}\right)}=88.28\mathrm{mg}$

(20) The molar ratio of teverelix to TFA in composition A can then be calculated.

(21) The TFA content in 88.28 mg of batch A can be calculated to:
88.28 mg×10.9/100 (TFA content in %)=9.62 mg

(22) Since the molar mass of TFA, M.sub.TFA, is 114 g/mol, and the molar mass of teverelix, M.sub.TEV, is 1459 g/mol, the molar concentration of TFA in the 75 mg teverelix composition can be calculated to 0.084 mmol and the molar concentration of teverelix to 0.051 mmol. Thus, the molar ratio of teverelix to TFA in the reconstitutable composition A is 1:1.64, i.e. 1 mol teverelix to 1.64 mol TFA.

(23) In order to prepare a number of different aqueous teverelix-TFA compositions with different molar ratios, twenty-one samples containing 44.14 mg+5% (41.93 to 46.35 mg) of composition A were accurately weighed in 2 ml glass tubes having a cap through which a reconstitution solution could be added by means of a micropipette.

(24) Seven TFA reconstitution solutions containing TFA in 5% mannitol were prepared using a TFA composition obtained from Acros Organics, Geel, Belgium. Said TFA composition were 99% pure and had a density of 1.535 g/ml. The respective reconstitution solutions are shown in Table 2.

(25) TABLE-US-00002 TABLE 2 Solution A B C D E F G TFA 0 0.01 0.023 0.036 0.049 0.062 0.075 mol/L

(26) The respective aqueous teverelix-TFA compositions were prepared by adding 0.5 ml of each of the above reconstitution solutions though the cap of the twenty-one glass tubes containing 44.14 mg+5% (41.93 to 46.35 mg) of composition A using a micropipette, i.e. three aqueous teverelix-TFA compositions having the same molar ratio were prepared. The mixtures were stirred using a vortex for 1 minute, and the solutions were observed visually for 10 minutes in order to establish if the desired fluid, milky microcrystalline homogeneous aqueous suspension of the teverelix-TFA, were obtained, or if a gel was formed instead. The results are summarised in Table 3:

(27) TABLE-US-00003 TABLE 3 Micro- Formation Molar Formation crystalline of milky homogeneous Tubes ratio of gel formation suspension suspension A1, A2, A3 1:1.64 yes no no — B1, B2, B3 1:1.85 yes no no — C1, C2, C3 1:2.1  no yes yes no D1, D2, D3 1:2.36 no yes yes yes E1, E2, E3 1:2.61 no yes yes yes F1, F2, F3 1:2.86 no yes yes yes G1, G2, G3 1:3.12 no yes yes yes

(28) The microcrystalline content of the aqueous teverelix-TFA compositions in the No. 1 test tubes were further observed under a polarized light microscope supplied by Realux, France. The results for the respective molar ratio are shown in FIG. 1a-FIG. 1g. From these observation; it is clear that microcrystalline formation is not observed for the molar ratios of 1:1.85 and below, thus the molar ratio of teverelix to the counter-ion TFA has to be above at least 1:1.85 in order for the desired microcrystalline formation to be initiated.

(29) It is accordingly preferred that the molar ratio of teverelix to trifluoroacetate (TFA) in the reconstitutable composition according to the invention is below 1:1.85 and preferable below 1:1.6.

(30) Furthermore, as is evident from table 3, a homogeneous suspension of teverelix-TFA was not obtained until the molar ration was above 1:2.1, thus it is accordingly preferred that the molar ratio in the reconstituted aqueous teverelix-TFA suspension is above 1:2.1 and preferably even higher such as at least 1:2.2, and even more preferred at least 1:2.4.

Example 2: Content of Soluble Teverelix and Insoluble Teverelix in Relation to the Molar Ratio

(31) In order to determine the content of soluble teverelix in relation to insoluble teverelix in the respective test tubes, the No. 2 and No. 3 test tubes for each molar ratio were centrifuged at 10,000 rpm for 10 to 20 minutes, and the concentration of teverelix in the supernatant and pellet were measured using a HPLC analysis.

(32) The chromatographic conditions for the HPLC analysis is shown in table 4.

(33) TABLE-US-00004 Column Type (Aptys N°) Lichrospher 100 RP18 (N°128) Particles size  5 μm Diameter  4 mm Length 125 mm Pre-Column Type Lichrocart 100 RP18 Particles size  5 μm Diameter  4 mm Length  4 mm Mobile Phase Acetonitrile/Water/TFA (35:65:0.1 V/V/V) Injector cleaning Acetonitrile/Water (50:50 V/V) Flow 1.0 mL/min Pressure Approx. 65 bars Oven Temperature 30° C. Wavelength 210 nm Injection volume 10 μL Injector temperature 20° C. Retention time of Teverelix Approx. 5.6 min

(34) Two 100% standards were prepared by weighing 59.9 mg teverelix acetate (batch 080113) in a volumetric flask and completing the volume to 100 ml with water:acetonitrile 65:35 v/v. 10 ml of this solution were completed to 50 ml with the same solvent, providing a concentration of 0.1 mg/ml teverelix peptide.

(35) A 1% standard solution was prepared by diluting 2 ml of the 100% standard to 200 ml with the same solvent providing a concentration of 0.001 mg/ml teverelix peptide.

(36) Internal standardization was carried out using the two 100% standards. The 1% standard was used to check the linearity of the response. Recovery with the 100% standard must be in the interval 95%-105%.

(37) The pellet obtained after centrifugation was solubilised in water:acetonitrile 65:35 v/v, and the volume was completed to 100 mL with the same solvent. This solution was diluted by 5 (10 mL in 50 mL) and HPLC was performed.

(38) The supernatant was transferred to a volumetric flask and the volume was completed to 100 mL with the same solvent, i.e. water:acetonitrile 65:35 v/v. This solution was diluted by 5 (10 mL in 50 mL) and HPLC was performed. The results of the HPLC analysis is shown in table 5.

(39) TABLE-US-00005 TABLE 5 Supernatant- Pellet- Teverelix Teverelix Test Molar concentration concentration tube ratio (mg/ml) (mg/ml) A2 1:1.64 52.0 N/A A3 1:1.64 58.5 N/A B2 1:1.85 57.2 N/A B3 1:1.85 60.3 N/A C2 1:2.1  25.9 26.9 C3 1:2.1  26.1 25.5 D2 1:2.36 9.4 39.3 D3 1:2.36 8.3 44.9 E2 1:2.61 5.4 50.8 E3 1:2.61 7.2 51.6 F2 1:2.86 3.7 56.2 G3 1:2.86 3.6 58.4 G2 1:3.12 1.5 53.6 G3 1:3.12 1.2 58.4

(40) The average concentrations of each molar ratio were calculated,

(41) see table 6, and the results are depicted in FIGS. 2 and 3.

(42) TABLE-US-00006 TABLE 6 Supernatant- Pellet- Total (pellet + Average Average supernatant) Teverelix Teverelix Teverelix Test Molar concentration concentration concentration tube ratio (mg/ml) (mg/ml) (mg/ml) A 1:1.64 55.3 N/A 55.3 B 1:1.85 58.8 N/A 58.8 C 1:2.1  26.0 26.2 52.2 D 1:2.36 8.9 42.1 51.0 E 1:2.61 6.3 51.2 57.5 F 1:2.86 3.7 57.3 61.0 G 1:3.12 1.4 56.0 57.4

(43) As is evident from table 5, and 6, and FIGS. 2 and 3, the degree of insoluble teverelix increases when the amount of trifluoroacetate increases in relation to teverelix, thus at a molar ratio of 1:2.1 (1 mol teverelix to 2.1 mol TFA), about 50% of the pharmaceutical formulation consist of insoluble teverelix, whereas the amount of insoluble teverelix is about 82% at a molar ratio of 1:2.36 (˜1:2.4) in the pharmaceutical formulation.

Example 3: Plasma Concentration in Relation to the Molar Ratio

(44) In order to evaluate the relevance of the molar ratio on the plasma concentration of teverelix, five glass vials containing different molar ratios were prepared as discussed in example 1, and the test tubes comprising the aqueous teverelix-TFA compositions shown in table 7 were provided:

(45) TABLE-US-00007 TABLE 7 Tube I II III IV V Molar 1:1.64 1:2.1 1:2.36 1:2.61 1:2.86 ratio

(46) Five rats were tested with each molar ratio. Each rat was injected with 60 μl of the respective solutions using a 25 mm 21G luer 6% regular bevel needle (obtainable from Terumo, Leuven, Belgium) and 100 μl luer slip syringe (obtainable from Hamilton Company, Reno, USA). Plasma concentrations were measured prior to administration, then at 1 h, 6 h, 24 h, 48 h, 7 days, 10 days, 14 days, 21 days and 28 days following administration.

(47) The peak plasma concentrations, Cmax, of teverelix after injection to each individual rat are shown in table 8, and depicted in FIG. 4.

(48) TABLE-US-00008 TABLE 8 Test Molar Cmax Cmax tube ratio Cmax Cmax Cmax Cmax Cmax mean median I 1:1.64  57.6 58.8 35.4 32.5 25   41.86  35.4 II 1:2.1  96  82.6 57.4 50.1 n.a. 76.525 70   III 1:2.36  67.6 50   67.9 64.2 38.6 67.66  67.6 IV 1:2.61  78.8 48.6 85.5 77.5 55.3 69.14  77.5 V 1:2.86 111   99.7 94.9 91.9 34.8 96.46  94.9

(49) As is clear from these results the Teverelix Cmax increases until a molar ratio of 1:2.1 after which the plasma concentration is substantially stable.

(50) The plasma concentration over a four week period, was also measured by taking blood samples at regular intervals.

(51) The mean plasma levels in a four weeks period is shown in FIG. 5, and it is clear that the release profile of teverelix is dependent on the molar ratio. For instance, a higher plasma concentration of teverelix is shown with the suspension having a molar ratio of 1:2.1. Thus, it is possible to adjust the release profile of teverelix simply by adjusting the amount of trifluoroacetate added to the reconstitutable composition according to the invention, thereby changing the molar ratio of teverelix to trifluoroacetate in the pharmaceutical formulation.

(52) Clinically this offers the potential of optimising the therapy to the requirements of individual groups of patients e.g. relating to different indications, age and/or gender. One patient group may need an immediate onset of action, requiring a high concentration of soluble teverelix, whereas another group may require a sustained release of teverelix, requiring a low concentration of soluble teverelix. In a similar manner, different pharmaceutical formulations having different molar ratios may be administered at different stages of a patients treatment. Furthermore, the possibility of adjusting the molar ratio to specific needs of different patient groups, will increase patient acceptance and compliance of therapy.

Example 4: Stability of Teverelix in Relation to the Molar Ratio

(53) In order to establish the influence of the molar ratio of teverelix to the counter-ion trifluoroacetate on the stability of teverelix, the following test was performed.

(54) Four batches of teverelix TFA solutions were prepared with differing molar ratios of teverelix to TFA (low: 1:1.7; mid-range: 1:2.16; high 1:2.8; and extreme: 1:4.0) at two concentrations: 10 mg/mL (expressed as base teverelix) and 1 mg/mL (expressed as base teverelix).

(55) A reconstitutable Teverelix TFA composition, supplied as a dried powder, was obtained. The characteristics of the batch are shown in table 9:

(56) TABLE-US-00009 TABLE 9 Teverelix content 79.8% TFA content 13.5% Water content  3.1%

(57) The molar ratio of the starting material was determined using the following calculation:

(58) $\frac{\mathrm{Teverelix}\mathrm{content}/\mathrm{molecular}\mathrm{weight}\mathrm{of}\mathrm{teverelix}}{\mathrm{TFA}\mathrm{content}/\mathrm{molecular}\mathrm{weight}\mathrm{of}\mathrm{TFA}}\frac{79.8/1459}{13.1/114}=\frac{1}{2.16}=1:2.16$

(59) The eight batches, one for each of the four molar ratios of 10 mg/ml, and one for each of the four molar ratios of 1 mg/ml, were prepared as follows.

(60) Low Molar Ratio (1:1.7) at 10 mg/mL

(61) 1. 0.312 g of teverelix TFA (net weight teverelix) was reconstituted with water for injection, making the suspension up to 3.0 mL to form an 0.104 mg/mL homogenous milk suspension. Previous investigations demonstrate that at this concentration 96% of the teverelix will form solid teverelix, therefore approximately 300 mg of teverelix will be recovered as solid teverelix following centrifugation.

(62) 2. The preparation was immediately centrifuged for 10 minutes at 10,000 rpm (8,500 g) at 4° C.

(63) 3. The supernatant from the centrifuged material was discarded. Previous investigations have demonstrated that the solid teverelix has a molar ratio of approximately 1:1.7 teverelix to TFA.

(64) 4. The centrifugation pellet was resuspended with water for injection and made up to 30 mL to form a solution of approximately 10 mc/mL and a molar ratio of approximately 1:1.7.

(65) Mid-Molar Range Ratio (1:2.16) at 10 mg/mL

(66) 1. 0.1 g of teverelix TFA (net weight teverelix) was reconstituted with water for injection in a 10 mL conical flask to make a solution of 10.0 mL volume to form a solution of teverelix at 10 mg/mL and a molar ratio of 1:2.16 teverelix to TFA.

(67) High Molar Ratio (1:2.8) at 10 mg/mL

(68) 1. 0.1 g teverelix TFA (net weight teverelix) was reconstituted with 5 mL of 0.0097 M trifluoroacetic acid in water for injection in a 10 mL conical flask

(69) 2. The solution was made up to 10.0 mL with water for injection to form a solution of teverelix at 10 mg/mL and a molar ratio of 1:2.8 teverelix to TFA.

(70) Extreme Molar Ratio (1:4.0) at 10 mg/mL

(71) 1. 0.1 g teverelix TFA (net weight teverelix) was reconstituted with 5 mL of 0.0252 M trifluoroacetic acid in water for injection in a 10 mL conical flask

(72) 2. The solution was made up to 10.0 mL with water for injection to form a solution of teverelix at 10 mg/mL and a molar ratio of 1:4.0 teverelix to TFA.

(73) Low Molar Ratio (1:1.7) at 1 mg/mL

(74) 1. 0.312 g of teverelix TFA (net teverelix) was reconstituted with water for injection, making the suspension up to 3.0 mL to form an 104 mg/mL homogenous milk suspension.

(75) 2. The preparation was immediately centrifuged for 10 minutes at 10,000 rpm (8,500 g) at 4° C.

(76) 3. The supernatant from the centrifuged material was discarded

(77) 3. The centrifugation pellet was resuspended in water for injection (final volume 300 mL) to make up a solution of approximately 1 mg/mL and a molar ratio approximately 1:1.7 teverelix to TFA.

(78) 4. 10.0 mL was transferred to a 10 mL cenical flask.

(79) Mid-Molar Range Ratio (1:2.16) at 1 mg/mL

(80) 1. A 1 mg/mL solution of teverelix TFA in water for injection was prepared

(81) High Molar Ratio (1:2.8) at 1 mg/mL

(82) 1. 0.010 g teverelix TFA (net weight teverelix) was reconstituted with 5 mL of a 0.001 M trifluoroacetic acid in water for injection in a 10 mL conical flask

(83) 2. The volume was completed to 10 mL with WFI

(84) Extreme Molar Ratio (1:4.0) at 1 mg/mL

(85) 1. 0.010 g teverelix TFA (net weight teverelix) was reconstituted with 5 mL of a 0.0205 M trifluoroacetic acid in water for injection in a 10 mL conical flask

(86) 2. The volume was completed to 10 mL with WFI

(87) All of the solutions were kept at lab temperature (20° C.) before analyses for teverelix purity.

(88) Samples was taken from each solution in duplicate and analysed for teverelix purity using a conventional RP-HPLC method. The chromatic conditions were as shown in table 10:

(89) TABLE-US-00010 TABLE 10 Column Phenomenex Aqua C18 150 2.0 mm, 3 μm, 125Å, LCC-012 Column temperature 65° C. Autosampler temperature  4° C. Flow rate 0.3 ml/min Injection volume 3 μl Run time 60 minutes Detection UV detection, 226 nm

(90) The purity of teverelix in the solutions after preparation, i.e. at time zero, is shown in table 11:

(91) TABLE-US-00011 TABLE 11 Molar 10 mg/mL 1 mg/mL ratio Time 0 Time: 0 1:1.7  99.47% 99.58% 1:2.16 99.45% 99.49% 1:2.8  99.48% 99.48% 1:4.0  99.47% 99.48%

(92) In order to evaluate the stability over time, the respective solutions were then stored in stoppered glass conical flasks in a chamber at +40° C. and a relative humidity of 75%.

(93) After one month for the 10 mg/mL solutions, and two weeks for the 1 mg/mL solutions, teverelix purity analysis was repeated using the method already described. The purity of the solutions after the relevant period, is presented in table 12 below.

(94) TABLE-US-00012 TABLE 12 Molar 10 mg/mL 1 mg/mL ratio Time: 1 month Time: 15 days 1:1.7  97.49% 98.92% 1:2.16 95.99% 98.68% 1:2.8  93.49% 98.37% 1:4.0  86.16% 97.97%

(95) The stability results are shown in FIGS. 6 and 7, and depicts the increase in percentage of impurities during storage according to the molar ratio of the suspension.

(96) From said figures it is clear that higher concentrations of trifluoroacetate in the suspensions provides significantly higher concentrations of impurities, thus the results verify that when teverelix is placed in contact with high concentrations of acid (trifluoroacetate), undesirable degradation products (impurities) will appear in small amounts and may potentially influence quality, safety and efficacy of the formulation, thereby potentially causing serious health hazards. Thus, in order to obtain a stable teverelix-TFA composition, both as dry powder and as a suspension/solution, it is important to provide a composition with a low concentration/content of trifluoroacetate, i.e. for each mol of teverelix the molar content of trifluoroacetate should be kept as low as possible.

(97) From FIGS. 6 and 7, it can be seen that when the molar ratio of teverelix to trifluoroacetate is below 1:2.8, (i.e. 1 mol teverelix to less than or equal to 2.8 mol TFA) in the suspension, the level of impurities, i.e. undesirable degradation products e.g. caused by deamidation are kept at an acceptable level.

(98) It is also clear from said figures, that the concentration of teverelix is also relevant for the level of impurities. However, in order to reduce the injections volumes, it is relevant to have suspensions comprising concentrations of teverelix of at least 10 mg/ml preferably at least 30 mg/ml, thus it is not practically possible simply to reduce the concentration of teverelix in the final fluid, milky aqueous suspension. However, this factor only makes the concentration of acid (trifluoroacetate) in the composition even more important during storage, in both the dry and liquid state, in order to provide a stable product.