Teverelix-TFA composition

Abstract

To provide a novel composition that prevents the composition from gelling and can be provided in the form of a microcrystalline homogeneous aqueous suspension, in sustained release injectable compositions of teverelix, a synthetic gonadotropin-releasing hormone antagonist (GnRH antagonist).SOLUTION: Provided is a 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 (TFA) of at least 1:2.2.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to teverelix-TFA compositions. [Background technology]

[0002] Teverelix is ​​a synthetic gonadotropin-releasing hormone antagonist (GnRH antagonist) that competes with the endogenous neurohormone GnRH (also known as luteinizing hormone-releasing hormone, LHRH) for binding to receptors in the anterior pituitary gland. GnRH antagonists reduce or block the action of GnRH, thereby inhibiting the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland.

[0003] Both FSH and LH are involved in normal reproductive function: in women, FSH stimulates the growth and maturation of immature Graafian follicles, and changes in LH levels control ovulation, while in men, FSH plays an important role in spermatogenesis, and LH stimulates the production of testosterone in the testes.

[0004] Teverelix is ​​therefore suitable for the treatment of hormone-dependent conditions such as benign prostatic hyperplasia, hormone-dependent prostate cancer, endometriosis, and uterine rhabdomyosarcoma.

[0005] Teverelix (Ac-D-Nal-D-pClPhe-D-Pal-Ser-Tyr-D-Hci-Leu-Lys(iPr)-Pro-D-Ala-NH2) is a hydrophobic peptide and therefore tends to form gels in the presence of many counterions. This problem is solved by WO2003 / 022243, which discloses that gel formation can be prevented by contacting the teverelix peptide with a counterion, such as trifluoroacetate (TFA), in a molar ratio of peptide to counterion of at least 1:1.6, thereby providing a microcrystalline aqueous suspension of a fluid, milky teverelix salt (e.g., teverelix-TFA).

[0006] According to WO2003 / 022243, a molar ratio of at least 1:1.6 between teverelix and the counterion trifluoroacetate is essential to ensure the desired microcrystalline suspension, otherwise a gel will be formed. However, the inventors of the present invention have found that such a molar ratio will result in both undesired gel formation and a non-uniform suspension. This is problematic not only because such a suspension will be difficult to inject, but also because the gel will interfere with the desired sustained action of the peptide, thus compromising the bioavailability of the teverelix peptide. Summary of the Invention

[0007] Therefore, there is a need to provide new Teverelix-TFA compositions that can provide a uniform microcrystalline aqueous suspension of Teverelix and that will provide a sustained release of Teverelix.

[0008] This and further aspects are achieved by the present invention by providing a Teverelix-TFA composition having a molar ratio of Teverelix to trifluoroacetate of at least 1:2.2.

[0009] Within the context of the present invention, the term "molar ratio of Teverelix to trifluoroacetate" refers to the molar relationship between Teverelix and trifluoroacetate, where the first number of the molar ratio is the molar content of Teverelix in the composition, and the second number refers to the molar content of TFA in the composition. For example, a molar ratio of 1:2.2 means that for each mole of Teverelix in the composition, the composition contains 2.2 moles of TFA, and a molar ratio of at least 1:2.2 means that for each mole of Teverelix in the composition, the composition contains at least 2.2 moles of trifluoroacetate (TFA). [Brief description of the drawings]

[0010] [Figure 1a-1g] 1 shows micrographs of suspensions A1 to G1. [Diagram 2] 1 is a graph showing the concentrations of soluble and insoluble Teverelix at different molar ratios. [Diagram 3] 1 is a graph showing the ratio of soluble to insoluble Teverelix. [Figure 4] 1 is a graph showing plasma concentrations of Teverelix at 1 hour at different TFA:Teverelix molar ratios. [Diagram 5] 1 is a graph showing the overall mean PK profile for administration of teverelix TFA at different TFA to teverelix molar ratios. [Figure 6] 1 is a graph showing the increase in impurities of Teverelix TFA in solution at different TFA to Teverelix molar ratios during storage at 40° C. [Figure 7] 1 is a graph showing the increase in impurities of Teverelix TFA in a 10 mg / mL solution at different molar ratios of TFA to Teverelix during storage of the solution at 40° C. for one month. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The inventors of the present invention have discovered that when the molar ratio of Teverelix to trifluoroacetate is at least 1:2.2, the composition contains both soluble and insoluble Teverelix, thereby providing unique bioavailability of Teverelix.

[0012] In order for Teverelix to be absorbed in the body, this component must be present in the form of a solution at the site of absorption. Although various techniques are used to enhance the solubility of poorly soluble drugs such as Teverelix, the inventors have found that crystal engineering of Teverelix and trifluoroacetate provides organization of the Teverelix peptide with improved physicochemical properties (e.g., solubility and stability) and improved efficacy (e.g., bioavailability), and the counter ions in the crystal structure provide an effective sustained release of Teverelix.

[0013] Without being bound by theory, the soluble teverelix is ​​in the form of an aqueous solution, and in some circumstances, a gel. The presence of the gel will inhibit any free aqueous teverelix, thus preventing or at least reducing the immediate release. The insoluble teverelix is ​​in the form of microcrystals. The microcrystals will prevent gel formation, thus "opening up" the aqueous teverelix. Over time, the TFA in the composition according to the invention will be absorbed by the body and the ratio will decrease, after which the microcrystals will gel and form a sustained release depot. Thus, the non-gel-soluble teverelix is ​​immediately available, providing a near-immediate onset of action, while the gel-soluble and insoluble teverelix (microcrystals) will help provide sustained release of teverelix. Thus, the composition according to the invention provides a soluble-insoluble transition at the administration site, and thus a sustained release of teverelix.

[0014] Thus, the compositions according to the invention have both an immediate onset of action resulting in rapid suppression of gonadotropins, as well as a sustained release of antagonist, ensuring that subjects maintain therapeutically effective concentrations in their blood plasma. This not only provides a more reliable composition for the treatment of diseases and conditions that relate to gonadotropins, but will also improve patient compliance as fewer administrations (e.g., injections) will be required.

[0015] The molar ratio of Teverelix to trifluoroacetate is preferably at least 1:2.2, i.e. for each mole of Teverelix, the composition contains at least 2.2 moles of trifluoroacetate (TFA), and even more preferably at least 1:2.4, as this provides an aqueous pharmaceutical formulation which may be used directly, i.e. the formulation is ready for use.

[0016] Teverelix deamidates when placed in contact with water and acid, and therefore undesirable degradation products (impurities) will appear in the composition / formulation during storage. These impurities may affect the quality, safety, and efficacy of the Teverelix composition / formulation, thereby creating potentially serious health risks.

[0017] The inventors of the present invention have found that the level of impurities is kept at an acceptable level when the molar ratio of Teverelix to TFA is 1:2.8 or less, i.e., the molar content of TFA per mole of Teverelix is ​​2.8 or less. Therefore, the optimal molar ratio in the composition according to the present invention is preferably between 1:2.2 (or 1:2.4) and 1:2.8.

[0018] The compositions according to the invention are particularly suitable for treating conditions such as prostate cancer through the suppression of gonadotropins such as testosterone and dihydrotestosterone (DHT). Such compositions have both an immediate onset of action resulting in complete suppression of testosterone, and a sustained release of antagonist, thereby ensuring that the subject maintains chemical castration, making the compositions valuable both for treating patients with prostate cancer who require rapid control of the disease, and for those in whom only sustained release is of interest.

[0019] However, the compositions according to the invention may also be used to at least partially ameliorate other diseases or conditions associated with the release of gonadotropin hormones. Such diseases or conditions may be benign prostatic hyperplasia, acute urinary retention, endometriosis, cancer such as prostate cancer, breast cancer, or cervical cancer, chemical castration, hormonal imbalance, androgen-sensitive conditions, estrogen-sensitive conditions, or combinations thereof.

[0020] The present invention also relates to an aqueous pharmaceutical formulation, preferably a milky microcrystalline homogeneous aqueous suspension, consisting of or comprising a Teverelix-TFA composition according to the present invention, having a molar ratio of Teverelix to trifluoroacetate of at least 1:2.2, preferably at least about 1:2.4. In a preferred embodiment of the aqueous pharmaceutical formulation, the molar ratio of Teverelix to trifluoroacetate is below 1:2.8, i.e. per mol of Teverelix, the formulation contains 2.8 mol or less of TFA.

[0021] Optionally, the aqueous pharmaceutical formulation may contain an isotonicity agent, such as mannitol and / or a pharma- ceutically acceptable excipient.

[0022] In a simple and preferred embodiment according to the present invention, the teverelix-TFA composition is provided as a unit dosage having a molar ratio of teverelix to TFA of at least 1:2.2, and even more preferably about 1:2.4, thereby ensuring that the suspension provided is substantially free of gel or contains at least a low enough concentration of gel that the suspension can be used for injection.

[0023] Therefore, another aspect of the present invention features a package, such as a syringe or vial, filled with a unit dose of teverelix-TFA composition.Within the context of the present invention, the term "unit dose" refers to the amount of active ingredient (teverelix) administered to a patient in a single dose.This unit dose is, for example, placed in a suitable syringe to provide easy administration.

[0024] In one embodiment, the unit dose provides a final aqueous teverelix-TFA formulation with a molar ratio of teverelix to counterion of 1:2.4. Preferably, the concentration of teverelix is ​​between 30mg / ml and 100mg / ml, even more preferably between 45mg / ml and 90mg / ml, for example about 75mg / ml. The concentration of teverelix may be higher than about 100mg / ml in some circumstances. The volume may be between 0.4ml and 1.6ml, for example about 1.2ml. At this concentration and volume, injections given subcutaneously and / or intramuscularly have been demonstrated to provide only mild injection site reactions. EXAMPLES

[0025] Several studies were performed to determine the effect of the molar ratio of Teverelix to the counterion trifluoroacetate.

[0026] Example 1: Preparation of Teverelix-TFA compositions with different molar ratios A special manufacturing batch of Teverelix with low TFA content was obtained, Batch A. The properties of this batch are shown in Table 1. TIFF2025004006000002.tif35170

[0027] If an initial composition containing 75 mg of Teverelix, Composition A, is desired, then 88.28 mg of Batch A should be used, calculated as follows: TIFF2025004006000003.tif14170

[0028] The molar ratio of Teverelix to TFA in Composition A can then be calculated: the TFA content in Batch A of 88.28 mg can be calculated as 88.28 mg x 10.9 / 100 (% TFA content) = 9.62 mg.

[0029] Molar mass of TFA, M TFA is 114 g / mol, and the molar mass of Teverelix, M TEVis 1459 g / mol, the molar concentration of TFA in the 75 mg Teverelix composition can be calculated to be 0.084 mmol and the molar concentration of Teverelix to be 0.051 mmol. Therefore, the molar ratio of Teverelix to TFA in Composition A is 1:1.64.

[0030] To prepare several different aqueous Teverelix-TFA compositions with different molar ratios, 21 samples containing 44.14 mg + 5% (41.93-46.35 mg) of composition A were accurately weighed into 2 ml glass tubes with lids that allowed the addition of reconstitution solution via micropipette.

[0031] Seven TFA solutions containing TFA in 5% mannitol were prepared using a TFA composition obtained from Acros Organics (Geel, Belgium). The TFA composition was 99% pure and had a density of 1.535 g / ml. The reconstituted solutions are shown in Table 2. TIFF2025004006000004.tif23170

[0032] Each aqueous Teverelix-TFA composition was prepared by adding 0.5 ml of each of the above reconstitution solutions using a micropipette through the caps of 21 glass tubes containing 44.14 mg + 5% (41.93-46.35 mg) Composition A, i.e., three aqueous Teverelix-TFA compositions with the same molar ratio were prepared. The mixtures were stirred for 1 minute using a vortex and the solutions were visually observed for 10 minutes to see if the desired fluid, milky, microcrystalline homogeneous aqueous suspension of Teverelix-TFA was obtained or if a gel had formed instead. The results are summarized in Table 3 below. TIFF2025004006000005.tif53170

[0033] The microcrystalline content of the aqueous Teverelix-TFA composition in the first test tube was further observed under a polarized light microscope supplied by Realux (France).

[0034] The results for each molar ratio are shown in Figure 1a-1g. From these observations, it is clear that for molar ratios below 1:1.85, no crystallite formation is observed, and therefore, the molar ratio of Teverelix to counterion TFA must be greater than 1:1.85 in order to initiate the desired crystallite formation.

[0035] Furthermore, as is evident from Table 3, a molar ratio of 1:2.1 or less does not result in a uniform suspension of teverelix-TFA, therefore it is preferred that the molar ratio in the aqueous teverelix-TFA suspension is greater than 1:2.2, preferably at least higher such as 1:2.36 (approximately 1:2.4), otherwise the composition cannot be administered by injection.

[0036] Example 2: Content of soluble and insoluble Teverelix relative to molar ratio To determine the content of soluble teverelix relative to insoluble teverelix in each test tube, the second and third test tubes of each molar ratio were centrifuged at 10,000 rpm for 10-20 minutes, and the concentrations of teverelix in the supernatant and pellet were measured using HPLC analysis.

[0037] The chromatographic conditions for the HPLC analysis are shown in Table 4. TIFF2025004006000006.tif110170

[0038] Two 100% standards were prepared by weighing 59.9 mg of teverelix acetate (batch 080113) into a volumetric flask and filling the volume to 100 ml with water:acetonitrile = 65:35 (v / v). 10 ml of this solution was made up to 50 ml with the same solvent to provide a concentration of 0.1 mg / ml of teverelix peptide.

[0039] A 1% standard solution was prepared by diluting 2 ml of the 100% standard to 200 ml with the same solvent to provide a concentration of 0.001 mg / ml of the Teverelix peptide.

[0040] The internal standard method was performed using two 100% standards. The linearity of the response was confirmed using a 1% standard. Recovery with the 100% standards should be in the interval 95%-105%.

[0041] The pellet obtained after centrifugation was solubilized in water:acetonitrile = 65:35 (v / v) and the volume was made up to 100 mL with the same solvent. This solution was diluted 5 times (10 mL in 50 mL) and run on HPLC.

[0042] The supernatant was transferred to a volumetric flask and the volume was filled up to 100 mL with the same solvent, i.e., water:acetonitrile = 65:35 (v / v). The solution was diluted 5 times (10 mL in 50 mL) and HPLC was performed. The results of the HPLC analysis are shown in Table 5. TIFF2025004006000007.tif87170

[0043] The average concentration of each molar ratio was calculated, see Table 6. The results are illustrated in Figures 2 and 3. TIFF2025004006000008.tif58170

[0044] As is evident from Tables 5 and 6 and Figures 2 and 3, as the amount of trifluoroacetate relative to Teverelix increases, the degree of insoluble Teverelix increases, such that at a molar ratio of 1:2.1, approximately 50% of the pharmaceutical formulation consists of insoluble Teverelix, while the amount of insoluble (microcrystalline) Teverelix in the pharmaceutical formulation is approximately 80% at a molar ratio of 1:2.2 and approximately 82% at a molar ratio of 1:2.36 (approximately 1:2.4).

[0045] Example 3: Plasma Concentration vs. Molar Ratio To evaluate the relevance of the molar ratio to the plasma concentration of Teverelix, five glass vials containing different molar ratios were prepared as discussed in Example 1, and test tubes containing the aqueous Teverelix-TFA compositions shown in Table 7 were prepared. TIFF2025004006000009.tif20170

[0046] Five rats were tested for each molar ratio. Each rat was injected with 60 μl of each solution using a 25 mm 21G Luer 6% regular bevel needle (available from Terumo, Leuven, Belgium) and a 100 μl Luer slip syringe (available from Hamilton Company, Reno, USA). Plasma concentrations were measured before dosing, then 1 hour, 6 hours, 24 hours, 48 ​​hours, 7 days, 10 days, 14 days, 21 days, and 28 days after dosing.

[0047] The peak plasma concentration Cmax of teverelix following injection into each individual rat is shown in Table 8 and illustrated in FIG. TIFF2025004006000010.tif48170

[0048] As is evident from these results, the Cmax of teverelix is ​​increased up to a molar ratio of 1:2.1, after which the plasma concentration essentially plateaus.

[0049] Plasma concentrations were also measured over a four week period by taking blood samples at regular intervals.

[0050] The mean plasma levels over a four week period are shown in FIG. 5 and it is clear that the release profile of Teverelix is ​​dependent on the molar ratio.

[0051] Example 4: Stability of Teverelix versus Molar Ratio To determine the effect of the molar ratio of Teverelix to the counterion trifluoroacetate on the stability of Teverelix, the following study was performed.

[0052] Four batches of Teverelix TFA solutions with different molar ratios of Teverelix to TFA (low 1:1.7; medium 1:2.16; high 1:2.8; and ultra-high 1:4.0) were prepared at two concentrations, 10 mg / mL (represented as base Teverelix) and 1 mg / mL (represented as base Teverelix).

[0053] A reconstitutable Teverelix TFA composition was obtained supplied as a dry powder, and the properties of this batch are shown in Table 9. TIFF2025004006000011.tif24170

[0054] The molar ratios of the starting materials were determined using the following calculation: TIFF2025004006000012.tif14170

[0055] Eight batches: one at 10 mg / ml of each of the four molar ratios and one at 1 mg / ml of each of the four molar ratios were prepared as follows.

[0056] Low molar ratio (1:1.7) at 10mg / mL 1. 0.312 g of Teverelix TFA (net weight Teverelix) was reconstituted with water for injection to make a suspension of 3.0 mL to form a 104 mg / mL homogeneous milky suspension. At this concentration, previous studies have demonstrated that 96% of Teverelix forms solid Teverelix, therefore, approximately 300 mg of Teverelix will be recovered as solid Teverelix after centrifugation. 2. The preparation was immediately centrifuged at 10,000 rpm (8,500 g) for 10 minutes at 4°C. 3. The supernatant of the centrifuged material was discarded.Previous studies have demonstrated that solid Teverelix has a molar ratio of Teverelix to TFA of approximately 1:1.7. 4. The centrifugation pellet was resuspended with water for injection and made up to 30 mL to form a solution of approximately 10 mg / mL, approximately 1:1.7 molar ratio.

[0057] Mid-molar range ratio at 10mg / mL (1:2.16) 1. 0.1 g of Teverelix TFA (net weight Teverelix) was reconstituted with water for injection in a 10 mL Erlenmeyer flask to make a 10.0 mL volume of solution to form a solution of Teverelix at 10 mg / mL with a molar ratio of Teverelix to TFA of 1:2.16.

[0058] High molar ratio (1:2.8) at 10mg / mL 1. 0.1 g of Teverelix TFA (net weight Teverelix) was reconstituted with 5 mL of 0.0097 M trifluoroacetic acid in water for injection in a 10 mL Erlenmeyer flask. 2. The solution was made up to 10.0 mL with water for injection to form a solution of Teverelix at 10 mg / mL with a molar ratio of Teverelix to TFA of 1:2.8.

[0059] Ultra-high molar ratio (1:4.0) at 10mg / mL 1. 0.1 g of Teverelix TFA (net weight Teverelix) was reconstituted with 5 mL of 0.0252 M trifluoroacetic acid in water for injection in a 10 mL Erlenmeyer flask. 2. The solution was made up to 10.0 mL with water for injection to form a solution of Teverelix at 10 mg / mL with a molar ratio of Teverelix to TFA of 1:4.0.

[0060] Low molar ratio (1:1.7) at 1 mg / mL 1. 0.312 g of Teverelix TFA (neat Teverelix) was reconstituted with water for injection and the suspension was made up to 3.0 mL to form a 104 mg / mL homogenous milk suspension. 2. The preparation was immediately centrifuged at 10,000 rpm (8,500 g) for 10 minutes at 4°C. 3. The supernatant of the centrifuged material was discarded. 3. The centrifugation pellet was resuspended in water for injection (final volume 300 mL) to prepare an approximately 1 mg / mL solution with an approximate 1:1.7 molar ratio of Teverelix to TFA. 4. 10.0 mL was transferred to a 10 mL Erlenmeyer flask.

[0061] Mid-molar range ratio at 1mg / mL (1:2.16) 1. A 1 mg / mL solution of Teverelix TFA in water for injection was prepared.

[0062] High molar ratio (1:2.8) at 1mg / mL 1. 0.010 g of Teverelix TFA (net weight Teverelix) was reconstituted with 5 mL of 0.001 M trifluoroacetic acid in water for injection in a 10 mL Erlenmeyer flask. 2. The volume was filled up to 10 mL with WFI.

[0063] Ultra-high molar ratio (1:4.0) at 1mg / mL 1. 0.010 g of Teverelix TFA (net weight Teverelix) was reconstituted with 5 mL of 0.0205 M trifluoroacetic acid in water for injection in a 10 mL Erlenmeyer flask. 2. The volume was filled up to 10 mL with WFI.

[0064] All solutions were kept at laboratory temperature (20° C.) prior to analysis for Teverelix purity.

[0065] Duplicate samples were taken from each solution and analyzed for Teverelix purity using conventional RP-HPLC methods. The chromatic conditions are as shown in Table 10. TIFF2025004006000013.tif52170

[0066] The purity of Teverelix in the solutions after preparation, i.e. at time 0, is shown in Table 11. TIFF2025004006000014.tif45170

[0067] To assess stability over time, each solution was stored in a stoppered glass Erlenmeyer flask in a chamber at +40° C. and 75% relative humidity.

[0068] Teverelix purity analysis was repeated after one month for the 10 mg / mL solutions and after two weeks for the 1 mg / mL solutions using the method previously described. The purity of the solutions after the appropriate periods is presented below in Table 12. TIFF2025004006000015.tif45170

[0069] The stability results are shown in Figures 6 and 7, which plot the percentage increase of impurities during storage by molar ratio in the solutions.

[0070] From these figures, it is clear that a higher concentration of trifluoroacetate in the solvent results in a significantly higher concentration of impurities, and thus the results demonstrate that when Teverelix is ​​placed in contact with a high concentration of acid (trifluoroacetate), a small amount of undesirable decomposition products (impurities) appears. Therefore, in order to obtain a stable Teverelix-TFA formulation, it is important to prepare a composition with a low concentration / content of trifluoroacetate, i.e., to keep the molar content of trifluoroacetate per mole of Teverelix as low as possible.

[0071] From Figures 6 and 7 it can be seen that when the molar ratio of Teverelix to trifluoroacetate in the suspension is below 1:2.8 (i.e. 1 mol Teverelix to 2.8 mol TFA or less), the level of impurities, i.e. undesirable degradation products resulting, for example, from deamidation, is kept at an acceptable level.

[0072] From these figures, it is clear that the concentration of teverelix is ​​also related to the level of impurities.However, in order to reduce the injection volume, it is relevant that the suspension contains a concentration of teverelix of at least 10mg / ml, preferably at least 30mg / ml, and therefore it is not practically possible to simply reduce the concentration of teverelix in the final formulation.However, this factor makes the content of acid (trifluoroacetate) in the composition even more important during storage, since a lower level of acid will provide a more stable product.

[0073] Therefore, the molar content of TFA per mole of Teverelix should be 2.2 to 2.8 inclusive.

[0074] A molar content of TFA of 2.2 or more per mole of Teverelix is ​​essential to ensure that the composition / formulation / suspension contains both soluble and insoluble Teverelix, thereby providing unique Teverelix bioavailability and ensuring that the suspension is easily administered by subcutaneous and / or intramuscular injection. A molar ratio below 1:2.2 would result in undesirable gel formation, making the suspension very difficult to inject. Furthermore, a molar content of TFA of 2.8 or less per mole of Teverelix is ​​relevant to provide a stable Teverelix-TFA product, in which the amount of impurities, such as undesirable deamidation products, is kept at an acceptable level.

[0075] The compositions and formulations provided herein are inexpensive to manufacture and also provide a very simple administration regime due to their ease of use.

[0076] Modifications and combinations of the above principles, as well as combinations thereof, are envisioned within the scope of the present invention.

Claims

1. At least 1:2.2 of teverelix (Ac-D-Nal-D-pClPhe-D-Pal-Ser-Tyr-D-Hci-Leu-Lys(iPr)-Pro-D-Ala-NH ２ ) and trifluoroacetate.

2. 2. The Teverelix-TFA composition of claim 1, wherein the molar ratio of Teverelix to trifluoroacetate is at least 1:2.

4.

3. The Teverelix-TFA composition according to claim 1 or 2, wherein the molar ratio of Teverelix to trifluoroacetate is 1:2.8 or less.

4. The Teverelix-TFA composition according to any one of claims 1 to 3 for use as a medicament.

5. A teverelix-TFA composition according to any one of claims 1 to 3 for use in the treatment of conditions or diseases associated with the release of gonadotropin hormones.

6. The teverelix-TFA composition of claim 5, wherein the condition or disease is benign prostatic hyperplasia; acute urinary retention; endometriosis; cancer, such as prostate cancer, breast cancer, or cervical cancer; chemical castration; hormone imbalance; androgen-sensitive conditions; estrogen-sensitive conditions; or combinations thereof.

7. A pharmaceutical formulation comprising the teverelix-TFA composition of any one of claims 1 to 6.

8. 8. The pharmaceutical formulation of claim 7, in the form of a microcrystalline homogeneous aqueous suspension, wherein the molar ratio of teverelix to trifluoroacetate is from 1:2.2 to 1:2.

8.

9. A package filled with a teverelix-TFA composition according to any one of claims 1 to 6, or a pharmaceutical formulation according to claim 7 or 8.

10. 10. The package of claim 9, comprising a unit dose of the teverelix-TFA composition of any one of claims 1 to 5, or the pharmaceutical formulation of claim 6.

11. 11. The package of claim 9 or 10, wherein the package is a syringe suitable for providing subcutaneous and / or intramuscular injections.

Images