Degarelix organic solvent formulation

Abstract

Described herein are long-acting injectable compositions and methods for using such long-acting injectable compositions. The long-acting injectable compositions comprise degarelix (a decapeptide gonadotropin-releasing hormone (GnRH) receptor antagonist) or a pharmaceutically acceptable salt thereof. These compositions may also optionally comprise a biocompatible organic solvent along with one or more additives in a single syringe system. In various embodiments, compositions comprising a therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof are disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 484,436, filed February 10, 2023, and U.S. Provisional Patent Application No. 63 / 613,236, filed December 21, 2023, each of which is incorporated by reference herein in its entirety.

[0002] Field The present invention relates generally to a sustained release degarelix / organic solvent injectable formulation. [Background technology]

[0003] background Degarelix is ​​a decapeptide gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the treatment of patients with advanced prostate cancer. Degarelix works by directly blocking the action of GnRH on the pituitary gland by competitively and reversibly binding to the GnRH receptor, resulting in rapid suppression of testosterone with no or minimal initial surge.

[0004] Drug-delivery technologies for degarelix currently marketed in the United States and Europe (e.g., FIRMAGON® (injectable degarelix), Ferring Pharmaceuticals Inc. or Ferring GmbH) have significant limitations, including a starting dose administered as two high-volume injections (3 mL each), followed by a maintenance dose administered as a single high-volume injection (1 × 4 mL) every 28 days. The only commercially available formulation with a dosing interval greater than monthly is marketed in Japan (GONAX® (injectable degarelix), Astellas Pharma Inc.), which has similar significant limitations, including a starting dose administered as two injections of 3 mL each, followed by a maintenance dose administered as two injections of 4 mL each every 12 weeks. Thus, for all currently available degarelix products, multiple high-volume injections (a total of 4–8 mL per administration period) are required for long-term treatment, which is associated with injection-related pain. Furthermore, degarelix has a tendency to self-aggregate in aqueous media. In the case of FIRMAGON®, degarelix is ​​supplied as a powder (lyophilized product containing mannitol as a bulking agent), which, once reconstituted with water, causes degarelix molecules to aggregate and crosslink in a gel-forming network to produce a hydrogel. Due to its self-aggregating properties and chemical instability in aqueous media, this hydrogel must be separated from the aqueous vehicle and maintained in a dry form by lyophilization. Therefore, the hydrogel must be reconstituted at the time of administration. Because the rate and extent of peptide self-aggregation / gel formation in aqueous media are concentration-dependent, preparing an extemporaneous injection formulation of injectable degarelix is ​​challenging. Furthermore, the commercially available form of degarelix is ​​manufactured by aseptic processing, and reconstitution requires multiple steps. Summary of the Invention [Problem to be solved by the invention]

[0005] There is an unmet need for a long-acting GnRH antagonist formulation that is easy to administer, can be terminally sterilized between manufactures, is administered less frequently than once a month, reduces the total number of injections during a single administration period, significantly reduces injection volume, and reduces injection pain. Therefore, it would be highly beneficial to have an injectable drug formulation of degarelix available in a single syringe system that is immediately injected and that provides sustained release of a therapeutically effective amount of degarelix for more than one month in a single injection in a range of small injection volumes (<2.5 mL or ≦2 mL). [Means for solving the problem]

[0006] overview In various embodiments, a composition is disclosed comprising a therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof, the composition comprising a biocompatible organic solvent, the composition being formulated for subcutaneous injection into a subject, wherein a single dose of the composition is about 2.5 mL or less, or about 2.0 mL or less, and upon injection into a subject, the composition forms an in situ depot that releases degarelix over a period of about 1 month to about 6 months.

[0007] In one embodiment of the composition, the in situ depot releases degarelix over a period selected from the group consisting of at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months and at least about 5 months.

[0008] In one embodiment of the composition, the pharmaceutically acceptable salt of degarelix is ​​selected from degarelix acetate, degarelix citrate, degarelix pamoate, degarelix palmitate, and degarelix mesylate.

[0009] In one embodiment of the composition, the amount of biocompatible solvent in the composition is from about 50% to about 99% by weight of the composition.

[0010] In one embodiment of the composition, the therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof in the composition is from about 1% to about 50% by weight of the composition.

[0011] In one embodiment of the composition, the therapeutically effective amount of degarelix is ​​about 40 mg to 500 mg.

[0012] In yet another embodiment of the composition, the therapeutically effective amount of degarelix is ​​about 80 mg to 500 mg.

[0013] In yet another embodiment of the composition, the therapeutically effective amount of degarelix is ​​about 120 mg to 500 mg.

[0014] In one embodiment of the composition, the biocompatible solvent is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), benzyl benzoate (BnBzO), polyethylene glycol 15 hydroxystearate, methyl ethyl ketone, methyl lactate, benzyl alcohol, propylene carbonate (PC), triacetin, tributyl citrate, tributyl acetyl citrate, triethyl acetyl citrate, triethyl citrate, diethylene glycol monomethyl ether, ethyl acetate, N-ethyl-2-pyrrolidone, glycofurol, and combinations thereof. In a preferred embodiment, the biocompatible organic solvent is NMP or DMSO.

[0015] In one embodiment of the composition, a single dose of the composition is about 2.5 mL or less, about 2.4 mL or less, about 2.3 mL or less, about 2.2 mL or less, about 2.1 mL or less, about 2.0 mL or less, about 1.9 mL or less, about 1.8 mL or less, about 1.7 mL or less, about 1.6 mL or less, about 1.5 mL or less, about 1.4 mL or less, about 1.3 mL or less, about 1.2 mL or less, about 1.1 mL or less, about 1 mL or less, about 0.75 mL or less, about 0.5 mL or less, or about 0.375 mL or less.

[0016] In one embodiment of the composition, a single dose of the composition is about 1.0 mL or less.

[0017] In one embodiment of the composition, degarelix is ​​dissolved or dispersed in a biocompatible solvent.

[0018] In one embodiment of the composition, the composition is terminally sterilized or sterile filtered. In one embodiment, the composition is terminally sterilized by electron (e-) beam.

[0019] In one embodiment of the composition, the composition further comprises one or more additives. In one embodiment, the additive is polysorbate 20, polysorbate 80, poloxamer 188, sorbitan trioleate, lecithin (e.g., soy or egg), polyethylene glycol (PEG), PEG 300, 2-pyrrolidone, alpha-tocopherol, vitamin E TPGS, sucrose cocoate, sucrose stearate, sucrose laurate, proline, arginine, sodium metabisulfite butylated hydroxyanisole, butylated hydroxyquinone, butylhydroxyanisole, hydroxycoumarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl-hydroxybenzoate, trihydroxybutylrophenone, vitamin E, lecithin, ethanolamine, ZnCl, MgCl, CaCl, DL-methionine citric acid acid), dimethylphenol, dibutylphenol, ethylenediaminotetraacetic acid (EDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), ascorbic acid, nitrilotriacetic acid, n-hydroxyethylethylenediaminetriacetic acid (HEDTA), mercaptoethanol, and combinations thereof.

[0020] In another embodiment, the additive is an acid additive. In one embodiment, the acid additive is selected from the group consisting of acetic acid (AcOH), citric acid, succinic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid (HCl), pamoic acid, palmitic acid, hydrobromic acid, nitric acid, chromic acid, trifluoroethanesulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 4-cyanobutanoic acid, perchloric acid, phosphoric acid, hydrogen iodide, and combinations thereof. In another embodiment, the acid additive is selected from the group consisting of acetic acid, citric acid, and succinic acid.

[0021] In yet another embodiment, the additive is an alcohol additive. In one embodiment, the alcohol additive is benzyl alcohol (BnOH).

[0022] In one embodiment of the composition, the amount of acid additive in the composition is from about 0.1% to about 10.0% by weight.

[0023] In one embodiment of the composition, the amount of alcohol additive in the composition is about 1.0% to 30% by weight.

[0024] In one embodiment, a pharmaceutical composition is disclosed that comprises about 20% to 40% by weight of degarelix acetate or degarelix citrate; and about 60% to 80% by weight of N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO). In one aspect of this embodiment, the composition further comprises about 0.1% to 10% by weight of an acid additive. In one aspect, the acid additive is selected from the group consisting of acetic acid, citric acid, and succinic acid.

[0025] In one embodiment, a pharmaceutical composition is disclosed that comprises about 25% to 45% by weight of degarelix acetate or degarelix citrate; and about 55% to 75% by weight of N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO). In one aspect of this embodiment, the composition further comprises about 1.0% to 30% by weight of an alcohol additive. In one aspect, the alcohol additive is benzyl alcohol (BnOH).

[0026] In one embodiment, a pharmaceutical composition is disclosed that includes about 35% by weight of degarelix acetate; and about 65% by weight of N-methyl-2-pyrrolidone (NMP).

[0027] In one embodiment, a pharmaceutical composition is disclosed comprising: about 35% by weight of degarelix acetate; and about 65% by weight of DMSO.

[0028] In one embodiment, a pharmaceutical composition is disclosed that includes about 35% by weight of degarelix acetate; about 60% by weight of NMP; and about 5% by weight of benzyl alcohol (BnOH).

[0029] In one embodiment, a pharmaceutical composition is disclosed comprising: about 35% by weight of degarelix citrate; and about 65% by weight of NMP.

[0030] In one embodiment, a pharmaceutical composition is disclosed that includes about 35% by weight of degarelix acetate; about 60% to about 64% by weight of NMP; and about 1% to about 5% by weight of AcOH. In one aspect, the NMP is in an amount of about 62% to about 64% by weight, and the AcOH is in an amount of about 1% to about 3% by weight. In yet another aspect, the NMP is in an amount of about 62.8% by weight, and the AcOH is in an amount of about 2.2% by weight.

[0031] In any of the above embodiments, in one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 30% to about 35% by weight of degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 31% to about 34% by weight of degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 31% to about 33% by weight of degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 31% to about 32% by weight of degarelix free base equivalents. In some aspects, when the target dose to be administered to a subject is calculated based on the degarelix free base equivalents in the composition, the weight percentage of the solvent and, if included, the weight percentage of the additive may be modified accordingly.

[0032] In one embodiment, a pharmaceutical composition is disclosed comprising about 24% by weight of degarelix acetate; about 56% by weight of NMP; and about 20% by weight of BnOH.

[0033] In one embodiment, a pharmaceutical composition is disclosed that includes about 24% by weight of degarelix acetate; about 66 to about 75% by weight of NMP; and about 1 to about 10% by weight of AcOH.

[0034] In one embodiment, a pharmaceutical composition is disclosed that includes about 24% by weight of degarelix acetate; about 70 to about 75% by weight of NMP; and about 1 to about 6% by weight of AcOH.

[0035] In one embodiment, a pharmaceutical composition is disclosed comprising about 24% by weight of degarelix acetate; about 73.3% by weight of NMP; and about 1.7% by weight of AcOH.

[0036] In any of the above embodiments, in one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 20% to about 23% by weight of degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 20% to about 22% by weight of degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 21% to about 23% by weight of degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 21% to about 22% by weight of degarelix free base equivalents. In some aspects, when the target dose to be administered to a subject is calculated based on the degarelix free base equivalents in the composition, the weight percentage of the solvent and, if included, the weight percentage of the additive may be modified accordingly.

[0037] Also contemplated, in various embodiments, are methods of treating prostate cancer and central precocious puberty (CPP), as well as methods of lowering serum testosterone levels and suppressing ovarian function, by subcutaneously administering the compositions disclosed herein to a subject in need thereof.

[0038] In one embodiment, a method for treating prostate cancer in a subject is disclosed, comprising subcutaneously administering to the subject a composition disclosed herein. In one aspect, the prostate cancer is advanced prostate cancer. In one aspect, the dosage of degarelix or a pharmaceutically acceptable salt in the composition is administered at a dosage of about 40 mg to about 500 mg.

[0039] In one embodiment, disclosed is a method for reducing the serum testosterone level of a subject to 50ng / dL or less, comprising subcutaneously administering to the subject the composition disclosed herein.In one aspect, the serum testosterone level is less than 20ng / dL.In yet another aspect, the serum testosterone level is less than 10ng / dL.

[0040] In one embodiment, a method is disclosed for suppressing ovarian function in a subject with hormone receptor-positive breast cancer, comprising subcutaneously administering a composition disclosed herein to the subject. In one aspect, the hormone receptor-positive breast cancer is estrogen receptor (ER)-positive breast cancer. In one aspect, the subject's estradiol (E2) production level is suppressed to a level of less than about 20 pg / mL to about less than about 2 pg / mL. In one aspect, the subject's follicle-stimulating hormone (FSH) level is suppressed to a level of less than about 40 IU / L. In one aspect, the subject's luteinizing hormone (LH) level is suppressed to a level of less than about 4 IU / L.

[0041] In one embodiment, a method for treating central precocious puberty (CPP) in a subject is disclosed, comprising subcutaneously administering to the subject a composition disclosed herein. In one aspect, the subject's CPP serum LH concentration level is reduced to a prepubertal concentration level of less than about 4 IU / L.

[0042] In any of the embodiments of the methods disclosed herein, the composition is administered about once every month, about once every two months, about once every three months, about once every four months, about once every five months, or about once every six months.

[0043] In any of the embodiments of the methods disclosed herein, the composition is administered to the subject about once every three months.

[0044] In any of the embodiments of the methods disclosed herein, the composition is administered as a loading dose, followed by a maintenance dose of the composition about 1 month, about 2 months, or about 3 months after the loading dose. In one embodiment, once the loading dose is administered, the maintenance dose is administered every month, every 2 months, or every 3 months thereafter. In one embodiment, no loading dose is administered, and the composition is administered about once per month, about once per 2 months, about once per 3 months, about once per 4 months, about once per 5 months, or about once per 6 months.

[0045] Another embodiment is a delivery system comprising a single pre-filled syringe with a composition disclosed herein, in some embodiments, together with suitable instructions for using the delivery system to administer the composition to a subject.

[0046] In one embodiment, a pre-filled syringe system for administering the compositions disclosed herein is contemplated, comprising a single syringe containing the compositions disclosed herein. In one aspect, degarelix is ​​dissolved in a biocompatible solvent, and degarelix remains in solution in the solvent. In one aspect, the syringe system is an auto-injector. In one aspect, the syringe system is a reusable auto-injector, which may be provided with a single-use cartridge containing a single dose of the composition of the present invention.

[0047] In one embodiment, a kit is disclosed that includes a pre-filled syringe system disclosed herein and instructions for the pre-filled syringe system for administering the composition contained therein.

[0048] In one embodiment, an article of manufacture comprising a composition disclosed herein for use in a method of treating prostate cancer.

[0049] In one embodiment, an article of manufacture is disclosed that includes the compositions disclosed herein for use in a method of treating CPP.

[0050] In one embodiment, an article of manufacture is disclosed comprising the composition disclosed herein for use in a method for reducing serum testosterone levels below castration levels of at least 50 ng / dL.

[0051] In one embodiment, an article of manufacture is disclosed comprising the composition disclosed herein for use in a method for suppressing ovarian function in a subject with hormone receptor-positive breast cancer. [Brief explanation of the drawings]

[0052] [Figure 1] Figure 1 shows the percentage recovery of degarelix from degarelix / organic solvent formulation samples (Formulations 1, 2, and 5 (F1, F2, and F5) (pre-filled syringes) stored at 25°C for 0 months, 1 month, 3 months, and 6 months. F1: degarelix acetate drug substance (DgA-DS) / NMP (65% / 35%); F2: DgA-DS / DMSO (65% / 35%); F5: DgA-DS / DMSO (60% / 35%).

[0053] [Figure 2] FIG. 2 shows a linear plot of in vivo plasma degarelix levels over the first 3 days after injection using the rat model described in item 13 of Example 1 in the Examples section.

[0054] [Figure 3] FIG. 3 shows a semi-logarithmic plot of in vivo plasma degarelix levels over 28 days post-injection using the rat model described in Example 1, item 13 in the Examples section.

[0055] [Figure 4]FIG. 4 shows plasma degarelix levels in vivo over a 63 day period following injection using the rat model described in Example 1, item 19 in the Examples section.

[0056] [Figure 5] FIG. 5 shows a semi-logarithmic plot of in vivo plasma degarelix levels over 119 days post-injection using the rat model described in Example 1, item 19 in the Examples section.

[0057] [Figure 6] FIG. 6 shows a semi-log plot of plasma testosterone levels in vivo over 105 days post-injection using the rat model described in Example 1, item 19 in the Examples section.

[0058] [Figure 7] FIG. 7 shows a semi-logarithmic plot of in vivo plasma degarelix levels over a 28-day period following injection of a degarelix formulation of the present invention using the rat model described in Example 2 in the Examples section.

[0059] [Figure 8] FIG. 8 shows a semi-logarithmic plot of in vivo plasma testosterone levels over a 28-day period following injection of a degarelix formulation of the present invention using the rat model described in Example 2 in the Examples section.

[0060] [Figure 9] FIG. 9 shows a semi-logarithmic plot of in vivo plasma degarelix levels over a 63 day period following injection of a degarelix formulation of the present invention using the rat model described in Example 2 in the Examples section.

[0061] [Figure 10]FIG. 10 shows a semi-logarithmic plot of in vivo plasma degarelix levels over a 90 day period following injection of a degarelix formulation of the present invention using the rat model described in Example 2 in the Examples section.

[0062] [Figure 11] FIG. 11 shows a semi-logarithmic plot of in vivo plasma testosterone levels over a 90-day period following injection of a degarelix formulation of the present invention using the rat model described in Example 2 in the Examples section.

[0063] [Figure 12] FIG. 12 shows a semi-logarithmic plot of in vivo plasma testosterone levels over a 140-day period following injection of a degarelix formulation of the present invention using the rat model described in Example 2 in the Examples section.

[0064] [Figure 13] FIG. 13 shows a semi-logarithmic plot of in vivo plasma testosterone levels over a 140-day period following injection of a degarelix formulation of the present invention using the rat model described in Example 2 in the Examples section.

[0065] [Figure 14] 14 shows the results of a stability study of various molar ratios of acid additives in degarelix acetate (DgA) / NMP formulations at 1 month, 3 months, and 6 months, as described in Example 3 in the Examples section. The control (DgA / NMP 35 / 65 ratio) received no acid additive. DETAILED DESCRIPTION OF THE INVENTION

[0066] Detailed Description definition As used herein, the terms "active pharmaceutical ingredient" and "drug," abbreviated as "API," can be used interchangeably and generally refer to a biologically active compound that has a therapeutic effect on the body. "Active pharmaceutical ingredient" may refer to an active drug or a pharmaceutically acceptable salt of an active drug. As used herein, these terms may be used to refer to degarelix or a pharmaceutically acceptable salt thereof.

[0067] As used herein, the term "ester" refers to the chemical functional group C(O)OR', where R' represents alkyl as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and the like.

[0068] As used herein, the term "antioxidant" refers to a compound used to extend the shelf life of a product by preventing or inhibiting the oxidation of active substances and additives.Antioxidants can react with free radicals, thereby blocking or inhibiting free radical chain reactions, or antioxidants can have a lower redox potential than the active substances and additives in the formulation.In addition or alternatively, synergistic antioxidants can enhance the effect of other antioxidants.

[0069] As used herein, the term "biocompatible" means "not harmful to living tissue" or "safe for injection into the human body."

[0070] As used herein, the term "biodegradable" refers to any substance that is converted, broken down, or decomposed under physiological conditions into harmless or naturally occurring by-products such as (but not limited to) water, gas, biomass, and / or organic salts, regardless of any particular degradation mechanism or process.

[0071] As used herein, the term "liquid" refers to the ability of a composition to undergo deformation under shear stress, regardless of the presence or absence of a non-aqueous solvent. A "liquid" (as that term is used herein) may also exhibit viscoelastic behavior (i.e., both viscous and elastic characteristics) when subjected to deformation, such as time-dependent strain and / or hysteretic strain. As a non-limiting example, a viscoelastic material that is generally flowable but has partially solid and / or plastic-like or gel-like characteristics (such as jelly, jam, cake batter, or raw pizza dough and similar substances) is a "liquid" as that term is used herein. In some embodiments, a material with a non-zero yield stress that does not deform below the yield stress and is easily deformable above the yield stress without the characteristics of material fracture or rupture can be a "liquid" as that term is used herein.

[0072] As used herein, the terms "patient" and "subject" are interchangeable and generally refer to an animal or human to whom the compositions disclosed herein have been or will be administered.

[0073] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include, but are not limited to: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, lauric acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor acid, and the like. or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinates to an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like.

[0074] As used herein, the term "solvent" refers to a liquid that dissolves a solid or liquid solute, or the liquid external phase of a suspension throughout which a solid or liquid substance may be suspended or dispersed. The term "biocompatible solvent" may be used interchangeably with the term "solvent."

[0075] As used herein, the term "cosolvent" refers to a substance added to a solvent to increase or modify the solubility of a solute in the solvent. Thus, a cosolvent can increase or decrease the solubility of a solute in a primary solvent and / or impart other desired characteristics to a formulation (e.g., the degree of water-insolubility of the solvent and cosolvent in a solvent system can affect the desired rate of diffusion into body fluids to control the rate and extent of gelation of degarelix API; or the solvent / cosolvent can control the viscosity of a composition of the present invention, which aids in the preparation of a sustained-release composition and its administration to a subject).

[0076] As used herein, the term "solvent system" refers to a combination of at least one biocompatible solvent as described herein, which may optionally include at least one co-solvent.

[0077] As used herein, the term "solubilizer" refers to a compound that increases the solubility of another substance.

[0078] As used herein, the term "surfactant" refers to a compound that reduces the surface tension between two liquids, between a gas and a liquid, or between a liquid and a solid.For example, surfactants can act as wetting agents or solubilizers to help disperse active pharmaceutical ingredients in liquid vehicles.

[0079] As used herein, the term "therapeutically effective amount" refers to the amount of a compound or drug product that, when administered to a patient for treating a disease and / or treating or preventing one or more symptoms of a disease, is sufficient to effect such treatment or prevention for the disease. A "therapeutically effective amount" may vary depending, for example, on the compound, disease progression, the disease or condition being treated, whether the treatment is adjuvant therapy or primary or curative therapy, and / or the age, weight, etc. of the patient being treated.

[0080] As used herein, the terms "at least one," "one or more," and "and / or" are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions "at least one of A, B, and C," "at least one of A, B, or C," "one or more of A, B, and C," "one or more of A, B, or C," "A, B, and / or C," and "A, B, or C" means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B, and C together. Each one of A, B, and C in the above expressions can refer to elements such as X, Y, and Z, or X1 through X2. n , Y1~Y m and Z1 to Z o When referring to a class of elements such as X, Y, and Z, the phrase includes a single element selected from X, Y, and Z, a combination of elements selected from the same class (e.g., X1 and X2), and a combination of elements selected from two or more classes (e.g., Y1 and Z). o ) is intended to refer to a combination of elements selected from:

[0081] As used herein, the term "depot" (which may also be referred to herein as "fibrils" or "gels") refers to degarelix compositions / formulations disclosed herein in which, once exposed to an aqueous environment (including, for example, the physiological environment within an animal's body), the degarelix API self-aggregates to create a drug reservoir from which degarelix is ​​released over an extended period of time.

[0082] Unless otherwise specified, the various amounts of API and solvent and co-solvent are reported as weight percentages of the solvent system or pharmaceutical composition.

[0083] Every maximum numerical limitation given throughout this disclosure is deemed to include, as an alternative, every lower numerical limitation, as if such lower numerical limitation were expressly written herein. Every minimum numerical limitation given throughout this disclosure is deemed to include, as an alternative, every higher numerical limitation, as if such higher numerical limitation were expressly written herein. Every numerical range given throughout this disclosure is deemed to include both limits, and every narrower numerical range that falls within such broader numerical range, as if such narrower numerical range were all expressly written herein. For example, the phrase "about 2 to about 4" includes integers and / or integer ranges from about 2 to about 3, from about 3 to about 4, and each possible range based on real (e.g., irrational and / or rational) numbers, such as about 2.1 to about 4.9, about 2.1 to about 3.4, etc.

[0084] Reference will now be made in detail to specific embodiments of the compounds, formulations and methods. The disclosed embodiments are not intended to limit the scope of the claims.

[0085] Degarelix is ​​a decapeptide selective gonadotropin-releasing hormone (GnRH) receptor antagonist (blocker) that competitively and reversibly binds to the pituitary GnRH receptor. This results in a significant reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thereby reducing testosterone levels in men or estrogen levels in women. In one embodiment of the present invention, degarelix is ​​indicated for LH suppression or testosterone suppression in adult male patients with hormone-dependent advanced prostate cancer, in whom androgen deprivation is required. Degarelix formulations of the present invention are also useful for LH suppression or estrogen (e.g., estradiol) suppression in adult female patients with premenopausal or perimenopausal breast cancer, and for conditions including, but not limited to, endometriosis. Degarelix formulations of the present invention are also useful for LH suppression or sex hormone suppression (testosterone or estrogen, depending on whether the patient is male or female) in children with central precocious puberty (CPP). There is an unmet need for a sustained release injectable formulation of degarelix that (1) is easy to prepare and administer (e.g., by a healthcare provider), (2) provides sustained or extended release of degarelix for more than one month after a single dose, and in one embodiment, for at least three months or longer, and (3) is administered in a total injection volume of about 2.5 mL or less, or about 2 mL or less.

[0086] Disclosed herein are sustained-release injectable compositions or formulations (used interchangeably and which may also be referred to as "drug products," "pharmaceutical products," "products," or "final drug products") comprising degarelix or a pharmaceutically acceptable salt thereof in a sustained-release injectable formulation in an organic solvent. These formulations do not contain biodegradable polymers. The formulations comprise a biocompatible, water-miscible solvent and may optionally further comprise one or more additives disclosed herein. The degarelix compositions / formulations disclosed herein are flowable solutions or suspensions in which, upon delivery (i.e., injection) into an aqueous environment (e.g., the human body), the water-miscible solvent exchanges with the surrounding aqueous body fluid, resulting in the formation of a degarelix depot or fibrils, or gelation, which act as a drug reservoir for sustained release of the degarelix peptide (i.e., releasing the drug over an extended period of time).

[0087] The compositions / formulations disclosed herein, when injected subcutaneously in small volumes (e.g., ≦2.5 mL or ≦2 mL), provide sustained or extended release of degarelix or a pharmaceutically acceptable salt thereof for greater than one month. Long-acting injectable compositions suitable for use in the disclosed methods, which may also be referred to as pharmaceutical compositions or formulations, sustained release compositions or formulations, or controlled release compositions or formulations, provide a biodegradable or biodegradable in situ-forming depot of degarelix or a pharmaceutically acceptable salt thereof in a subject, from which degarelix or a pharmaceutically acceptable salt thereof is released over a period of one month or longer. The composition / formulation may be supplied in a single pre-filled syringe containing an injection volume of less than or equal to 2.5 mL, less than or equal to 2.4 mL, less than or equal to 2.3 mL, less than or equal to 2.2 mL, less than or equal to 2.1 mL, less than or equal to 2.0 mL, less than or equal to 1.9 mL, less than or equal to 1.8 mL, less than or equal to 1.7 mL, less than or equal to 1.6 mL, or less than or equal to 1.5 mL, and is suitable for subcutaneous injection. This composition solves the problem of multiple high-volume injections presented by the currently marketed degarelix product.

[0088] After administration of the compositions disclosed herein, degarelix or a pharmaceutically acceptable salt thereof is released from the depot over a period of at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months, at least about 5 months, or at least about 6 months. The release period from the depot can depend on one or several factors, including, for example, the solvent, the amount of components in the composition, optional additives in the composition, and any combination of the above or other factors.

[0089] Active Pharmaceutical Ingredients (API) The compositions / formulations disclosed herein comprise degarelix or a pharmaceutically acceptable salt thereof in a solvent-based drug delivery system. Pharmaceutically acceptable salts of degarelix include, but are not limited to, degarelix acetate, degarelix citrate, degarelix pamoate, and degarelix mesylate. "Degarelix API" (whether capitalized or not) as used herein refers to degarelix or any pharmaceutically acceptable salt thereof.

[0090] Generally, the disclosed compositions comprise a biocompatible solvent and degarelix or a pharmaceutically acceptable salt thereof. The pharmaceutical composition is administered to a patient by subcutaneous injection as a liquid or gel, and the solid, semi-solid, or liquid depot is composed of fibrils that form a gel of degarelix in situ upon dissipation of the solvent. The depot thus formed releases degarelix or a pharmaceutically acceptable salt thereof in a controlled or sustained release manner.

[0091] The concentration of degarelix or a pharmaceutically acceptable salt thereof in the disclosed compositions can vary and may range from 1% to 50% by weight of the composition (including from any integer percent to any other integer percent within the range of about 1 weight percent to about 50 weight percent). The concentration of degarelix or a pharmaceutically acceptable salt thereof in the compositions can be about 5% by weight of the composition, or about 10% by weight of the composition, or about 15% by weight of the composition, or about 20% by weight of the composition, or about 21% by weight of the composition, or about 22% by weight of the composition, or about 23% by weight of the composition, or about 24% by weight of the composition, or about 25% by weight of the composition, or about 26% by weight of the composition, or about 27% by weight of the composition, or about 28% by weight of the composition, It can be about 29% by weight of the composition, or about 30% by weight of the composition, or about 31% by weight of the composition, or about 32% by weight of the composition, or about 33% by weight of the composition, or about 34% by weight of the composition, or about 35% by weight of the composition, or about 36% by weight of the composition, or about 37% by weight of the composition, or about 38% by weight of the composition, or about 40% by weight of the composition, or about 45% by weight of the composition, or about 50% by weight of the composition. In other embodiments, the amount of degarelix API in the compositions of the present invention can range from any 0.1 percent to any other 0.1 percent within the range of about 1% to about 50% by weight.

[0092] In some embodiments, the amount of degarelix API in the compositions of the invention is referred to in terms of the amount of a pharmaceutically acceptable salt of degarelix, such as acetate or other salts of degarelix, in the composition. In some embodiments, the amount of degarelix API in the compositions of the invention is referred to in terms of the amount of degarelix free base equivalent in the composition (which may also be simply referred to as the amount of degarelix in the composition). For example, determining the dosage of degarelix API to be administered to a subject may be calculated based on the amount of degarelix free base equivalent in the composition, rather than the amount of degarelix salt, to account for differences in purity, water, or acetic acid content (e.g., in the case of degarelix acetate) between various API lots. Calculating the amount of degarelix free base equivalent in a composition is well understood within the skill of the art. For example, the percentage (by weight) of degarelix as the free base in a composition in which the degarelix API is degarelix acetate is 100 - (% water content of drug substance by weight - % acetic acid content of drug substance by weight) * Degarelix Purity by Assay (Anhydrous / Acid Free Base) * It can be calculated by a simple formula such as % by weight of degarelix acetate in the composition. The free base equivalent can also be obtained from the United States Pharmacopeia monograph for the drug substance.

[0093] In one embodiment, the amount of degarelix or a pharmaceutically acceptable salt thereof (degarelix API) in the compositions of the present invention is about 30% to about 35% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 31% to about 34% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 31% to about 33% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 31% to about 32% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 20% to about 23% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 20% to about 22% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 21% to about 23% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 21% to about 22% by weight of degarelix free base equivalents. In some embodiments, when the target dose to be administered to a subject is calculated based on the amount of degarelix free base equivalents in the composition, the weight percentage of the solvent and, if included, the weight percentage of the excipient may be modified accordingly.

[0094] solvent Any suitable water-miscible solvent can be used, provided that the solvent is miscible to dispersible in aqueous media or body fluids. Examples of suitable solvents are disclosed, for example, in Aldrich Handbook of Fine Chemicals and Laboratory Equipment, Milwaukee, Wis. (2000); and U.S. Patent Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194. In various embodiments, the solvent is diffusible into body fluids, resulting in the flowable composition coagulating or solidifying. The solvents and co-solvents that can be used in the disclosed compositions are preferably biocompatible, non-toxic solvents, which may be either hydrophilic or hydrophobic solvents, or a combination of hydrophilic solvents, hydrophobic solvents, or a combination of hydrophilic and hydrophobic solvents, depending on the desired release profile and the solubility of the degarelix API in the composition. In one embodiment, the solvent and / or co-solvent is an organic solvent. In yet another embodiment, the solvent and / or co-solvent is a polar aprotic solvent.

[0095] Suitable solvents and co-solvents can include one or more solvents selected from the group consisting of amides, acids, alcohols, esters of monobasic acids, ether alcohols, sulfoxides, lactones, polyhydroxy alcohols, esters of polyhydroxy alcohols, ketones, and ethers. By way of non-limiting example, the solvent or co-solvent can include at least one of N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), acetone, benzyl benzoate (BnBzO), polyethylene glycol 15-hydroxystearate, ethyl acetate, glycofurol, N-hydroxyethyl-2-pyrrolidone, polyethylene glycol (PEG), benzyl alcohol (BzOH), propylene carbonate (PC), propylene glycol, 2-pyrrolidone, α-tocopherol, triacetin, tributyl citrate, tributyl acetyl citrate, triethyl acetyl citrate, triethyl citrate, esters thereof, and combinations thereof.

[0096] In an embodiment of the invention, a suitable solvent is selected from N-methyl-2-pyrrolidone (NMP) and / or dimethyl sulfoxide (DMSO). In an embodiment of the invention, a suitable co-solvent comprises benzyl alcohol (BzOH).

[0097] As also disclosed herein, degarelix or a pharmaceutically acceptable salt thereof is preferably substantially or completely dissolved in a biocompatible solvent or solvent system.

[0098] The biocompatible solvent, or combination or mixture of solvents and / or co-solvents, used in the compositions of the present invention generally comprises between about 50% and about 99% by weight of the final formulation, or between about 30% and about 69% by weight of the final formulation, or between about 40% and about 59% by weight of the final formulation, or alternatively, the solvent, or combination or mixture of solvents and / or co-solvents, may range from any integer weight percentage of the formulation between about 50% and about 99% by weight to any other integer weight percentage of the formulation. When the formulation includes optional co-solvents and / or additives, the ratio of solvent to degarelix API may remain the same, although the weight percentages of each in the final formulation may vary due to the presence of the co-solvents and / or additives.

[0099] additives If desired, the pharmaceutical compositions disclosed herein may contain various additives (which may also be referred to as "excipients") to improve the stability, injectability, or / and other properties of the composition, including reducing pain or inflammation upon injection of the composition. For example, the pharmaceutical compositions may contain one or more of an antioxidant, a chelating agent, a surfactant, a cosolvent (also discussed above), a stabilizer, a complexing agent, an antioxidant, and a solubilizing agent.

[0100] In some embodiments, the pharmaceutical composition may contain one or more solubilizers to improve the solubility of one or more other components of the composition.Solubilizers useful in the disclosed compositions include any solubilizers useful for parenteral injection, including but not limited to surfactants and other solubilizers that reduce the surface tension between two liquids, between a gas and a liquid, or between a liquid and a solid. Examples of solubilizers and / or surfactants suitable for use in the present invention include, but are not limited to, polysorbate 20, polysorbate 80, poloxamer 188, sorbitan trioleate, lecithin (e.g., soy or egg), vitamin E TPGS, sugar-based esters or ethers (e.g., sugar acid esters of fatty alcohols or sugar alcohol esters of fatty acids (including, but not limited to, sucrose cocoate, sucrose stearate, sucrose laurate, etc.)), amino acid-based solubility enhancers (e.g., proline, arginine, DL-methionine), protein-based solubility enhancers (e.g., hydrophobin), and the like.

[0101] In some embodiments, the pharmaceutical compositions may include one or more antioxidants to inhibit oxidation of the API and improve formulation stability. Examples of antioxidants suitable for use in the present invention include, but are not limited to, citric acid, methanesulfonic acid, ascorbic acid, ethylenediaminotetraacetic acid (EDTA), mercaptoethanol, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxyquinone, butylhydroxyanisole, hydroxycoumarin, butylated hydroxytoluene, cephalum, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl-hydroxybenzoate, trihydroxybutylrophenone, dimethylphenol, dibutylphenol, vitamin E, lecithin, and ethanolamine.

[0102] In some embodiments, the pharmaceutical compositions may include one or more complexing agents to prevent oxidation and / or degradation of the API and improve the stability of the formulation. Examples of complexing agents suitable for use in the present invention include, but are not limited to, ethylenediaminotetraacetic acid (EDTA), divalent metal salts (ZnCl, MgCl, CaCl), nitrilotriacetic acid, n-hydroxyethylethylenediaminetriacetic acid (HEDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and some simple organic acids such as polycarboxylic acids (citric acid), hydrochloric acid, sulfuric acid, pamoic acid, and palmitic acid.

[0103] In some embodiments, the pharmaceutical composition may include one or more modified release additives.

[0104] In some embodiments, the pharmaceutical compositions may contain one or more stabilizers to prevent drug degradation (physical or chemical) and improve formulation stability and shelf life. Examples include, but are not limited to, surfactants (e.g., polysorbate 20, polysorbate 80, poloxamer 188), complexing agents (e.g., divalent metal salts), acid additives (e.g., acetic acid (AcOH), citric acid, succinic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid (HCl), pamoic acid, palmitic acid), and alcohols (e.g., benzyl alcohol).

[0105] For example, in some embodiments, an acid additive is optionally included in the pharmaceutical compositions of the present invention as an additional additive (i.e., in addition to the degarelix API and solvent and / or co-solvent). The acid additive as an additive provides additional acid in the compositions of the present invention in addition to any acid provided by the pharmaceutical salt of the API itself (e.g., the acid content in the degarelix acetate drug substance). Such an acid additive can improve the stability and increase the shelf life of the formulation, for example, by reducing the level of impurities appearing in the formulation over time prior to use and / or by reducing the amount of aggregates of the degarelix API over time prior to use. Acid additives can include, but are not limited to, acetic acid (AcOH), citric acid, succinic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid (HCl), pamoic acid, palmitic acid, hydrobromic acid, nitric acid, chromic acid, trifluoroethanesulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 4-cyanobutanoic acid, perchloric acid, phosphoric acid, hydrogen iodide, and combinations thereof. In one embodiment, the acid additive is acetic acid, citric acid, and / or succinic acid.

[0106] In embodiments, the concentration of the acid additive as an additive in the disclosed compositions can vary and may range from about 0.1% to about 10% by weight of the composition (including any 0.1 percent increments within the range of about 0.1 weight percent to about 10 weight percent). In one embodiment, the concentration of the acid additive as an additive in the disclosed compositions is from about 0.1% to about 9% by weight; or from about 0.1% to about 8% by weight; or from about 0.1% to about 7% by weight; or from about 0.1% to about 6% by weight; or from about 0.1% to about 5% by weight; or from about 0.1% to about 4% by weight; or from about 0.1% to about 3% by weight; or from about 0.1% to about 2% by weight; or from about 0.1% to about 2% by weight; or from about 0.5% to about 10% by weight; or from about 0.5% to about 9% by weight; or from about 0.5% to about 8% by weight; or from about 0.5% to about 7% by weight. % by weight; or about 0.5% by weight to about 6% by weight; or about 0.5% by weight to about 5% by weight; or about 0.5% by weight to about 4% by weight; or about 0.5% by weight to about 3% by weight; or about 0.5% by weight to about 2% by weight; or about 1% by weight to about 10% by weight; or about 1% by weight to about 10% by weight; or about 1% by weight to about 9% by weight; or about 1% by weight to about 8% by weight or about 1% by weight to about 7% by weight or about 1% by weight to about 6% by weight; or about 1% by weight to about 5% by weight; or about 1% by weight to about 4% by weight; or about 1% by weight to about 3% by weight; or about 1% by weight to about 2% by weight.

[0107] In an embodiment, the amount of acid additive as an additive in the disclosed compositions can be expressed as a molar ratio of degarelix API (the drug substance before addition to the formulation) to the acid additive. In an embodiment, the molar ratio of degarelix API (calculated as the free base) to the acid additive in the formulation is 1:1 or 1:2 or 1:3 or 1:4 or 1:5 or 1:6. In another embodiment, the molar ratio of degarelix API (calculated as the free base) to the total amount of acid (attributable to degarelix API salt forms and the acid additive, if present) in the formulation is 1:1 or 1:2 or 1:3 or 1:4 or 1:5 or 1:6 or 1:7 or 1:8 or 1:9.

[0108] In embodiments, the amount of acid in a composition of the invention can alternatively be expressed as the total amount of acid attributable to all components in the formulation (i.e., from the degarelix API salt form and any acid additives as excipients). In embodiments, the total amount of acid in the composition (as a weight percent of the composition) is from about 1% to about 10%, or from about 1.5% to about 10%, or from about 2.0% to about 10%, or from about 2.5% to about 10%, or from about 3.0% to about 10%, or from about 3.5% to about 10%, or from about 4.0% to about 10%, or from about 4.5% to about 10%, or from about 5.0% to about 10%, or from about 5.5% to about 10%, or from about 6.0% to about 10%, or from about 6.5% to about 10%, or is about 7.0% to about 10%; or about 7.5% to about 10%; or about 8.0% to about 10%; or about 8.5% to about 10%; or about 9.0% to about 10%; or about 9.5% to about 10%, or about 1.0% to about 7.0%, or about 1.0% to about 6.0%, or about 1.0% to about 5.0%, or about 1.0% to about 4.0%, or about 1.0% to about 3.0%, or about 1.0% to about 2.0%, or any range between 1% and 10% in increments of 0.1%.

[0109] In an embodiment, the amount of acid in the degarelix drug substance (the degarelix API itself, not as an excipient) prior to addition to a composition or formulation is in the range of about 0% to about 10% by weight, 1% to about 10% by weight, or about 2% to about 10% by weight, or about 3% to about 10% by weight, or about 3.5% to about 10% by weight, or about 4% to about 10% by weight, or about 4.5% to about 10% by weight, or about 5% to about 10% by weight, or about 5.5% to about 10% by weight, or about 6% to about 10% by weight, or about 6.5% to about 10% by weight, or about 7% to about 10% by weight, or about 7.5% to about 10% by weight, or about 8% to about 10% by weight, or about 8.5% to about 10% by weight, or about 9% to about 10% by weight, or about 9.5% to about 10% by weight.

[0110] In yet other embodiments, the compositions further comprise an additive (additive) that is alcohol, which can act as a co-solvent and can also provide additional properties to the composition, including, but not limited to, improving formulation stability, improving injectability, and / or reducing pain, inflammation, or irritation upon injection into the body. In one embodiment, the formulations of the present invention optionally comprise benzyl alcohol as an additive / additive. In embodiments, the concentration of the alcohol additive as an additive in the disclosed compositions can vary and may range from about 1% to about 30% by weight of the composition, including any 1 percent increment within the range of about 1 percent to about 30 percent by weight of the composition. In one embodiment, the concentration of the alcohol additive as an additive in the disclosed compositions is from about 1% to about 30% by weight; or from about 5% to about 30% by weight; or from about 10% to about 30% by weight; or from about 11% to about 30% by weight; or from about 12% to about 30% by weight; or from about 13% to about 30% by weight; or from about 14% to about 30% by weight; or from about 15% to about 30% by weight; or from about 16% to about 30% by weight; or from about 17% to about 30% by weight; or from about 18% to about 30% by weight. or about 24% to about 30% by weight; or about 25% to about 30% by weight; or about 26% to about 30% by weight; or about 27% to about 30% by weight; or about 28% to about 30% by weight; or about 29% to about 30% by weight.

[0111] composition In various embodiments, the present disclosure provides a sustained-release injectable pharmaceutical composition comprising degarelix or a pharmaceutically acceptable salt thereof, a biocompatible solvent, and optionally one or more additives.All of these compositions are intended to be administered to subjects to treat diseases or conditions that may benefit from the administration of GnRH agonists or GnRH antagonists.In various embodiments, the compositions of the present invention are intended to be used to treat prostate cancer, including advanced prostate cancer, central precocious puberty (CPP), premenopausal or perimenopausal breast cancer, or other conditions, including but not limited to endometriosis.In addition, these compositions are intended to be administered to subjects to reduce luteinizing hormone (LH) levels, and to reduce serum testosterone levels in men and serum estrogen levels in women.

[0112] Depending on the other components in the composition, degarelix or a pharmaceutically acceptable salt thereof in the disclosed compositions may form a single-phase mixture (e.g., a solution) or a two-phase mixture (e.g., a suspension or dispersion) within the composition. Thus, a sustained-release composition comprising degarelix or a pharmaceutically acceptable salt thereof according to the present invention may suitably be either a "solution" or a "dispersion" or a "suspension" of degarelix or a pharmaceutically acceptable salt thereof in a biocompatible solvent. Preferably, degarelix or a pharmaceutically acceptable salt thereof is in solution in a biocompatible solvent and is thus single-phase. More preferably, the degarelix API is a stable solution and remains in solution in the biocompatible solvent, and therefore does not require reconstitution or mixing to maintain a stable solution.

[0113] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 20% to about 40% by weight of degarelix acetate or degarelix citrate; and about 60% to about 80% by weight of N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO).

[0114] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 25% to about 45% by weight of degarelix acetate or degarelix citrate and about 55% to about 75% by weight of NMP or DMSO.

[0115] In some embodiments, the present disclosure provides pharmaceutical compositions comprising degarelix API in an amount of about 20% to about 45% by weight of degarelix free base equivalents. In some aspects, the present disclosure provides pharmaceutical compositions comprising degarelix API in an amount of about 20% to about 40% by weight of degarelix free base equivalents, or about 20% to about 35% by weight of degarelix free base equivalents, or about 20% to about 34% by weight of degarelix free base equivalents, or about 20% to about 33% by weight of degarelix free base equivalents, or about 20% to about 32% by weight of degarelix free base equivalents. In some embodiments, the present disclosure provides pharmaceutical compositions comprising degarelix API in an amount of about 30% to about 35% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 31% to about 34% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 31% to about 33% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 31% to about 32% by weight of degarelix free base equivalents.

[0116] In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 20% to about 23% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 20% to about 22% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 21% to about 23% by weight of degarelix free base equivalents. In one embodiment, the amount of degarelix API in the pharmaceutical composition is about 21% to about 22% by weight of degarelix free base equivalents. In some embodiments, when the target dose to be administered to a subject is calculated based on the amount of degarelix free base equivalents in the composition, the weight percentage of the solvent and, if included, the weight percentage of the excipient may be modified accordingly.

[0117] In some embodiments, the present disclosure provides pharmaceutical compositions, as described in more detail above, further comprising an acid additive as an excipient. In one aspect, the composition further comprises about 0.1% to about 10.0% by weight of the acid additive, or about 1.0% to about 6.0% by weight of the acid additive, or about 1.0% to about 5.0% by weight of the acid additive, or about 1.0% to about 4.0% by weight of the acid additive, or about 1.0% to about 3.0% by weight of the acid additive, or about 1.0% to about 2.0% by weight of the acid additive. In one aspect, the acid is acetic acid, citric acid, or succinic acid.

[0118] In yet another embodiment, the present disclosure provides a pharmaceutical composition further comprising benzyl alcohol as an additional excipient. In one aspect, the composition further comprises about 5.0% to about 30% by weight of benzyl alcohol (BnOH).

[0119] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35% by weight of degarelix acetate; and about 65% by weight of N-methyl-2-pyrrolidone (NMP).

[0120] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35% by weight of degarelix acetate; and about 65% by weight of DMSO.

[0121] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 to about 40% by weight of degarelix acetate; about 55 to about 70% by weight of NMP; and about 5 to about 10% by weight of benzyl alcohol (BnOH).

[0122] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35% by weight of degarelix citrate; and about 65% by weight of NMP.

[0123] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35% by weight of degarelix acetate; about 62 to about 64% by weight of NMP; and about 1 to about 5% by weight of AcOH.

[0124] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35% by weight of degarelix acetate; about 62 to about 64% by weight of NMP; and 1 to 3% by weight of AcOH.

[0125] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35% by weight of degarelix acetate; about 62.8% by weight of NMP; and about 2.2% by weight of AcOH.

[0126] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24% by weight of degarelix acetate; about 50 to about 60% by weight of NMP; and about 16 to about 26% by weight of BnOH.

[0127] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24% by weight of degarelix acetate; about 54 to about 58% by weight of NMP; and about 18 to about 22% by weight of BnOH.

[0128] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24% by weight of degarelix acetate; about 56% by weight of NMP; and about 20% by weight of BnOH.

[0129] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24% by weight of degarelix acetate; about 66 to about 75% by weight of NMP; and about 1 to about 10% by weight of AcOH.

[0130] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24% by weight of degarelix acetate; about 70 to about 75% by weight of NMP; and about 1 to about 6% by weight of AcOH.

[0131] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24% by weight of degarelix acetate; about 73.3% by weight of NMP; and about 1.7% by weight of AcOH.

[0132] Treatment, Use and Administration The disclosed methods are used to treat diseases or conditions including prostate cancer, including advanced prostate cancer. Furthermore, the disclosed methods are used to reduce serum testosterone levels to below castration levels of at least 50 ng / dL, or below 20 ng / dL or below 10 ng / dL.

[0133] Furthermore, the disclosed method is used to suppress ovarian function in a subject with hormone receptor-positive breast cancer. In one embodiment, the hormone receptor-positive breast cancer is premenopausal breast cancer. In one embodiment, the hormone receptor-positive breast cancer is perimenopausal breast cancer. In one embodiment, the hormone receptor-positive breast cancer is estrogen receptor (ER)-positive breast cancer. In one embodiment, the composition disclosed herein suppresses the subject's estradiol (E2) production to a level of less than about 20 pg / ml, less than about 15 pg / mL, less than about 10 pg / mL, less than about 5 pg / mL, less than about 4 pg / mL, less than about 3 pg / mL, or less than about 2 pg / mL. In a preferred embodiment, the E2 production level is reduced to about 2.7 pg / mL. In yet another embodiment, the composition disclosed herein suppresses follicle-stimulating hormone (FSH) in a breast cancer subject to a level of less than about 40 IU / L. In yet another aspect, the compositions disclosed herein suppress luteinizing hormone (LH) in a subject with breast cancer to a level of less than about 4 IU / L.

[0134] Still further, the methods of the present disclosure are used to treat endometriosis.

[0135] The disclosed method is used to treat central precocious puberty (CPP). CPP is defined by precocious sexual development driven by the production and release of gonadotropins and / or sex steroids from normal endogenous sources, including the hypothalamus or pituitary gland. Abnormal gonadotropin and / or sex hormone levels in children with CPP can result from a variety of causes, including, but not limited to, physical injury, infection, genetic disease, or related tumors. CPP caused by genetic or unknown pathology is classified as idiopathic in nature, while CPP caused by tumors and / or lesions of the central nervous system (CNS) is classified as organic in nature. CPP is associated with advanced bone age, accelerated growth rate, and activation of the hypothalamic-pituitary-gonadal axis. In one embodiment, the composition disclosed herein reduces serum LH levels in subjects with CPP to prepubertal levels of <4 IU / L.

[0136] The method involves subcutaneously or intramuscularly administering the disclosed sustained-release injectable composition to subjects / patients suffering from prostate cancer, advanced prostate cancer, CPP, premenopausal breast cancer, postmenopausal breast cancer, and subjects in need of reducing serum testosterone and / or LH levels. Upon injection of the pharmaceutical composition into the body and contact of the composition with bodily fluids, the solvent dissipates, causing degarelix to self-aggregate or gel, forming a drug reservoir or depot. The resulting depot releases degarelix or a pharmaceutically acceptable form thereof over a desired extended period of time. In various embodiments, degarelix or a pharmaceutically acceptable salt thereof is released to the subject / patient for, for example, at least about 30 days or longer, at least about 60 days or longer, at least about 90 days or longer, at least about 120 days or longer, at least about 150 days or longer, or 180 days or longer. In still other embodiments, degarelix or a pharmaceutically acceptable salt thereof is released to the subject / patient for, for example, at least about 1 month or longer, at least about 2 months or longer, at least about 3 months or longer, at least about 4 months or longer, at least about 5 months or longer, or 6 months or longer.

[0137] The sustained-release composition may be administered to a patient / subject about once every 30 days, about once every 60 days, about once every 90 days, about once every 120 days, about once every 150 days, or about once every 180 days. In another embodiment, the sustained-release composition may be administered to a patient / subject about once every month, about once every 2 months, about once every 3 months, about once every 4 months, about once every 5 months, or about once every 6 months. In a preferred embodiment, the composition is administered about once every 3 months. For clarity, according to the present invention, a "month" can have a duration of between 28 and 31 days.

[0138] The amount of degarelix or a pharmaceutically acceptable salt thereof effective in treating or ameliorating the above-described diseases or conditions will depend on the nature / severity of the condition or symptoms. In vitro or in vivo assays may be employed, as needed, to help identify optimal dosage ranges. The amount of degarelix or a pharmaceutically acceptable salt thereof administered will, of course, depend on the subject being treated, the subject's age / weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician, among other factors.

[0139] The dosage of degarelix or a pharmaceutically acceptable salt thereof in the composition for treating prostate cancer and / or advanced prostate cancer is about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 210 mg g, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, or about 500 mg. In one embodiment, a single dose may be administered in a single injection. In yet another embodiment, a single dose may be administered in more than one injection.

[0140] In one aspect, the disclosed compositions will be administered to a subject / patient once per dosing period, with varying durations between doses (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months). In one aspect, the disclosed compositions will be administered to a subject / patient with an initial loading dose, followed by one or more maintenance doses of the disclosed compositions. Administration may be given alone or in combination with other drugs and may continue as long as necessary for effective treatment of the disease state or disorder. In some embodiments, the disclosed compositions are formulated to provide a dose of between about 40 mg and about 500 mg. In these embodiments, the compositions are delivered in a total volume or per injection volume not exceeding 2.5 mL, or not exceeding 2 mL. In some embodiments, the injection volume is about 2.5 mL or less, about 2.4 mL or less, about 2.3 mL or less, about 2.2 mL or less, about 2.1 mL or less, about 2.0 mL or less, about 1.9 mL or less, about 1.8 mL or less, about 1.7 mL or less, about 1.6 mL or less, about 1.5 mL or less, about 1.4 mL or less, about 1.3 mL or less, about 1.2 mL or less, about 1.1 mL or less, about 1 mL or less, about 0.75 mL or less, about 0.5 mL or less, or about 0.375 mL or less. In some embodiments, the injection volume is about 0.375 mL, about 0.5 mL, about 0.75 mL, about 1 mL, about 1.5 mL, or about 1.75 mL, or about 2 mL, about 2.2 mL, or about 2.5 mL.

[0141] In some embodiments, the composition is terminally sterilized, such as by electron (e-) beam or gamma irradiation or X-ray. In yet another aspect, the composition is sterile filtered.

[0142] In some embodiments, the sustained-release composition is administered to a patient as a monotherapy. The treatment of this embodiment can reduce or eliminate one or more symptoms of the diseases and / or conditions disclosed herein. In other embodiments, the sustained-release composition is administered as a monotherapy other than chemotherapy, radiation therapy, surgery, endocrine therapy (e.g., selective estrogen receptor modulators (SERMs; such as tamoxifen, toremifene, raloxifene, ospemifene, and bazedoxifene), selective estrogen receptor degraders (SERDs; such as fulvestrant), aromatase inhibitors (AIs; such as anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole); mammalian target of rapamycin (mTOR) inhibitors; temsirolimus, sirolimus, everolimus, and ribozyme. daforolimus, etc.); phosphatidylinositol 3-kinase inhibitors (PI-3 kinase or PI3K; such as alpelisib, idelalisib, and buparlisib); inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 / 6 inhibitors; such as abemaciclib, palbociclib, and ribociclib); LHRH agonists (such as leuprolide, gonadorelin, goserelin, histrelin, nafarelin, buserelin, and triptorelin, and pharmaceutically acceptable salts thereof), immunotherapy, and gene therapy, etc.

[0143] The disclosed sustained-release compositions may be supplied as part of a delivery system comprising a syringe system, with the composition or formulation contained within the syringe. In some embodiments, the syringe is a pre-filled syringe system containing the disclosed composition as a single dose or multiple doses. The syringe may contain single or multiple doses of the composition / formulation of the present invention. In one aspect of the pre-filled syringe system, the syringe is a mixing syringe (e.g., a syringe that provides a mechanism for mixing formulations contained therein as needed). In one aspect, the pre-filled syringe is a single-chamber syringe, and the composition contained therein is a stable, single-phase or substantially single-phase composition that does not require mixing prior to injection. In one aspect, the syringe system is an auto-injector. In one aspect, the syringe system is a reusable auto-injector, which may be provided with a single-use cartridge containing a single dose of the composition of the present invention. In one aspect, the syringe system may be referred to as a container. The containers may also be syringes and vials containing single or multiple doses of the pharmaceutical compositions of the present invention, the contents from which can be drawn into the syringe for injection.

[0144] In some embodiments, the pharmaceutical compositions may be administered to a patient by injection using a syringe system, including those described herein. In aspects, the compositions are injected by subcutaneous injection, although other parenteral routes, including intramuscular injection, are contemplated herein.

[0145] The composition may be administered by manual injection with a syringe equipped with, for example, an 18-32 gauge needle, a 22-25 gauge needle, an 18-24 gauge needle, or an 18-22 gauge needle, or an 18-20 gauge needle, or by injection using an autoinjector.

[0146] Also contemplated herein are kits that include the pre-filled syringe systems disclosed herein.

[0147] The following experimental results are presented for illustrative purposes and are not intended to limit the scope of the present invention. [Example]

[0148] The following examples describe methods used to prepare and test sustained release compositions containing degarelix acetate (DgA) active pharmaceutical ingredient (API) or other forms of degarelix, where the counterion is formed with other acids, such as poly-carboxylic acids (citric acid), strong acids (methanesulfonic acid), hydrophobic acids (pamoic acid, palmitic acid), etc. The following examples discuss the preparation and use of only the degarelix citrate form.

[0149] Example 1 1. Preliminary screening of DgA-drug substance (DS) solubility in various pharmaceutically acceptable water-miscible organic solvents Various organic solvents were screened for maximum solubility of DgA-DS. Pharmaceutically acceptable, non-aqueous, water-miscible organic solvents such as N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), and N,N-dimethylacetamide (DMA) demonstrated superior degarelix dissolution capacity (at least 35-40% w / w) compared with aqueous-based solvents. NMP and DMSO are capable of dissolving larger amounts of DgA without inducing self-aggregation, as seen in aqueous solvents. Other solvents tested included benzyl alcohol, PEG 300, propylene carbonate, triacetin, triethyl citrate, ethyl acetate, and benzyl benzoate. In most of these solvents, the drug is either insoluble or has a significantly lower solubility limit than NMP, DMSO, or DMA.

[0150] 2. Degarelix citrate (DgC)-DS preparation DgC-DS was formed by dissolving degarelix as degarelix acetate (purchased from a supplier) in water (approximately 40 mg / mL concentration) and then adding aqueous citric acid (1 M) dropwise. The molar ratio of degarelix free base to citric acid in the solution was varied as desired. The resulting solution was mixed for 10-15 minutes and placed in a -80°C freezer. The contents were lyophilized to remove water (and lyophilization may remove some amounts of acetic acid formed as a result of ion exchange). The dried powder was redissolved in water and lyophilized again. The purity of the lyophilized degarelix citrate powder was tested using HPLC analysis. See the description of the degarelix citrate drug substance powder in Table 1. Table 1 Degarelix Citrate (DgC) - Description of bulk powder [Table 1]

[0151] 3. Preparation of bulk solutions and pre-filled syringes of Dg-DS or Dg-DS / organic solvent formulations Bulk Solution: To produce a drug / solvent bulk solution containing the active pharmaceutical ingredient (DgA or DgC), the desired amount of DgA-DS or DgC-DS was combined with the solvent NMP or DMSO, or a combination of solvents, with or without cosolvents or other additives, in the amounts indicated (see individual experiments below). The API and solvent were combined in a glass vial or jar and blanketed with nitrogen. The jar was mixed at room temperature using a jar mill, Turbula, or shaker until homogenous. DgA or DgC is highly soluble in NMP or DMSO and can be dosed at higher concentrations (at least 40% w / w).

[0152] Syringe filling: After dissolving the API in an organic solvent, the liquid formulation was manually filled into syringes and stoppered with tip caps. The syringe barrels selected for filling were made of either polypropylene or cyclic olefin copolymer (COC) materials. The filled syringes were then packaged in labeled foil pouches containing desiccant packs, and the pouches were sealed. After the syringes were filled with the formulation, the filled syringes were stored under refrigerated conditions (e.g., 2-8°C) or accelerated conditions (≥25°C, see individual experiments). For terminal sterilization, the syringes may be irradiated using electron (e-) beam or gamma irradiation (see individual experiments).

[0153] 4. In situ gelation screening Solutions of either DgA-DS (40 mg / mL) in water, DgA-DS in NMP (approximately 35% w / w), or DgA-DS in DMSO (approximately 34% w / w) were injected into deionized water and phosphate-buffered saline (PBS). When DgA solutions were injected into PBS (approximately 50 mg of DgA was injected into 10–15 mL), rapid peptide aggregation and gelation were observed; however, this rapid aggregation and gelation was not observed when a similar amount of DgA solution was injected into deionized water. The liquid in the vial immediately became slightly cloudy after injection and eventually became a translucent gel overnight. NMP- or DMSO-based formulations exhibited similar drug aggregation behavior when injected into PBS, as observed with aqueous-based DgA solutions.

[0154] 5. In situ gelation versus injection volume A solution of DgA-DS in DMSO (approximately 35% w / w) was injected into 2.5 mL of PBS (pH 7.4, 37°C) at various injection volumes (10 μL, 25 μL, 50 μL, and 80 μL) to see whether aggregation / gelation behavior could be observed at smaller injection volumes. Aggregation was observed at all levels, regardless of injection volume. The degree of gelation (which can be observed by the thickness of the translucent gel phase) was higher with larger injection volumes, which may be due in part to the higher drug dose.

[0155] 6. XRD characterization of DgA solutions Sample preparation: Using a spatula, the sample was loaded into a 2mm x 20mm zero background sample holder. A microscope slide was used to press the sample down, flush with the top of the sample holder.

[0156] XRD Instrument Settings: Sample analysis was performed using a Rigaku MiniFlex XRD instrument. The X-ray tube was set to 40 kV and 15 mA. The detector was a D / tex Ultra2, 2D detector. The filter was KβNi(1.5). The scan mode was continuous with a 2θ / θ scan axis, a 0.02° step width, and a 5° / min scan rate. The scan range was 3° to 45°. The optical configuration was as follows: entrance Soller slit 5.0°, divergence slit 0.625 mm, entrance height limiting slit 10.0 mm, Soller slit 8.0 mm, receiving Soller slit 5.0°, and the receiving slit open (no slit). Analysis was performed at ambient temperature.

[0157] Analysis: Sample analysis was controlled using MiniFlex software. After running a series of samples, the data was processed using separate software called PDXL2. The biopolymer degarelix acetate was amorphous and did not show any crystallinity as an API powder or at a concentration of 66 mg / mL in water. At higher concentrations, the peptide forms gels. Gels are not crystalline. In theory, gels show peaks indicative of higher order structure due to stacking of beta-sheets forming aggregates that result in gel formation. The addition of salt may help gels form at lower concentrations than without salt. In the presence of NMP solvent, gelation does not occur, even in the presence of water.

[0158] 7. Analysis (Assay) of Degarelix and All Related Compounds in Formulations The formulation was transferred to a 50 mL volumetric flask or the contents of the syringe were dispensed and the weight was recorded. The aliquot was diluted to volume with mobile phase A and mixed thoroughly by vortexing. Dilutions were made as needed. 2 mL was diluted to 20 mL with mobile phase A (0.1% trifluoroacetic acid in water) and mixed thoroughly by vortexing. A second dilution from 2 mL to 20 mL was made with mobile phase A to obtain the working sample.

[0159] HPLC Analysis: HPLC analysis of the assay and related compounds was performed at 30°C with a flow rate of 0.75 mL / min using an Agilent AdvanceBio Peptide 3.0 x 100 mm, 2.7 μm column and an Agilent AdvanceBio Peptide Map Guard 3.0 x 5 mm, 2.7 μm guard column. Run times were 15 minutes with 10 μL injections for assays and related compounds in solution gel depot formulations. Mobile phases were 0.1% trifluoroacetic acid in water for mobile phase A and 0.1% trifluoroacetic acid in acetonitrile for mobile phase B. Detection was UV with a diode array detector set at 220 nm. A gradient method was used. See Table 2 below for the gradient method for example chromatograms. (Table 2 HPLC gradient method) [Table 2]

[0160] 8. Drug Recovery from Various Degarelix / Organic Solvent Formulations Pre-filled syringes of degarelix / organic solvent formulations were prepared as described in item 3. An HPLC method was used to test the recovery of drug from the various formulations (see item 7), which is listed in Table 3.

[0161] Findings in Table 3: All formulations showed good recoveries (90.0-110.0%), demonstrating the applicability of the method in various solvent systems and the initial stability of the API. Table 3. Drug recovery studies from pre-filled syringes of organic solvent-based formulations. [Table 3] ("F#" stands for "Formulation Number").

[0162] 9. Stability of Degarelix / Organic Solvent Formulations Prefilled syringes of degarelix / organic solvent formulation were prepared as described in section 3. Samples were not irradiated with an electron (e-) beam. The composition of the samples is shown in Table 4. The sealed foil pouches containing the prefilled syringes were placed under accelerated storage conditions (6 months at 25±2°C) and tested for drug assay or recovery and related compounds at each time point (0, 1, 3, and 6 months) (see section 7 for procedures). The results of this study are presented in Figure 1. No degradation of the drug was observed at 6 months. The slight increase in percentage recovery over time may be due to solvent loss / absorption in the prefilled syringes at accelerated conditions. (Table 4: Composition of the formulation) [Table 4] ("F#" stands for "Formulation Number").

[0163] Findings in Figure 1: Degarelix acetate was found to be stable in NMP and DMSO (at the concentrations tested) for 6 months (accelerated conditions) at 25°C. There was no significant increase in related compounds. At 6 months, the total related compounds was less than 2%. A slight increase in the recovery percentage observed for formulations F1, F2, and F5 upon storage may be due in part to solvent loss over time due to absorption by the prefilled syringe or stopper at accelerated storage conditions. No gelation was observed for formulations F1, F2, and F5. The F5 formulation was made at a higher concentration than F2, and both were found to be stable and did not exhibit any gelation. This supports the idea that higher concentrations, such as 40% w / w, are feasible.

[0164] 10. Feasibility of terminal sterilization by electron (e-) beam or gamma irradiation Pre-filled syringes of degarelix / organic solvent formulation were exposed to different doses of electron (e-) beam or gamma radiation, and the drug concentration or recovery of the samples before and after irradiation was tested using HPLC (see item 7). The results are presented in Table 5. Table 5: Results of the feasibility study of radiation exposure [Table 5] ("F#" stands for "Formulation Number").

[0165] Findings in Table 5: These results showed that degarelix solutions in organic solvents are feasible for terminal sterilization by irradiation, depending on the radiation type, radiation dose, drug concentration, salt form, and stabilizer.

[0166] Degarelix citrate in formulation F4-e25-2 showed better stability upon electron (e-) beam irradiation than degarelix acetate formulation F1-e25-2.

[0167] In general, the 35% drug solution samples (F1-e34, F2-e34, F1-g22) showed better stability upon irradiation compared to the 40% drug solution formulations (F6-e34, 5-e34, F6-g22).

[0168] All related compounds in formulations F1-e25, F2-e25, F3-e25 and F4-e25 were tested and no significant increase was observed after irradiation of the samples with electron (e-) beam.

[0169] 11. Stability of irradiated samples under accelerated storage conditions Irradiated pre-filled syringes of the degarelix / organic solvent formulation were stored at various accelerated storage conditions (25° C.) and assayed at 30 and 120 days using the HPLC method (see item 7). The results are presented in Table 6. Table 6 Accelerated storage stability testing of pre-filled syringes of degarelix solution formulation after irradiation [Table 6] ("F#" stands for "Formulation Number") "NA": Indicates not available.

[0170] Findings in Table 6: No appreciable degradation of degarelix was observed in irradiated samples over the study period. The slight increase in recovery percentage over time may be due to solvent loss or absorption in the pre-filled syringes during accelerated storage conditions.

[0171] 12. Viscosity of the formulation 500 μL of formulation was transferred to a Hamilton syringe and the viscosity of the formulation was measured using the RheoSense. Prior to measurement, the instrument underwent an equilibration step to determine the best instrument parameters before conducting the test. The results are presented in Table 7. The viscosity of the formulations ranged from 100 to 250 cP. Table 7 Viscosity of formulations after electron (e-) beam irradiation of pre-filled syringes [Table 7] ("F#" stands for "Formulation Number").

[0172] 13. Nonclinical evaluation of formulations for drug release Prefilled syringes of degarelix / organic solvent formulations were prepared as described in section 3. Samples were not irradiated with an electron (e-) beam. Degarelix release rates for these formulations were obtained using a rat model. Male rats were each injected with a single subcutaneous injection of the degarelix / organic solvent formulation. Formulation composition and administration details are listed in Table 8. Formulation F1 tested the effect of organic solvent compared to the control (reconstituted in water). Formulation F2 tested the effect of the type of organic solvent (NMP vs. DMSO) in the formulation. Formulation F3 tested the effect of adding benzyl alcohol to the formulation. Formulation F4 tested the effect of various salt forms of degarelix (citrate) on the formulation.

[0173] At designated time points, rats were bled to determine plasma degarelix levels using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Each data point is based on the average plasma degarelix concentration. Six rats per group were dosed, and small blood samples were taken at early time points. FIRMAGON® (injectable degarelix) was included in the study as a control. To understand steady-state and accumulation, controls were injected at 15 mg / kg on days 0 and 28, while test groups received a single injection of 15 mg / kg. Dosing was calculated using the amount of degarelix free base in each formulation, calculated for the formulation after correction for purity. A 120 mg vial of FIRMAGON® was reconstituted by adding 3 mL of sterile water for injection provided with the FIRMAGON® kit; the resulting reconstituted solution had a degarelix concentration of 40 mg / mL. Table 8: Non-clinical trial administration details [Table 8]

[0174] The in vivo degarelix release amounts for organic solvent-based formulations of degarelix in rats at 28 days post-injection are presented in Figures 2 and 3. Figure 2 shows the C max This is an expanded version of the levels from day 0 to day 3, showing the levels.

[0175] Findings in Figures 2 and 3: All organic solvent-based degarelix formulations (groups B-TA1, C-TA2, D-TA3, and E-TA4) showed a sustained drug release profile with detectable drug for at least 28 days.

[0176] All organic solvent-based degarelix formulations (Groups B-TA1, C-TA2, D-TA3, and E-TA4) showed a lower initial release (Cmax) than the control (Group A-CA1), which may be due in part to differences in i) the solvent used in the formulation (water in the control vs. organic solvent in the test formulations) and ii) the gelation rate of the drug from the different formulations.

[0177] There are three levels of Cmax observed for this series of test articles. Higher Cmax - relative to water-based control formulation A-CA1 Moderate Cmax - NMP-based formulations B-TA1, D-TA3, and E-TA4 Lower Cmax - for DMSO-based formulation of C-TA2.

[0178] These results suggest that the main / major solvent of the formulation has a greater effect on the initial release amount (Cmax) of the drug than the salt form or the co-solvent.

[0179] The in vivo degarelix release for solvent-based degarelix formulations in rats at 63 days post-injection is presented in Figure 4. Figure 4 shows that all of the formulations released drug resulting in measurable degarelix levels in vivo for more than 60 days.

[0180] The in vivo degarelix release for solvent-based degarelix formulations in rats at 119 days post-injection is presented in Figure 5. Figure 5 shows that all of the formulations released drug resulting in measurable degarelix levels in vivo for more than 90 days (at least 119 days).

[0181] Table 9 shows the PK data for the above experiments. The Cmax of formulations B-TA1, D-TA3, and E-TA4 occurs earlier than the control (A-CA-1) for the solvent-based formulations. This may result in a more rapid decline in testosterone levels. (Table 9 pK data) [Table 9] *Dose is given once on day 0 and once on day 28. Dose-normalized parameters are calculated separately from total dose.

[0182] In vivo testosterone concentration levels (ng / mL) in rats at 105 days post-injection for the solvent-based degarelix formulations of this example are presented in Figure 6. Figure 5 shows that all of these formulations were sustained throughout the 119-day study period. Furthermore, the results show that all formulations had plasma concentrations above 1 ng / mL, the minimum drug concentration to induce chemical castration. Furthermore, testosterone levels remained below "historic testosterone baseline" levels, and testosterone suppression occurred by day 4. Finally, a second dose of FIRMAGON® (A-CA1) on day 28 did not suppress testosterone concentration levels as well as the other formulations administered once on day 0.

[0183] Example 2 This example describes the results of a non-clinical animal study demonstrating the effect of additives in certain sustained-release degarelix formulations on in vivo pharmacokinetics (PK) and testosterone levels (pharmacodynamics, PD) in male Sprague-Dawley rats following subcutaneous injection of the formulation.

[0184] The study included a control formulation (such as FIRMAGON®) and the degarelix formulations listed in Table 10 below. The additives included in the degarelix formulations, when present, were either acetic acid (AcOH) or benzyl alcohol (BnOH). At the conclusion of the study, the rats were euthanized and the injection sites were harvested for histological and residual drug analysis. These degarelix and control formulations were delivered by subcutaneous injection to male rats, after which the rats were bled periodically to assess plasma degarelix and testosterone levels. (Table 10) [Table 10] 1 API percentage refers to degarelix acetate content rather than peptide (degarelix free base) content. DgA = degarelix acetate drug substance; AcOH = acetic acid; BnOH = benzyl alcohol; NMP = N-methyl-2-pyrrolidone; DMSO = dimethyl sulfoxide.

[0185] Preparation of degarelix bulk solution and syringe filling The drug substance (DgA) and solvent, with or without the listed excipients (NMP:acetic acid, or NMP:benzyl alcohol, or DMSO), were combined in a 40 mL amber scintillation vial and blanketed with nitrogen. The vial was mixed at room temperature until complete dissolution, indicated by a clear solution with no visible solids. The bulk drug solution was manually filled into labeled male syringes and stoppered with female tip caps. The syringes were packaged in labeled foil pouches containing desiccant packs, and the pouches were sealed. A portion of the syringes were sent for electron (e-) beam irradiation for stability testing, as shown in Table 10. Samples were irradiated at a target delivery dose range of 34 to 34 kGy, with an internal dosimeter reading of 31.7 kGy in the syringes. Samples were refrigerated at 5°C until use.

[0186] Non-clinical animal testing Prefilled syringes of the degarelix test formulation were prepared as described above. The degarelix release rates and resulting testosterone levels of these formulations were obtained using a rat model. Male rats were each injected with a single subcutaneous injection of the degarelix test formulation and the control formulation. Formulation composition and administration details are listed in Table 11. At designated time points, rats were bled to determine plasma degarelix levels using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Testosterone levels were also determined. Each data point is based on the mean plasma degarelix concentration. Six rats were dosed per group, and small blood samples were taken at early time points (days 0-7). FIRMAGON® (injectable degarelix, Ferring) was included in the study as a control. To understand steady state and accumulation, controls were injected at 45 mg / kg on days 0 and 28, while the test group received a single injection of 45 mg / kg. The dose of test formulation was calculated using the amount of degarelix acetate in each formulation (at this dose volume, there would be no significant difference in the amount of formulation administered if the dose were instead calculated based on the degarelix free base in the formulation after correction for purity). One vial of the FIRMAGON® 240 mg kit contains two 120 mg vials of degarelix. Each vial is reconstituted with 2 mL of water from a pre-filled syringe (provided in the kit) containing 3 mL of sterile water for injection. The final API concentration is 60 mg / mL. Table 11 Non-clinical trial administration details [Table 11] 1 The target API is 35% or 24% (wt%) degarelix acetate (DgA) drug substance, as labeled for each formulation. NMP = N-methyl-2-pyrrolidone; DMSO = dimethyl sulfoxide; AcOH = acetic acid; BnOH = benzyl alcohol. 2 The actual amount of degarelix as degarelix free base (degarelix free base equivalents) in the formulation after correction for purity.

[0187] The in vivo degarelix release for organic solvent-based degarelix formulations in rats at 28 days post-injection is presented in FIG.

[0188] In vivo testosterone levels for organic solvent-based degarelix formulations in rats at 28 days post-injection are presented in FIG.

[0189] The in vivo degarelix release for solvent-based degarelix formulations in rats at 63 days post-injection is presented in FIG.

[0190] The in vivo degarelix release for solvent-based degarelix formulations in rats at 90 days post-injection is presented in FIG.

[0191] In vivo testosterone levels for organic solvent-based degarelix formulations in rats at 90 days post-injection are presented in FIG.

[0192] The in vivo degarelix release for solvent-based degarelix formulations in rats at 140 days post-injection is presented in FIG.

[0193] In vivo testosterone levels for organic solvent-based degarelix formulations in rats at 140 days post-injection are presented in FIG.

[0194] The results presented in this example demonstrate that all degarelix test formulations tested herein maintained the minimum degarelix concentration of 1 ng / mL required for castration for over four months. Furthermore, testosterone suppression to below castration levels occurs by day 1 in all degarelix test formulations tested herein, as well as in controls administered at 45 mg / kg (note that controls were administered on both days 0 and 28, while test formulations were administered as a single dose on day 0). Furthermore, testosterone suppression does not appear to be dose-dependent (data not shown). Furthermore, clinical observations do not appear to affect drug release or testosterone suppression, as the 45 mg / kg control, Formulation B (DgA / NMP / AcOH), Formulation I (Dg / DMSO), and Formulation J (Dg / NMP / AcOH—no e-beam) all had no or minimal effects. The gelation through the first 7 days appeared different compared to the control, which, without being bound by theory, may be due to the solvent in the test formulation and the strength of the gelation that occurred.

[0195] Example 3 This example demonstrates the effect of acid additive content on the stability of degarelix formulations. This study was designed to determine the stability of degarelix formulations of the present invention when various levels of acid as an additive were added to the formulation.

[0196] To study the impact of pH control, pH studies were initiated using either a control without acid additives or three ratios of acid additives (acetic acid, citric acid, or succinic acid) as models of degarelix formulation stability to monitor impurity growth on stability. A control sample of degarelix acetate and NMP (DgA / NMP 35% / 65% w / w) containing no acid additive was compared to other formulations of the same composition containing acid additives at various molar ratios of degarelix peptide (calculated as the free base) to acid (acetic acid, citric acid, or succinic acid) (see Table 12). Samples were stored at 5°C, 25°C, and 40°C and tested for periods ranging from 3 to 12 months. Testing included assay recovery, related compound, and pH analysis. (Table 12) [Table 12] DgA-DA = degarelix acetate; NMP = N-methyl-2-pyrrolidone.

[0197] conclusion NMP has a pH of approximately 8–9 (National Center for Biotechnology Information, 2023), and in the presence of water, the pH of the formulation decreases due to the free movement of more H+ ions. It may be beneficial to consider how the subcutaneous environment affects the pH of these formulations. In this experiment, compared to the control sample without an acid additive, all formulations containing an acid additive showed better stability at all ratios, both at 6 months at accelerated conditions at 25°C and at 3 months at accelerated conditions at 40°C. All three acids in this study reduced the apparent pH of the formulation to a new value that depended on both the amount of acid added and its pKa. Minimal impurity increases were observed at 3 months at 40°C, indicating that the addition of acid improved the formulation's stability (data not shown). Figure 14 shows impurity data at 1 month, 3 months, and 6 months from the stability study at 25°C, demonstrating that the addition of a specific amount of acid as an additive can optimize the overall formulation stability. The molar ratio of degarelix API (calculated as the free base) to acetic acid additive used in the test formulations shown in Example 2 ranged from a molar ratio of 1:1 to about 1:3, or approximately 1:2, as shown in Figure 12. Stability studies at 5°C are expected to show a similar pattern of stability enhancement with the addition of the acid additive to the formulation.

[0198] Overall, this study demonstrated that acid additives or reduced apparent pH can stabilize formulations. Without being bound by theory, the ability of acid to stabilize these formulations may be due to acid-induced inhibition of peptide hydrolysis and oxidation, two degradation pathways that may be the primary cause of increased impurities in degarelix acetate.

[0199] Various modifications of the above-described invention will be apparent to those skilled in the art, and such modifications are intended to fall within the scope of the following claims.

Claims

1. a therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof, and Biocompatible organic solvents A composition comprising: the composition is formulated for subcutaneous injection into a subject; a single dose of the composition is about 2.5 mL or less; Upon injection into the subject, the composition forms an in situ depot that releases the degarelix over a period of about 1 month to about 6 months. composition.

2. 2. The composition of claim 1, wherein the in situ depot releases the degarelix over a period selected from the group consisting of at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months and at least about 5 months.

3. 2. The composition of claim 1, wherein the pharmaceutically acceptable salt of degarelix is ​​selected from degarelix acetate, degarelix citrate, degarelix pamoate, degarelix palmitate, and degarelix mesylate.

4. The composition of claim 1, wherein the amount of biocompatible solvent in the composition is from about 50% to about 99% by weight of the composition.

5. 10. The composition of claim 1, wherein the therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof in the composition is from about 1% to about 50% by weight of the composition.

6. 10. The composition of claim 1, wherein the therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof in the composition is from about 20% to about 40% by weight of the composition.

7. 10. The composition of claim 1, wherein the therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof in the composition is about 20% to about 40% by weight of degarelix free base equivalents.

8. 2. The composition of claim 1, wherein the therapeutically effective amount of degarelix is ​​about 40 mg to 500 mg.

9. 2. The composition of claim 1, wherein the therapeutically effective amount of degarelix is ​​about 80 mg to 500 mg.

10. 2. The composition of claim 1, wherein the therapeutically effective amount of degarelix is ​​about 120 mg to 500 mg.

11. 2. The composition of claim 1, wherein the biocompatible solvent is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), benzyl benzoate (BnBzO), polyethylene glycol 15 hydroxystearate, methyl ethyl ketone, methyl lactate, benzyl alcohol, propylene carbonate (PC), triacetin, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, diethylene glycol monomethyl ether, ethyl acetate, N-ethyl-2-pyrrolidone, glycofurol, and combinations thereof.

12. The composition of claim 11 , wherein the biocompatible organic solvent is NMP or DMSO.

13. 10. The composition of claim 1, wherein a single dose of the composition is about 2.5 mL or less, about 2.4 mL or less, about 2.3 mL or less, about 2.2 mL or less, about 2.1 mL or less, about 2.0 mL or less, about 1.9 mL or less, about 1.8 mL or less, about 1.7 mL or less, about 1.6 mL or less, about 1.5 mL or less, about 1.4 mL or less, about 1.3 mL or less, about 1.2 mL or less, about 1.1 mL or less, about 1 mL or less, about 0.75 mL or less, about 0.5 mL or less, or about 0.375 mL or less.

14. 10. The composition of claim 1, wherein a single dose of the composition is about 1.0 mL or less.

15. 10. The composition of claim 1, wherein the degarelix is ​​dissolved or dispersed in the biocompatible solvent.

16. The composition of any one of claims 1 to 15, which has been terminally sterilized or sterile filtered.

17. 17. The composition of claim 16, which is terminally sterilized by electron beam.

18. The composition of any one of claims 1 to 17, further comprising one or more additives.

19. The additives may be polysorbate 20, polysorbate 80, poloxamer 188, sorbitan trioleate, lecithin (e.g., soy or egg), polyethylene glycol (PEG), PEG 300, 2-pyrrolidone, alpha-tocopherol, vitamin E TPGS, sucrose cocoate, sucrose stearate, sucrose laurate, proline, arginine, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxyquinone, butylated hydroxyanisole, hydroxycoumarin, butylated hydroxytoluene, cephalum, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl-hydroxybenzoate, trihydroxybutyrophenone, vitamin E, lecithin, ethanolamine, ZnCl ２ , MgCl ２ , CaCl ２ , DL-methionine citrate, dimethylphenol, dibutylphenol, ethylenediaminotetraacetic acid (EDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), ascorbic acid, nitrilotriacetic acid, n-hydroxyethylethylenediaminetriacetic acid (HEDTA), mercaptoethanol, and combinations thereof.

20. 20. The composition of claim 18, wherein the additive is an acid additive.

21. 21. The composition of claim 20, wherein the acid additive is selected from the group consisting of acetic acid (AcOH), citric acid, succinic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid (HCl), pamoic acid, palmitic acid, hydrobromic acid, nitric acid, chromic acid, trifluoroethanesulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 4-cyanobutanoic acid, perchloric acid, phosphoric acid, hydrogen iodide, and combinations thereof.

22. 21. The composition of claim 20, wherein the acid additive is selected from the group consisting of acetic acid, citric acid, and succinic acid.

23. 20. The composition of claim 18, wherein the additive is an alcohol additive.

24. 24. The composition of claim 23, wherein the alcohol additive is benzyl alcohol (BnOH).

25. 21. The composition of claim 20, wherein the amount of the acid additive in the composition is from about 0.1% to about 10.0% by weight.

26. 24. The composition of claim 23, wherein the amount of the alcohol additive in the composition is about 1.0% to 30% by weight.

27. (a) about 20% to 40% by weight of degarelix acetate or degarelix citrate; and (b) about 60% to 80% by weight of N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO) A pharmaceutical composition comprising:

28. (a) about 25% to 45% by weight of degarelix acetate or degarelix citrate; and (b) about 55% to 75% by weight of N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO) A pharmaceutical composition comprising:

29. 29. The pharmaceutical composition of claim 27 or 28, wherein the therapeutically effective amount of degarelix or a pharmaceutically acceptable salt in the composition is about 20% to about 40% by weight of degarelix free base equivalent.

30. 29. The pharmaceutical composition of claim 27 or 28, further comprising about 0.1% to 10% by weight of an acid additive.

31. 31. The pharmaceutical composition of claim 30, wherein the acid additive is selected from the group consisting of acetic acid, citric acid, and succinic acid.

32. 29. The pharmaceutical composition of claim 27 or 28, further comprising about 1.0% to 30% by weight of an alcohol additive.

33. 33. The pharmaceutical composition of claim 32, wherein the alcohol additive is benzyl alcohol (BnOH).

34. (a) about 35% by weight of degarelix acetate; and (b) about 65% by weight of N-methyl-2-pyrrolidone (NMP) A pharmaceutical composition comprising:

35. (a) about 35% by weight of degarelix acetate; (b) about 65% by weight DMSO A pharmaceutical composition comprising:

36. (a) about 35% by weight of degarelix acetate; (b) about 60 wt. % NMP; and (c) about 5% by weight of benzyl alcohol (BnOH) A pharmaceutical composition comprising:

37. (a) about 35% by weight of degarelix citrate; and (b) about 65 wt. % NMP A pharmaceutical composition comprising:

38. (a) about 35% by weight of degarelix acetate; (b) about 60% to about 64% by weight of NMP; and (c) about 1% to about 5% by weight of AcOH A pharmaceutical composition comprising:

39. 39. The pharmaceutical composition of claim 38, wherein the NMP is in an amount of about 62% to about 64% by weight and the AcOH is in an amount of about 1% to about 3% by weight.

40. 39. The pharmaceutical composition of claim 38, wherein the NMP is in an amount of about 62.8% by weight and the AcOH is in an amount of about 2.2% by weight.

41. 41. The pharmaceutical composition of any one of claims 34 to 40, wherein the amount of degarelix acetate or degarelix citrate in the pharmaceutical composition is about 31% to about 34% by weight of degarelix free base equivalents, or about 31% to about 33% by weight of degarelix free base equivalents, or about 31% to about 32% by weight of degarelix free base equivalents.

42. (a) about 24% by weight of degarelix acetate; (b) about 56 wt. % NMP; and (c) about 20% by weight of BnOH A pharmaceutical composition comprising:

43. (a) about 24% by weight of degarelix acetate; (b) about 66 to about 75 wt. % NMP; and (c) about 1 to about 10 wt. % AcOH A pharmaceutical composition comprising:

44. 44. The pharmaceutical composition of claim 43, wherein the NMP is in an amount of about 70 to about 75% by weight and the AcOH is in an amount of about 1 to about 6% by weight.

45. 44. The pharmaceutical composition of claim 43, wherein the NMP is in an amount of about 73.3% and the AcOH is in an amount of about 1.7% by weight.

46. 46. ​​The pharmaceutical composition of any one of claims 42 to 45, wherein the amount of degarelix acetate in the pharmaceutical composition is about 20% to about 23% by weight of degarelix free base equivalents, or about 20% to about 22% by weight of degarelix free base equivalents, or about 21% to about 23% by weight of degarelix free base equivalents, or about 21% to about 22% by weight of degarelix free base equivalents.

47. 47. A method of treating prostate cancer in a subject, comprising subcutaneously administering to the subject a composition of any one of claims 1 to 46.

48. 48. The method of claim 47, wherein the prostate cancer is advanced prostate cancer.

49. 49. The method of claim 47 or 48, wherein the dosage of degarelix or a pharmaceutically acceptable salt in the composition is administered at a dosage of about 40 mg to about 500 mg.

50. 47. A method of lowering serum testosterone levels in a subject to 50 ng / dL or less, comprising subcutaneously administering to the subject a composition of any one of claims 1-46.

51. 51. The method of claim 50, wherein the serum testosterone level is less than 20 ng / dL.

52. 51. The method of claim 50, wherein the serum testosterone level is less than 10 ng / dL.

53. 47. A method of suppressing ovarian function in a subject with hormone receptor positive breast cancer, comprising subcutaneously administering to the subject a composition of any one of claims 1-46.

54. 54. The method of claim 53, wherein the hormone receptor-positive breast cancer is estrogen receptor (ER)-positive breast cancer.

55. 54. The method of claim 53, wherein the subject's estradiol (E2) production level is suppressed to a level of less than about 20 pg / mL to about less than about 2 pg / mL.

56. 54. The method of claim 53, wherein the subject's follicle-stimulating hormone (FSH) levels are suppressed to a level of less than about 40 IU / L.

57. 54. The method of claim 53, wherein the subject's luteinizing hormone (LH) levels are suppressed to a level of less than about 4 IU / L.

58. 47. A method of treating central precocious puberty (CPP) in a subject, comprising subcutaneously administering to the subject a composition according to any one of claims 1 to 46.

59. 59. The method of claim 58, wherein the subject's CPP serum LH concentration level is reduced to a prepubertal concentration level of less than about 4 IU / L.

60. 60. The method of any one of claims 47-59, wherein the composition is administered about once every month, about once every two months, about once every three months, about once every four months, about once every five months, or about once every six months.

61. 60. The method of any one of claims 47-59, wherein the composition is administered to the subject about once every three months.

62. 60. The method of any one of claims 47-59, wherein the composition is administered as a loading dose, followed by a maintenance dose of the composition about 1 month, about 2 months, or about 3 months after the loading dose is administered.

63. 60. The method of any one of claims 47-59, wherein a loading dose of the composition is not administered and the composition is administered about once per month, about once every two months, about once every three months, about once every four months, about once every five months, or about once every six months.

64. A pre-filled syringe system for administering a composition according to any one of claims 1 to 46, comprising a single syringe containing the composition according to any one of claims 1 to 46.

65. 65. The pre-filled syringe system of claim 64, wherein the degarelix is ​​dissolved in a biocompatible solvent, and the degarelix remains in solution in the solvent.

66. 65. The pre-filled syringe system of claim 64, wherein the syringe is an auto-injector syringe.

67. 67. A kit comprising the pre-filled syringe system of any one of claims 64 to 66 and instructions.

68. 47. An article of manufacture comprising the composition of any one of claims 1 to 46 for use in a method of treating prostate cancer.

69. 47. An article of manufacture comprising the composition of any one of claims 1 to 46 for use in a method for treating CPPs.

70. 47. An article of manufacture comprising the composition of any one of claims 1 to 46 for use in a method for reducing serum testosterone levels below castration levels of at least 50 ng / dL.

71. 47. An article of manufacture comprising the composition of any one of claims 1 to 46 for use in a method for suppressing ovarian function in a subject with hormone receptor positive breast cancer.

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