Degarelix organic solvent formulation

Abstract

Described herein are long-acting injectable compositions and methods of using such long-acting injectable compositions. The long-acting injectable composition comprises degarelix (a decapeptide gonadotropin releasing hormone (GnRH) receptor antagonist) or a pharmaceutically acceptable salt thereof. These compositions may also include a biocompatible organic solvent, optionally with one or more additives in a single syringe system.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 484,436, filed on February 10, 2023, and U.S. Provisional Patent Application No. 63 / 613,236, filed on December 21, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention generally relates to long-acting injectable degarelix / organic solvent formulations. Background Art

[0004] 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 effects of GnRH on the pituitary gland by competitively and reversibly binding to the GnRH receptor and producing a rapid suppression of testosterone with no or minimal initial surge.

[0005] The drug delivery technology currently marketed in the United States and Europe for degarelix (e.g., FIRMAGON® (degarelix for injection), Ferring Pharmaceuticals Inc. or Ferring GmbH) has significant limitations, including administration of the initial dose as two large-volume injections (3 mL each), followed by maintenance doses as single large-volume injections (1 × 4 mL) every 28 days. The only commercially available formulation with a dosing interval greater than once a month is marketed only in Japan (GONAX®). ®(degarelix for injection), Astellas Pharma Inc.), and has similar significant limitations, including administration of an initial dose of two injections of 3 mL each, followed by maintenance doses of two injections of 4 mL each every 12 weeks. Therefore, for all currently available degarelix products, multiple, large-volume injections (4-8 mL total per dosing period) are required for extended therapy, which is associated with injection-related pain. In addition, degarelix has a tendency to self-aggregate in aqueous media. In the case of FIRMAGON®, degarelix is ​​provided as a powder (lyophilized, containing mannitol as a filler), and once it is reconstituted with water, the degarelix molecules aggregate and cross-link into a gel-forming network, thereby producing a hydrogel. Due to its self-aggregating nature and chemical instability in aqueous media, degarelix must be separated from the aqueous vehicle and maintained in dry form by lyophilization. Therefore, reconstitution is required at the time of administration. Preparation of a ready-to-inject dosage form of degarelix for injection is challenging because the rate and extent of peptide self-aggregation / gel formation in aqueous media is concentration-dependent. Furthermore, commercially available forms of degarelix are manufactured by aseptic processing and involve multiple reconstitution steps.

[0006] There is an unmet need for a long-acting GnRH antagonist formulation that is easy to administer, can be terminally sterilized during manufacturing, can be administered less frequently than monthly, reduces the total number of injections during a single dosing period, significantly reduces the injection volume, and reduces pain during injection. Therefore, it would be very beneficial to have an injectable pharmaceutical formulation of degarelix in a single syringe system that is ready for injection and provides a therapeutically effective amount of degarelix in a single injection at low injection volumes (<2.5 mL or <10 mL). < 2 mL) for more than one month of extended release. Summary of the Invention

[0007] In various embodiments, the present application discloses a composition comprising a therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof. The composition comprises an organic biocompatible solvent, wherein the composition is 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 the subject, the composition forms an in situ depot that releases degarelix over a period of about 1 month to about 6 months.

[0008] In one aspect of the composition, the in situ depot releases degarelix over a period of time 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.

[0009] In one aspect of the composition, the pharmaceutically acceptable salt of degarelix is ​​selected from degarelix acetate, degarelix citrate, degarelix pamoate, degarelix palmitate and degarelix mesylate.

[0010] In one aspect of the composition, the amount of biocompatible solvent in the composition is from about 50% to about 99% by weight of the composition.

[0011] In one aspect 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.

[0012] In one aspect of the composition, the therapeutically effective amount of degarelix is ​​about 40 mg - 500 mg.

[0013] In yet another aspect of the composition, the therapeutically effective amount of degarelix is ​​about 80 mg - 500 mg.

[0014] In yet another aspect of the composition, the therapeutically effective amount of degarelix is ​​about 120 mg - 500 mg.

[0015] In one aspect 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, acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, diethylene glycol monomethyl ether, ethyl acetate, N-ethyl-2-pyrrolidone, glycofurol, and combinations thereof. In a preferred aspect, the biocompatible organic solvent is NMP or DMSO.

[0016] In one aspect 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.

[0017] In one aspect of the composition, a single dose of the composition is about 1.0 mL or less.

[0018] In one aspect of the composition, degarelix is ​​dissolved or dispersed in a biocompatible solvent.

[0019] In one aspect of the composition, the composition has been terminally sterilized or sterile filtered. In one aspect, the composition has been terminally sterilized by electron beam.

[0020] In one aspect of the composition, the composition further comprises one or more additives. In one aspect, the additive is selected from polysorbate 20, polysorbate 80, poloxamer 188, sorbitan trioleate, lecithin (e.g., soy or egg), polyethylene glycol (PEG), PEG 300, 2-pyrrolidone, α-tocopherol, vitamin E TPGS, sucrose cocoate, sucrose stearate, sucrose laurate, proline, arginine, sodium metabisulfite, butylhydroxyanisole, butylhydroxyquinone, butylhydroxyanisol, hydroxycoumarin, butylhydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl hydroxybenzoate, trihydroxybutylrophenone, vitamin E, lecithin, ethanolamine, ZnCl2, MgCl2, CaCl2, DL-methioninecitric acid (DL-methioninecitric acid) acid), dimethylphenol, dibutylphenol, ethylenediaminetetraacetic 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.

[0021] In another aspect, the additive is an acid additive. In one aspect, the acid additive is selected from 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-chloropropionic acid, 4-cyanobutyric acid, perchloric acid, phosphoric acid, hydroiodic acid, and combinations thereof. In another aspect, the acid additive is selected from acetic acid, citric acid, and succinic acid.

[0022] In yet another aspect, the additive is an alcohol additive. In one aspect, the alcohol additive is benzyl alcohol (BnOH).

[0023] In one aspect of the composition, the amount of the acid additive in the composition is from about 0.1 wt % to about 10.0 wt %.

[0024] In one aspect of the composition, the amount of alcohol additive in the composition is from about 1.0 wt% to 30 wt%.

[0025] In one embodiment, the present application discloses a pharmaceutical composition comprising about 20 wt% to 40 wt% of degarelix acetate or degarelix citrate; and about 60 wt% to 80 wt% of N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO). In one aspect of this embodiment, the composition further comprises about 0.1 wt% to 10 wt% of an acid additive. In one aspect, the acid additive is selected from acetic acid, citric acid, and succinic acid.

[0026] In one embodiment, the present application discloses a pharmaceutical composition comprising about 25 wt% to 45 wt% of degarelix acetate or degarelix citrate; and about 55 wt% to 75 wt% of N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO). In one aspect of this embodiment, the composition further comprises about 1.0 wt% to 30 wt% of an alcohol additive. In one aspect, the alcohol additive is benzyl alcohol (BnOH).

[0027] In one embodiment, the present application discloses a pharmaceutical composition comprising about 35 wt% of degarelix acetate; and about 65 wt% of N-methyl-2-pyrrolidone (NMP).

[0028] In one embodiment, a pharmaceutical composition is disclosed comprising about 35 wt% degarelix acetate and about 65 wt% DMSO.

[0029] In one embodiment, the present application discloses a pharmaceutical composition comprising about 35 wt% degarelix acetate; about 60 wt% NMP; and about 5 wt% benzyl alcohol (BnOH).

[0030] In one embodiment, the present application discloses a pharmaceutical composition comprising about 35 wt% of degarelix citrate; and about 65 wt% of NMP.

[0031] In one embodiment, the present application discloses a pharmaceutical composition comprising about 35 wt% degarelix acetate; about 60 wt% to about 64 wt% NMP; and about 1 wt% to about 5 wt% AcOH. In one aspect, the amount of NMP is about 62 wt% to about 64 wt%, and the amount of AcOH is about 1 wt% to about 3 wt%. In another aspect, the amount of NMP is about 62.8 wt%, and the amount of AcOH is about 2.2 wt%.

[0032] 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 wt % to about 35 wt % degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 31 wt % to about 34 wt % degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 31 wt % to about 33 wt % degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 31 wt % to about 32 wt % degarelix free base equivalents. In some aspects, when calculating the target dose to be administered to a subject based on the degarelix free base equivalents in the composition, the percentage by weight of the solvent and the percentage by weight of the additive (if included) can be modified accordingly.

[0033] In one embodiment, the present application discloses a pharmaceutical composition comprising about 24 wt% degarelix acetate; about 56 wt% NMP; and about 20 wt% BnOH.

[0034] In one embodiment, a pharmaceutical composition is disclosed comprising about 24 wt% degarelix acetate; about 66 to 75 wt% NMP; and about 1 to 10 wt% AcOH.

[0035] In one embodiment, a pharmaceutical composition is disclosed comprising about 24 wt% degarelix acetate; about 70 to 75 wt% NMP; and about 1 to 6 wt% AcOH.

[0036] In one embodiment, a pharmaceutical composition is disclosed comprising about 24 wt% degarelix acetate; about 73.3 wt% NMP; and about 1.7 wt% AcOH.

[0037] 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 wt % to about 23 wt % degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 20 wt % to about 22 wt % degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 21 wt % to about 23 wt % degarelix free base equivalents. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 21 wt % to about 22 wt % degarelix free base equivalents. In some aspects, when calculating the target dose to be administered to a subject based on the degarelix free base equivalents in the composition, the percentage by weight of the solvent and the percentage by weight of the additive (if included) can be modified accordingly.

[0038] In various embodiments, methods of treating prostate cancer and central precocious puberty (CPP), as well as methods of reducing serum testosterone levels and suppressing ovarian function by subcutaneously administering the compositions disclosed herein to a subject in need thereof are also contemplated.

[0039] In one embodiment, a method of treating prostate cancer in a subject is disclosed, comprising subcutaneously administering a composition disclosed herein to the subject. In one aspect, the prostate cancer is advanced prostate cancer. In one aspect, the composition comprises administering degarelix or a pharmaceutically acceptable salt thereof in an amount of about 40 mg to about 500 mg.

[0040] In one embodiment, a method of reducing serum testosterone levels in a subject to 50 ng / dL or less is disclosed, comprising subcutaneously administering a composition disclosed herein to the subject. In one aspect, the serum testosterone level is less than 20 ng / dL. In yet another aspect, the serum testosterone level is less than 10 ng / dL.

[0041] In one embodiment, a method for suppressing ovarian function in a subject suffering from hormone receptor positive breast cancer is disclosed, comprising administering a composition disclosed herein to the subject subcutaneously. In one aspect, hormone receptor positive breast cancer is estrogen receptor (ER) positive breast cancer. In one aspect, the estradiol (E2) production level of the subject is suppressed to a level lower than about 20 pg / mL to a level lower than about 2 pg / mL. In one aspect, the follicle stimulating hormone (FSH) level of the subject is suppressed to a level lower than about 40 IU / L. In one aspect, the luteinizing hormone (LH) level of the subject is suppressed to a level lower than about 4 IU / L.

[0042] In one embodiment, a method of treating central precocious puberty (CPP) in a subject is disclosed, the method comprising subcutaneously administering a composition disclosed herein to the subject. In one aspect, the CPP serum LH concentration level of the subject is reduced to a prepubertal concentration level below about 4 IU / L.

[0043] In any aspect of the methods disclosed herein, the composition is administered about once every 1 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.

[0044] In any of the aspects of the methods disclosed herein, the composition is administered to the subject about once every three months.

[0045] In any aspect of the methods disclosed herein, the composition is administered as a loading dose, followed by a maintenance dose of the composition about 1 month, 2 months, or 3 months after the loading dose has been administered. In one aspect, when a loading dose is administered, a maintenance dose is administered every 1 month, every 2 months, or every 3 months thereafter. In one embodiment, no loading dose is administered, and the composition is administered about once every 1 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 six months.

[0046] Another embodiment is a delivery system comprising a single syringe prefilled with a composition disclosed herein and, in some embodiments, instructions suitable for using the delivery system to administer the composition to a subject.

[0047] In one embodiment, a pre-filled syringe system for administering a composition disclosed herein is contemplated, the system comprising a single syringe containing a composition disclosed herein. In one aspect, degarelix is ​​dissolved in a biocompatible solvent, and degarelix is ​​maintained as a solution in the solvent. In one aspect, the syringe system is an autoinjector. In one aspect, the syringe system is a reusable autoinjector that can be provided with a disposable cartridge containing a single dose of a composition of the invention.

[0048] In one embodiment, a kit is disclosed comprising a pre-filled syringe system disclosed herein and instructions for using the pre-filled syringe system to administer a composition contained therein.

[0049] In one embodiment, a product comprising a composition disclosed herein is used in a method of treating prostate cancer.

[0050] In one embodiment, disclosed is a product comprising a composition disclosed herein for use in a method of treating CPP.

[0051] In one embodiment, disclosed is a product comprising a composition disclosed herein for use in a method of reducing serum testosterone levels to below castrate levels of at least 50 ng / dL.

[0052] In one embodiment, disclosed is a product comprising a composition disclosed herein for use in a method of suppressing ovarian function in a subject with hormone receptor-positive breast cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 Shown are the percent recoveries of degarelix from degarelix / organic solvent formulation samples (Formulations 1, 2, and 5 (F1, F2, and F5) (prefilled syringes)) stored at 25°C for 0, 1, 3, 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%).

[0054] Figure 2 In vivo degarelix levels in plasma during the first 3 days after injection using the rat model described in section 13 of Example 1 in the Examples section are shown in a line graph.

[0055] Figure 3 In vivo degarelix levels in plasma over 28 days post-injection using the rat model described in section 13 of Example 1 in the Examples section are shown in a semi-logarithmic plot.

[0056] Figure 4 In vivo degarelix levels in plasma over 63 days after injection are shown using the rat model described in section 19 of Example 1 in the Examples section.

[0057] Figure 5 In vivo degarelix levels in plasma over 119 days post-injection using the rat model described in section 19 of Example 1 in the Examples section are shown in a semi-logarithmic plot.

[0058] Figure 6 A semi-logarithmic view of in vivo testosterone levels in plasma over 105 days post-injection using the rat model described in Example 1, section 19 in the Examples section is shown.

[0059] Figure 7 In vivo degarelix levels in plasma over 28 days after injection of the degarelix formulations of the present invention are shown in a semi-logarithmic plot using the rat model described in Example 2 in the Examples section.

[0060] Figure 8In vivo testosterone levels in plasma over 28 days following injection of the degarelix formulation of the present invention are shown in a semi-logarithmic plot using the rat model described in Example 2 in the Examples section.

[0061] Figure 9 In vivo degarelix levels in plasma over 63 days after injection of the degarelix formulation of the present invention are shown in a semi-logarithmic plot using the rat model described in Example 2 in the Examples section.

[0062] Figure 10 In vivo degarelix levels in plasma over 90 days following injection of the degarelix formulations of the present invention are shown in a semi-logarithmic plot using the rat model described in Example 2 in the Examples section.

[0063] Figure 11 In vivo testosterone levels in plasma over 90 days following injection of the degarelix formulation of the present invention are shown in a semi-logarithmic plot using the rat model described in Example 2 in the Examples section.

[0064] Figure 12 In vivo testosterone levels in plasma over 140 days following injection of the degarelix formulation of the present invention are shown in a semi-logarithmic plot using the rat model described in Example 2 in the Examples section.

[0065] Figure 13 In vivo testosterone levels in plasma over 140 days following injection of the degarelix formulation of the present invention are shown in a semi-logarithmic plot using the rat model described in Example 2 in the Examples section.

[0066] Figure 14 Results are shown of a stability study of different molar ratios of acid excipients in a degarelix acetate (DgA) / NMP formulation at 1, 3 and 6 months as described in Example 3 in the Examples section. The control (DgA / NMP 35 / 65 ratio) had no acid additive added. Detailed Description of the Invention

[0068] definition

[0069] As used herein, the terms "active pharmaceutical ingredient" (abbreviated as "API") and "drug" are used interchangeably and generally refer to a biologically active compound that has a therapeutic effect on the body. "Active pharmaceutical ingredient" can refer to the active drug, or a pharmaceutically acceptable salt of the active drug. As used herein, these terms can be used to refer to degarelix or a pharmaceutically acceptable salt thereof.

[0070] As used herein, the term "ester" refers to the chemical functional group C(O)OR', wherein R' represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and the like.

[0071] 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 excipients. Antioxidants can react with free radicals, thereby blocking or inhibiting free radical chain reactions, or they can have a lower redox potential than the active substances and excipients in the formulation. Additionally or alternatively, synergist antioxidants can enhance the effects of other antioxidants.

[0072] As used herein, the term "biocompatible" means "not harmful to living tissue" or "safe for injection in the human body."

[0073] As used herein, the term "biodegradable" refers to any material that transforms, decomposes, or degrades into harmless or natural byproducts (such as, but not limited to, water, gases, biomass, and / or organic salts) under physiological conditions, without regard to any particular degradation mechanism or process.

[0074] 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. As used herein, the term "liquid" may also exhibit viscoelastic behavior, i.e., have viscous and elastic properties when undergoing deformation (e.g., time-dependent and / or hysteresis strain). By way of non-limiting example, a viscoelastic material (e.g., jelly, jam, cake batter, or raw pizza dough and similar materials) that is generally flowable but has partial solid properties and / or plastic or gel-like properties is a term "liquid" as used herein. In some embodiments, a material that does not deform when the stress is lower than the yield stress, and is easily deformed when the material is higher than the yield stress without material fracture or rupture properties and having a non-zero yield stress may be a term "liquid" as used herein.

[0075] As used herein, the terms "patient" and "subject" are interchangeable and generally refer to an animal or human to whom a composition disclosed herein is or will be administered.

[0076] 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, which are formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or with organic acids, such as 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-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid , 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, pamoic acid, palmitic acid, etc.; or (2) a salt formed when an acidic proton present in the parent compound is replaced by a metal ion (such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion); or a coordination compound formed with an organic base (such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.).

[0077] As used herein, the term "solvent" refers to a liquid that dissolves solid or liquid solutes, or refers to the liquid external phase of a suspension in which solid or liquid substances can be suspended or dispersed. The term "biocompatible solvent" can be used interchangeably with the term "solvent."

[0078] As used herein, the term "cosolvent" refers to a substance added to a solvent to increase or alter the solubility of a solute in the solvent. Thus, a cosolvent can increase or decrease the solubility of a solute in the primary solvent and / or can impart other desirable properties to the formulation (e.g., the degree of water insolubility of the solvent and cosolvent in the solvent system can affect the desired rate of diffusion into body fluids to control the rate and extent of gelation of the degarelix API; or the solvent / cosolvent can control the viscosity of the compositions of the invention, which facilitates the preparation and administration of an extended-release composition to a subject).

[0079] 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.

[0080] As used herein, the term "solubilizer" refers to a compound that increases the solubility of another substance.

[0081] 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, a surfactant can act as a wetting agent, which helps disperse an active pharmaceutical ingredient in a liquid vehicle, or as a solubilizer.

[0082] As used herein, the term "therapeutically effective amount" refers to an amount of a compound or pharmaceutical product that, when administered to a patient to treat a disease and / or treat or prevent one or more symptoms of a disease, is sufficient to affect such treatment or prevention of the disease. The "therapeutically effective amount" may vary depending on, for example, the compound, the progression of the disease, the disease or condition being treated, whether the therapy is adjunctive or primary or curative, and / or the age, weight, etc. of the patient being treated.

[0083] As used herein, the terms "at least one," "one or more," and "and / or" are open-ended expressions that operate as both conjunctions and disjunctions. 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" refers to A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B, and C together. When each of A, B, and C in the above expressions refers to an element, such as X, Y, and Z, or a class of elements, such as X1-X n 、Y1-Y m and Z1-Z o When the phrase is used, it is intended to refer to individual elements selected from X, Y, and Z, combinations of elements selected from the same category (e.g., X1 and X2), and combinations of elements selected from two or more categories (e.g., Y1 and Z o ).

[0084] As used herein, the term "depot" (which may also be referred to herein as "fibrils" or "gel") refers to the degarelix compositions / formulations disclosed herein, upon exposure to an aqueous environment (e.g., including the physiological environment within an animal body), wherein the degarelix API self-aggregates and creates a drug depot from which degarelix is ​​released over an extended period of time.

[0085] Unless otherwise indicated, the amounts of various APIs and solvents and co-solvents are reported as weight percent of the solvent system or pharmaceutical composition.

[0086] Each maximum numerical value limit provided throughout the disclosure is considered as including each lower numerical value limit as an alternative, as if these lower numerical value limits are clearly written out in this article. Each minimum numerical value limit provided throughout the disclosure is considered as including each higher numerical value limit as an alternative, as if these higher numerical value limits are clearly written out in this article. Each numerical range provided throughout the disclosure is considered as including end value and each narrower numerical range falling within such a wide numerical range, as if these narrower numerical ranges are clearly written out in this article. For example, the phrase of approximately 2 to approximately 4 includes whole integers and / or approximately 2 to approximately 3, approximately 3 to approximately 4 integer ranges, and each possible range based on real number (for example, irrational number and / or rational number), for example, approximately 2.1 to approximately 4.9, approximately 2.1 to approximately 3.4 etc.

[0087] Reference will now be made in detail to specific embodiments of compounds, formulations, and methods.The disclosed examples are not intended to limit the claims.

[0088] Degarelix is ​​a decapeptide selective gonadotropin-releasing hormone (GnRH) receptor antagonist (blocker) that competitively and reversibly binds to GnRH receptors in the pituitary gland. This results in a significant decrease in follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thereby reducing testosterone levels in males or estrogen levels in females. In one embodiment of the invention, degarelix is ​​indicated for LH suppression or testosterone suppression in adult male patients with advanced hormone-dependent prostate cancer who require androgen deprivation. The degarelix formulations of the present invention can also be used for LH suppression or estrogen (e.g., estradiol) suppression in adult female patients with premenopausal or perimenopausal breast cancer, and can also be used for conditions including, but not limited to, endometriosis. The degarelix formulations of the present invention can also be used 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 long-acting 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, and in one embodiment, for at least three months or longer, after a single dose; and (3) is administered in a total injection volume of about 2.5 mL or less, or about 2 mL or less.

[0089] Disclosed herein are long-acting injectable compositions or formulations (used interchangeably and which may also be referred to as "drug products," "pharmaceutical products," "products," or "finished drug products") comprising degarelix or a pharmaceutically acceptable salt thereof in an organic solvent extended-release injectable formulation. These formulations do not contain a biodegradable polymer. The formulations contain a biocompatible, water-miscible solvent and may optionally further contain one or more additives as disclosed herein. The degarelix compositions / formulations disclosed herein are flowable solutions or suspensions that, when delivered (i.e., injected) into an aqueous environment (e.g., the human body), exchange the water-miscible solvent with the surrounding aqueous body fluids, resulting in the formation of degarelix reservoirs, fibrils, or gels that act as extended-release drug reservoirs for the degarelix peptide (i.e., release the drug over an extended period of time).

[0090] When used at low volumes (e.g. < 2.5 mL or < The compositions / formulations disclosed herein provide sustained or extended release of degarelix or a pharmaceutically acceptable salt thereof for more than one month when injected subcutaneously (e.g., 2 mL). Long-acting injectable compositions suitable for use in the disclosed methods (which may also be referred to as pharmaceutical compositions or formulations, extended-release compositions or formulations, or controlled-release compositions or formulations) provide a biodegradable or bioerodible in situ formed reservoir 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 compositions / formulations can be provided in a prefilled single syringe having 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 are suitable for subcutaneous injection. The composition solves the problem of multiple, high-volume injections provided by degarelix products currently on the market.

[0091] Following administration of the compositions disclosed herein, degarelix or a pharmaceutically acceptable salt thereof is released from the reservoir 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 duration of release from the reservoir may depend on one or more factors, including, for example, the solvent, the amount of the components in the composition, any additives in the composition, combinations of any of the foregoing, or other factors.

[0092] Active Pharmaceutical Ingredients (API)

[0093] 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. As used herein, "degarelix API" (whether capitalized or not) refers to degarelix or any pharmaceutically acceptable salt thereof.

[0094] 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, wherein the solid, semisolid, or liquid reservoir is composed of fibrils that form a degarelix gel in situ upon dissipation of the solvent. The reservoir thus formed releases degarelix or a pharmaceutically acceptable salt thereof in a controlled-release or extended-release manner.

[0095] The concentration of degarelix or a pharmaceutically acceptable salt thereof in the disclosed compositions can vary and can range from 1% to 50% by weight of the composition, including any integer percentage to any other integer percentage within the range of about 1% to about 50% by weight. The concentration of degarelix or a pharmaceutically acceptable salt thereof in the composition can be about 5 weight % of the composition, or about 10 weight % of the composition, or about 15 weight % of the composition, or about 20 weight % of the composition, or about 21 weight % of the composition, or about 22 weight % of the composition, or about 23 weight % of the composition, or about 24 weight % of the composition, or about 25 weight % of the composition, or about 26 weight % of the composition, or about 27 weight % of the composition, or about 28 weight % of the composition, or about 29 weight % of the composition, or about 30 weight % of the composition, or about 31 weight % of the composition, or about 32 weight % of the composition, or about 33 weight % of the composition, or about 34 weight % of the composition, or about 35 weight % of the composition, or about 36 weight % of the composition, or about 37 weight % of the composition, or about 38 weight % of the composition, or about 40 weight % of the composition, or about 45 weight % of the composition, or about 50 weight % of the composition. In other embodiments, the amount of degarelix API in the compositions of the present invention may range from any tenth percent to any other tenth percent within the range of about 1 weight percent to about 50 weight percent.

[0096] In some aspects, the amount of degarelix API in the compositions of the present invention refers to the amount of a pharmaceutically acceptable salt of degarelix, such as degarelix acetate or other salt, in the composition. In some aspects, the amount of degarelix API in the compositions of the present invention refers to the amount of degarelix free base equivalents in the composition (which may also be simply referred to as the amount of degarelix in the composition). For example, the dose of degarelix API administered to a subject can be calculated based on the amount of degarelix free base equivalents 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 batches. The calculation of the free base equivalent of degarelix in a composition is well understood in the art. For example, in a composition where the degarelix API is degarelix acetate, the percentage of degarelix as free base (by weight) can be calculated using a simple formula, e.g., 100 - (wt% water content of drug substance - wt% acetic acid content of drug substance) * measured purity of degarelix (anhydrous / acid free base) * wt% degarelix acetate in the composition. The free base equivalent of the drug substance can also be provided by the USP monograph.

[0097] In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof (degarelix API) in the composition of the present invention is about 30 wt % to about 35 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 31 wt % to about 34 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 31 wt % to about 33 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 31 wt % to about 32 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 20 wt % to about 23 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 20 wt % to about 22 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 21 wt% to about 23 wt% degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 21 wt% to about 22 wt% degarelix free base equivalents. In some aspects, when calculating the target dose to be administered to a subject based on the degarelix free base equivalents in the composition, the weight percentage of the solvent and the weight percentage of the additive (if included) can be modified accordingly.

[0098] solvent

[0099] Any suitable water-miscible solvent may be employed, provided that the solvent is miscible for dispersion in an aqueous medium or body fluid. Examples of suitable solvents are disclosed, for example, in the Aldrich Handbook of Fine Chemicals and Laboratory Equipment, Milwaukee, Wis. (2000); and in U.S. Patent Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194. In various aspects, the solvent is capable of diffusing into the body fluid, causing the flowable composition to solidify or solidify. The solvents and co-solvents that can be used in the disclosed compositions are preferably biocompatible, non-toxic solvents that can be hydrophilic or hydrophobic, or a combination of hydrophilic, hydrophobic, or hydrophilic and hydrophobic solvents, depending on the desired release profile and the solubility of the degarelix API in the composition. In one aspect, the solvent and / or co-solvent is an organic solvent. In yet another aspect, the solvent and / or co-solvent is a polar aprotic solvent.

[0100] Suitable solvents and co-solvents may include one or more solvents selected from the group consisting of amides, acids, alcohols, esters of monoacids, ether alcohols, sulfoxides, lactones, polyhydroxy alcohols, esters of polyhydroxy alcohols, ketones, and ethers. As non-limiting examples, the solvent or co-solvent may 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, glyceryl triacetate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, esters thereof, and combinations thereof.

[0101] In aspects of the invention, suitable solvents are selected from N-methyl-2-pyrrolidone (NMP) and / or dimethyl sulfoxide (DMSO). In aspects of the invention, suitable co-solvents include benzyl alcohol (BzOH).

[0102] It is also disclosed herein that degarelix or a pharmaceutically acceptable salt thereof is preferably substantially or completely dissolved in a biocompatible solvent or solvent system.

[0103] The biocompatible solvent or combination or mixture of solvents and / or co-solvents used in the compositions of the present invention will typically comprise from about 50 wt % to about 99 wt % of the final formulation, or from about 30 wt % to about 69 wt % of the final formulation, or from about 40 wt % to about 59 wt % of the final formulation, or alternatively, the amount of solvent or combination or mixture of solvents and / or co-solvents can range from any integer percentage by weight of the formulation between about 50 wt % and about 99 wt % to any other integer percentage by weight of the formulation. If the formulation includes optional co-solvents and / or additives, although the ratio of solvent to degarelix API can be the same, the wt % of each in the final formulation may be altered due to the presence of the co-solvents and / or additives.

[0104] additive

[0105] Optionally, the pharmaceutical compositions disclosed herein may include various additives (which may also be referred to as "excipients") to improve the stability, injectability, and / or other properties of the composition, including reducing pain or inflammation when the composition is injected. For example, the pharmaceutical composition may include one or more antioxidants, chelating agents, surfactants, cosolvents (also discussed above), stabilizers, complexing agents, antioxidants, and solubilizers.

[0106] In some embodiments, pharmaceutical composition may include one or more solubilizing agents to increase the solubility of one or more other components of the composition. The solubilizing agent that can be used for the disclosed composition includes any solubilizing agent that can be used for parenteral injection, and includes but is not limited to surfactants and other solubilizing agents that reduce the surface tension between two liquids, between gas and liquid, or between liquid and solid. The example of suitable solubilizing agents and / or surfactants for the present invention includes but is not limited to polysorbate 20, polysorbate 80, poloxamer 188, sorbitan trioleate, lecithin (such as soybean or egg), vitamin E TPGS, esters or ethers based on sugar (such as sugar acid esters of fatty alcohol or sugar alcohol esters of fatty acid, including but not limited to sucrose cocoate, sucrose stearate, sucrose laurate, etc.), solubility enhancers based on amino acid (such as proline, arginine, DL-methionine), solubility enhancers based on protein (such as hydrophobin), etc.

[0107] In some embodiments, the pharmaceutical composition may comprise one or more antioxidants to inhibit oxidation of the API and improve the stability of the formulation. Examples of suitable antioxidants for use in the present invention include, but are not limited to, citric acid, methanesulfonic acid, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), mercaptoethanol, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxyquinone, butylated hydroxyanisole, hydroxycoumarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl hydroxybenzoate, trihydroxybutyrophenone, dimethylphenol, dibutylphenol, vitamin E, lecithin, and ethanolamine.

[0108] In some embodiments, the pharmaceutical composition may comprise one or more complexing agents to inhibit oxidation and / or degradation of the API and improve the stability of the formulation. Examples of suitable complexing agents for use in the present invention include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), divalent metal salts (ZnCl2, MgCl2, CaCl2), nitrilotriacetic acid, n-hydroxyethylethylenediaminetriacetic acid (HEDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and several simple organic acids, such as polycarboxylic acids (citric acid), hydrochloric acid, sulfuric acid, pamoic acid, and palmitic acid.

[0109] In some embodiments, the pharmaceutical compositions may include one or more release-modifying additives.

[0110] In some embodiments, the pharmaceutical composition may include one or more stabilizers to prevent drug degradation (physical or chemical) and to improve formulation stability and increase 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).

[0111] For example, in some embodiments, an acid additive is optionally included in the pharmaceutical composition of the present invention as an additional excipient (i.e., in addition to the degarelix API and solvent and / or cosolvent). Acid additives as excipients provide additional acids in the composition of the present invention in addition to any acid provided by the pharmaceutically acceptable salt of the API itself (e.g., the acid content in the degarelix acetate drug substance). Such acid excipients can improve the stability of the formulation and increase the shelf life by, for example, reducing the level of impurities produced by the formulation over time before use and / or reducing the amount of aggregation of the degarelix API over time before 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-chloropropionic acid, 4-cyanobutyric acid, perchloric acid, phosphoric acid, hydroiodic acid, and combinations thereof. In one aspect, the acid additive is acetic acid, citric acid, and / or succinic acid.

[0112] In various aspects, the concentration of the acid additive as an excipient in the disclosed compositions can vary and can range from about 0.1% to about 10% by weight of the composition, including any 0.1% increment within the range of about 0.1% to about 10% by weight. In one aspect, the concentration of the acid additive as an excipient in the disclosed compositions ranges from about 0.1 wt % to about 9 wt %; or about 0.1 wt % to about 8 wt %; or about 0.1 wt % to about 7 wt %; or about 0.1 wt % to about 6 wt %; or about 0.1 wt % to about 5 wt %; or about 0.1 wt % to about 4 wt %; or about 0.1 wt % to about 3 wt %; or about 0.1 wt % to about 2 wt %; or about 0.1 wt % to about 2 wt %; or about 0.5 wt % to about 10 wt %; or about 0.5 wt % to about 9 wt %; or about 0.5 wt % to about 8 wt %; or about 0.5 wt % to about 7 wt %; or about 0.5 wt % to about 6 wt %; or about 0.5 wt % to about 5 wt %; or about 0.5 wt % to about 4 wt %; or about 0.5 wt % to about 3 wt %; or about 0.5 % to about 2 wt %; or about 1 wt % to about 10 wt %; or about 1 wt % to about 10 wt %; or about 1 wt % to about 9 wt %; or about 1 wt % to about 8 wt % or about 1 wt % to about 7 wt % or about 1 wt % to about 6 wt %; or about 1 wt % to about 5 wt %; or about 1 wt % to about 4 wt %; or about 1 wt % to about 3 wt %; or about 1 wt % to about 2 wt %.

[0113] In one aspect, the amount of the acid additive as an excipient in the disclosed composition can be expressed as a molar ratio of degarelix API (drug substance before addition to the formulation) to the acid additive. In one aspect, the molar ratio of degarelix API (calculated as 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 aspect, the molar ratio of degarelix API (calculated as free base) to the total amount of acid (contributed by degarelix API salt form and acid additive (if any)) 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.

[0114] In various aspects, the amount of acid in the compositions of the present invention can alternatively be expressed as the total amount of acid contributed by all components of the formulation (i.e., from the API salt form of degarelix and any acid additives as excipients). In various aspects, the total amount of acid in the composition (as wt % of the composition) ranges from about 1% to about 10%; or about 1.5% to about 10%; or about 2.0% to about 10%; or about 2.5% to about 10%; or about 3.0% to about 10%; or about 3.5% to about 10%; or about 4.0% to about 10%; or about 4.5% to about 10%; or about 5.0% to about 10%; or about 5.5% to about 10%; or about 6.0% to about 10%; or about 6.5% to about 10%; or From about 7.0% to about 10%; or from about 7.5% to about 10%; or from about 8.0% to about 10%; or from about 8.5% to about 10%; or from about 9.0% to about 10%; or from about 9.5% to about 10%, or from about 1.0% to about 7.0%, or from about 1.0% to about 6.0%, or from about 1.0% to about 5.0%, or from about 1.0% to about 4.0%, or from about 1.0% to about 3.0%, or from about 1.0% to about 2.0%, or in any increment of 0.1% between 1% and 10%.

[0115] In aspects, the amount of acid in the degarelix drug substance (in the degarelix API itself, not as an excipient) prior to addition to the composition or formulation is in the range of about 0 wt% to about 10 wt%, 1 wt% to about 10 wt%, or about 2 wt% to about 10 wt%, or about 3 wt% to about 10 wt%, or about 3.5 wt% to about 10 wt%, or about 4 wt% to about 10 wt%, or about 4.5 wt% to about 10 wt%, or about 5 wt% to about 10 wt%, or about 5.5 wt% to about 10 wt%, or about 6 wt% to about 10 wt%, or about 6.5 wt% to about 10 wt%, or about 7 wt% to about 10 wt%, or about 7.5 wt% to about 10 wt%, or about 8 wt% to about 10 wt%, or about 8.5 wt% to about 10 wt%, or about 9 wt% to about 10 wt%, or about 9.5 wt% to about 10wt%.

[0116] In still other aspects, the composition further comprises an additive (excipient) that is an 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 after injection into the body. In one aspect, the formulations of the present invention optionally contain benzyl alcohol as an additive / excipient. In various aspects, the concentration of the alcohol additive as an excipient in the disclosed compositions can vary and can range from about 1% to about 30% by weight of the composition, including any 1% increment within the range of about 1% to about 30% by weight of the composition. In one aspect, the concentration of the alcohol additive as an excipient in the disclosed compositions ranges from about 1 wt % to about 30 wt %; or about 5 wt % to about 30 wt %; or about 10 wt % to about 30 wt %; or about 11 wt % to about 30 wt %; or about 12 wt % to about 30 wt %; or about 13 wt % to about 30 wt %; or about 14 wt % to about 30 wt %; or about 15 wt % to about 30 wt %; or about 16 wt % to about 30 wt %; or about 17 wt % to about 30 wt %; or about 18 wt % to about 30 wt %; or about 19 wt % to about 30 wt %; or about 20 wt % to about 30 wt %; or about 21 wt % to about 30 wt %; or about 22 wt % to about 30 wt %; or about 23 wt % to about 30 wt %; or about 24 wt % to about 30 wt %; or about 25 wt % to about 30 wt % to about 30 wt %; or about 27 wt % to about 30 wt %; or about 28 wt % to about 30 wt %; or about 29 wt % to about 30 wt %.

[0117] Composition

[0118] In various aspects, the present disclosure provides a long-acting injectable pharmaceutical composition comprising degarelix or a pharmaceutically acceptable salt thereof, a biocompatible solvent, and optionally one or more additives. All such compositions are intended for administration to a subject to treat a disease or condition for which administration of a GnRH agonist or GnRH antagonist may be useful. In various aspects, the compositions of the present invention are intended for treating prostate cancer, including advanced prostate cancer; treating central precocious puberty (CPP); treating premenopausal or perimenopausal breast cancer; or treating other conditions, including but not limited to endometriosis. In addition, it is expected that such compositions will be administered to a subject to reduce the subject's luteinizing hormone (LH) levels, and to reduce serum testosterone levels in males, and to reduce serum estrogen levels in females.

[0119] Depending on the other components in the composition, degarelix or a pharmaceutically acceptable salt thereof in the disclosed compositions may form a monophasic mixture (e.g., a solution) or a biphasic mixture (e.g., a suspension or dispersion) within the composition. Thus, the extended-release composition comprising degarelix or a pharmaceutically acceptable salt thereof according to the present invention may suitably be a "solution" or "dispersion" or "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 therefore monophasic. More preferably, the degarelix API is a stable solution and remains in solution in the solvent and therefore does not require reconstitution or mixing to maintain a stable solution.

[0120] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 wt % to about 40 wt % of degarelix acetate or degarelix citrate; and about 60 wt % to about 80 wt % of N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO).

[0121] In some embodiments, the present disclosure provides pharmaceutical compositions comprising about 25 wt% to about 45 wt% degarelix acetate or degarelix citrate and about 55 wt% to about 75 wt% NMP or DMSO.

[0122] In some embodiments, the present disclosure provides pharmaceutical compositions comprising degarelix API in an amount of about 20 wt% to about 45 wt% degarelix free base equivalents. In some aspects, the present disclosure provides pharmaceutical compositions comprising degarelix API in an amount of about 20 wt% to about 40 wt% degarelix free base equivalents, or about 20 wt% to about 35 wt% degarelix free base equivalents, or about 20 wt% to about 34 wt% degarelix free base equivalents, or about 20 wt% to about 33 wt% degarelix free base equivalents, or about 20 wt% to about 32 wt% degarelix free base equivalents. In some embodiments, the present disclosure provides pharmaceutical compositions comprising degarelix API in an amount of about 30 wt% to about 35 wt% degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 31 wt% to about 34 wt% degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 31 wt% to about 33 wt% degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 31 wt% to about 32 wt% degarelix free base equivalents.

[0123] In one aspect, the amount of degarelix API in the pharmaceutical composition is about 20 wt % to about 23 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 20 wt % to about 22 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 21 wt % to about 23 wt % degarelix free base equivalents. In one aspect, the amount of degarelix API in the pharmaceutical composition is about 21 wt % to about 22 wt % degarelix free base equivalents. In some aspects, when calculating the target dose to be administered to a subject based on the degarelix free base equivalents in the composition, the percentage by weight of the solvent and the percentage by weight of the additive (if included) can be modified accordingly.

[0124] In some embodiments, as described in more detail above, the present disclosure provides a pharmaceutical composition further comprising an acid additive as an excipient. In one aspect, the composition further comprises about 0.1 wt% to about 10.0 wt% of an acid additive, or about 1.0 wt% to about 6.0 wt% of an acid additive, or about 1.0 wt% to about 5.0 wt% of an acid additive, or about 1.0 wt% to about 4.0 wt% of an acid additive, or about 1.0 wt% to about 3.0 wt% of an acid additive, or about 1.0 wt% to about 2.0 wt% of an acid additive. In one aspect, the acid is acetic acid, citric acid, or succinic acid.

[0125] In still other embodiments, 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 wt% to about 30 wt% benzyl alcohol (BnOH).

[0126] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35 wt% degarelix acetate and about 65 wt% N-methyl-2-pyrrolidone (NMP).

[0127] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35 wt% degarelix acetate and about 65 wt% DMSO.

[0128] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 20-40 wt% degarelix acetate; about 55-70 wt% NMP; and about 5-10 wt% benzyl alcohol (BnOH).

[0129] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35 wt% degarelix citrate; and about 65 wt% NMP.

[0130] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35 wt% degarelix acetate; about 62 to 64 wt% NMP; and about 1 to 5 wt% AcOH.

[0131] In some embodiments, the present disclosure provides pharmaceutical compositions comprising about 35 wt% degarelix acetate; about 62 to 64 wt% NMP; and 1 to 3 wt% AcOH.

[0132] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 35 wt% degarelix acetate; about 62.8 wt% NMP; and about 2.2 wt% AcOH.

[0133] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24 wt% degarelix acetate; about 50 to 60 wt% NMP; and about 16 to 26 wt% BnOH.

[0134] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24 wt% degarelix acetate; about 54 to 58 wt% NMP; and about 18 to 22 wt% BnOH.

[0135] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24 wt% degarelix acetate; about 56 wt% NMP; and about 20 wt% BnOH.

[0136] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24 wt% degarelix acetate; about 66 to 75 wt% NMP; and about 1 to 10 wt% AcOH.

[0137] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24 wt% degarelix acetate; about 70 to 75 wt% NMP; and about 1 to 6 wt% AcOH.

[0138] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 24 wt% degarelix acetate; about 73.3 wt% NMP; and about 1.7 wt% AcOH.

[0139] Methods of treatment, use and administration

[0140] The methods of the present disclosure are used to treat diseases or conditions including prostate cancer (including advanced prostate cancer). Still further, the methods of the present disclosure are used to reduce serum testosterone levels to below castrate levels of at least 50 ng / dL or below 20 ng / dL or below 10 ng / dL.

[0141] In addition, the method of the present disclosure is used to suppress ovarian function in a subject suffering from hormone receptor positive breast cancer. In one aspect, hormone receptor positive breast cancer is premenopausal breast cancer. In one aspect, hormone receptor positive breast cancer is perimenopausal breast cancer. In one aspect, hormone receptor positive breast cancer is estrogen receptor (ER) positive breast cancer. In one aspect, the composition disclosed herein suppresses the estradiol (E2) production of the subject to a level lower than about 20 pg / ml, lower than about 15 pg / mL, lower than about 10 pg / mL, lower than about 5 pg / mL, lower than about 4 pg / ml, lower than about 3 pg / mL or lower than about 2 pg / mL. In a preferred aspect, E2 generation level is reduced to about 2.7 pg / mL. In still another aspect, the composition disclosed herein suppresses the follicle stimulating hormone (FSH) of breast cancer subjects to a level lower than about 40 IU / L. In yet another aspect, the composition disclosed herein suppresses the luteinizing hormone (LH) of breast cancer patients to a level lower than about 4 IU / L.

[0142] Still further, the methods of the present disclosure are used to treat endometriosis.

[0143] The method disclosed herein is used to treat central precocious puberty (CPP). CPP is defined as early sexual development caused 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 concentration levels in children with CPP can be caused by various sources, including but not limited to physical injury, infection, genetic disease or related tumors. CPP caused by hereditary or undetermined pathology is classified as idiopathic in nature, while CPP caused by central nervous system (CNS) tumors and / or lesions is classified as organic in nature. CPP is accompanied by early bone age, accelerated growth rate and activation of the hypothalamic-pituitary-gonadal axis. In one aspect, the compositions disclosed herein reduce the serum LH concentration of patients with CPP to a pre-pubertal concentration level of <4 IU / L.

[0144] The method comprises administering the disclosed long-acting injectable composition subcutaneously or intramuscularly to subjects / patients with prostate cancer, advanced prostate cancer, CPP, premenopausal breast cancer, postmenopausal breast cancer, and those in need of reducing serum testosterone levels and / or LH levels. When the pharmaceutical composition is injected into the body and the composition comes into contact with body fluids, the solvent dissipates and self-aggregation or gelation of degarelix occurs, 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 into the subject / patient, for example, for a period of 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, e.g., for a period of at least about one month or longer, at least about two months or longer, at least about three months or longer, at least about four months or longer, at least about five months or longer, or six months or longer.

[0145] Long-acting compositions can be administered to a patient / subject approximately once every 30 days, approximately once every 60 days, approximately once every 90 days, approximately once every 120 days, approximately once every 150 days, or approximately once every 180 days. In another aspect, long-acting compositions can be administered to a patient / subject approximately once every 1 month, approximately once every 2 months, approximately once every 3 months, approximately once every 4 months, approximately once every 5 months, or approximately once every 6 months. In a preferred aspect, the composition is administered approximately every 3 months. According to the present invention, for clarity, a "month" can be 28 to 31 days.

[0146] The amount of degarelix or a pharmaceutically acceptable salt thereof effective in treating or alleviating the above-mentioned diseases or conditions will depend on the nature / severity of the condition or symptoms. In vitro or in vivo assays may optionally be employed to help determine the optimal dosage range. The amount of degarelix or a pharmaceutically acceptable salt thereof administered will, of course, depend on factors such as the subject being treated, the subject's age / weight, the severity of the affliction, the route of administration, and the judgment of the prescribing physician.

[0147] The dosage of degarelix or a pharmaceutically acceptable salt thereof for treating prostate cancer and / or advanced prostate cancer in the composition 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, about 220 mg, about 225, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 In one aspect, a single dose can be administered in one injection. In another aspect, a single dose can be administered in more than one injection.

[0148] In one aspect, the disclosed composition will be administered once to the subject / patient during the administration period, and the administration period has a varying duration (e.g., one month, two months, three months, four months, five months, or six months) between administrations. In one aspect, the disclosed composition will be administered to the subject / patient with an initial loading dose, followed by a maintenance dose of one or more disclosed compositions. Administration can be provided alone, or in combination with other drugs, and as long as it is required for the effective treatment of a disease state or disorder, sustainable administration is possible. In some embodiments, the disclosed composition is formulated to provide a dosage between about 40 mg – about 500 mg. In these embodiments, the composition is delivered with a total volume or per injection volume of no more than 2.5 mL or no more than 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.

[0149] In some embodiments, the composition is terminally sterilized, for example, by electron beam, gamma irradiation, or X-rays. In yet another aspect, the composition is sterile filtered.

[0150] In some embodiments, the long-acting composition is administered to the patient as a monotherapy. The treatment method of this embodiment can reduce or eliminate one or more symptoms of the diseases and / or conditions disclosed herein. In other embodiments, the long-acting composition can be administered as a combination therapy, for example, with chemotherapy, radiotherapy, surgery, endocrine therapy such as selective estrogen receptor modulators (SERMs; for example, tamoxifen, toremifene, raloxifene, ospemifene and bazedoxifene), selective estrogen receptor degraders (SERDs; for example, fulvestrant), aromatase inhibitors (AIs; for example, anastrozole, letrozole, exemestane, vorozole, formestane and fadrozole); mammalian target of rapamycin (mTOR) inhibitors; for example, temsirolimus, sirolimus, everolimus and ridaforolimus); phosphatidylinositol 3-kinase inhibitors (PI-3 kinase or PI3K; for example, apelisib, idelalisib, and buparlisib); cyclin-dependent kinase 4 and 6 inhibitors (CDK4 / 6 inhibitors; for example, abemaciclib, palbociclib, and ribociclib); LHRH agonists (for example, leuprolide, gonadorelin, goserelin, histrelin, nafarelin, buserelin, and triptorelin, and pharmaceutically acceptable salts thereof), immunotherapy, and gene therapy.

[0151] The disclosed long-acting composition can be provided as part of a delivery system comprising a syringe system, wherein the composition or formulation is contained in a syringe. In some embodiments, the syringe is a pre-filled syringe system, which comprises the disclosed composition as a single dose or multiple doses. The syringe can contain a single dose 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 the formulation contained therein as needed). In one aspect, the pre-filled syringe is a single-chamber syringe, wherein the composition contained therein is a stable, single-phase or substantially single-phase composition that does not need to be mixed before injection. In one aspect, the syringe system is an automatic syringe. In one aspect, the syringe system is a reusable automatic syringe that can provide a disposable cartridge containing a single dose of the composition of the present invention. In one aspect, the syringe system can be referred to as a container. The container can also be a syringe and a bottle containing a single dose or multiple doses of the pharmaceutical composition of the present invention, wherein the contents from the bottle can be drawn into the syringe for injection.

[0152] In some embodiments, the pharmaceutical composition can be administered to a patient by injection using a syringe system (including a syringe system as described herein). In various aspects, the composition is injected subcutaneously, but other parenteral routes, including intramuscular injection, are also contemplated herein.

[0153] The composition can be administered by manual injection through a syringe with, for example, an 18 to 32 gauge needle, a 22 to 25 gauge needle, an 18 to 24 gauge needle, or an 18 to 22 gauge needle, or an 18 to 20 gauge needle, or can be administered by injection using an autoinjector.

[0154] Also contemplated herein are kits comprising the pre-filled syringe systems disclosed herein.

[0155] The following experimental results are provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0156] Example

[0157] The following examples describe methods for preparing and testing extended-release compositions containing degarelix acetate (DgA) active pharmaceutical ingredient (API) or other forms of degarelix in which the counterion is formed with other acids such as polycarboxylic acids (citric acid), strong acids (methanesulfonic acid), hydrophobic acids (pamoic acid, palmitic acid). The following examples discuss the preparation and use of degarelix citrate alone.

[0158] Example 1:

[0159] 1. Preliminary screening of the solubility of DgA-drug substance (DS) in various water-miscible pharmaceutically acceptable organic solvents:

[0160] Various organic solvents were screened for maximum solubility of DgA-DS. Non-aqueous, water-miscible, pharmaceutically acceptable organic solvents, such as N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), and N,N-dimethylacetamide (DMA), have demonstrated superior solubility capabilities for degarelix (at least 35-40% w / w) compared to water-based solvents. NMP and DMSO can dissolve higher 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 was insoluble or had solubility limits much lower than those of NMP, DMSO, or DMA.

[0161] 2. Degarelix citrate (DgC)-DS formulation

[0162] DgC-DS was formed by dissolving degarelix acetate (purchased from a commercial supplier) in water (~40 mg / mL concentration) and then adding an aqueous solution of citric acid (1 M) dropwise. The molar ratio of degarelix free base to citric acid in the solution was varied as needed. The resulting solution was mixed for 10-15 minutes and placed in a -80°C freezer. The contents were lyophilized to remove water (and freeze drying to remove a certain amount of acetic acid formed due to 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 Table 1 for a description of the degarelix citrate drug substance powder.

[0163] Table 1 Description of Degarelix Citrate (DgC) - Drug Substance Powder

[0164]

[0165] 3. Preparation of Dg-DS or Dg-DS / Organic Solvent Formulation Bulk Solution and Prefilled Syringes

[0166] Bulk Solution: To prepare a drug / solvent bulk solution containing the active pharmaceutical ingredient (DgA or DgC), combine the desired amount of DgA-DS or DgC-DS with the solvent NMP or DMSO, or a combination of solvents (with or without co-solvents or other additives) in the specified amounts (see individual experiments below). Combine the API and solvent in a glass vial or jar and blanket with nitrogen. Mix the jar at room temperature using a jar mill, Turbula, or shaker until homogeneous. DgA or DgC is very soluble in NMP or DMSO and can be loaded at higher concentrations (at least 40% w / w).

[0167] Syringe Filling: After dissolving the API in an organic solvent, the liquid dosage form is manually filled into a syringe and capped with a top cap. The syringe barrels selected for filling are made of polypropylene or cyclic olefin copolymer (COC) materials. The filled syringes are then packaged in labeled foil pouches with a desiccant pack and the pouches are sealed. After filling the syringes with the dosage form, the filled syringes are stored under refrigerated conditions (e.g., 2-8°C) or accelerated conditions (≥25°C, see individual experiments). The syringes can be irradiated by electron beam or gamma irradiation (see individual experiments) for terminal sterilization.

[0168] 4. In situ gelation screening

[0169] The solution of DgA-DS in water (40 mg / mL), the solution of DgA-DS in NMP (~35% w / w) or the solution of DgA-DS in DMSO (~34% w / w) were injected into deionized water and phosphate buffered saline (PBS). When the DgA solution was injected into PBS (~50 mg of DgA was injected into 10-15 mL), the immediate aggregation and gelation of the peptide were observed. However, when the DgA solution of similar amounts was injected into deionized water, this rapid aggregation and gelation effect were not observed. After the injection, the liquid in the bottle became slightly turbid immediately, and finally became a translucent gel overnight. When injected into PBS, the preparations based on NMP or DMSO demonstrated the similar drug aggregation effect as seen with the DgA solution based on water.

[0170] 5. In situ gelation relative to injection volume

[0171] A solution of DgA-DS in DMSO (~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 investigate whether aggregation / gelation could be observed at smaller injection volumes. Aggregation was observed at all injection levels, regardless of injection volume. The extent of gelation (visible by the thickness of the translucent gel phase) was greater at higher injection volumes, which can be attributed to the higher drug loading.

[0172] 6. XRD Characterization of DgA Solution

[0173] Sample Preparation: Use a spatula to load the sample into a 2 mm x 20 mm zero-background sample holder. Use a microscope slide to press down on the sample so that it is flush with the top of the sample holder.

[0174] XRD instrument setup: Sample analysis was run using a Rigaku MiniFlex XRD instrument. The X-ray tube was set to 40 kV and 15 mA. The detector was a D / tex Ultra 2, 2D detector. The filter was KβNi (1.5). The scan mode was continuous with the scan axis at 2θ / θ, a step width of 0.02 degrees, and a scan speed of 5 degrees / minute. The scan range was 3°-45°. The optical arrangement was as follows: incident Soller slit 5.0 degrees, divergence slit 0.625 mm, incident height limiting slit 10.0 mm, Soller slit 8.0 mm, receiving Soller slit 5.0 degrees, and receiving slit open (no slit). The analysis was run at ambient temperature.

[0175] Analysis: Sample analysis was controlled using MiniFlex software. After running a series of samples, the data was processed using stand-alone software called PDXL2. Degarelix acetate, a biopolymer, is amorphous and does not show any crystallinity as an API powder or at a concentration of 66 mg / mL in water. At higher concentrations, the peptide formed a gel. The gel was not crystalline. Theoretically, the gel exhibited peaks indicative of a higher-order structure, which is attributed to the formation of β-sheets that form aggregates leading to gel formation. The addition of salt can facilitate gelation at lower concentrations than in the absence of salt. Gelation also did not occur in the presence of water or in the presence of NMP solvent.

[0176] 7. Analysis of Degarelix (assay) and Total Related Compounds in the Formulation.

[0177] Transfer the preparation or dispense the contents of the syringe into a 50 mL volumetric flask and record the weight. Dilute to volume with mobile phase A and mix thoroughly by vortexing. Dilute as needed - dilute 2 mL to 20 mL with mobile phase A (0.1% trifluoroacetic acid in water) and mix thoroughly by vortexing. Make a second dilution of 2 mL to 20 mL with mobile phase A to obtain a working sample.

[0178] HPLC Analysis: HPLC analysis of test compounds and related compounds was performed 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 at 30°C at a flow rate of 0.75 mL / min. The run time was 15 minutes, with 10-μL injections for solution-gel reservoir formulations of test compounds and related compounds. The 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 used in the example chromatograms.

[0179] Table 2 HPLC gradient method

[0180]

[0181] 8. Drug Recovery from Different Degarelix / Organic Solvent Formulations

[0182] Prefilled syringes of degarelix / organic solvent formulations were prepared as described in Section 3. The different formulations were tested for drug recovery using the HPLC method (see Section 7) and are listed in Table 3.

[0183] Table 3 Observations: All formulations showed good recoveries (90.0-110.0%), indicating the applicability of the method and the initial stability of the API in different solvent systems.

[0184] Table 3. Drug recovery testing of prefilled syringes for organic solvent-based formulations

[0185]

[0186] (“F#” stands for “Formulation Number”)

[0187] 9. Stability of Degarelix / Organic Solvent Formulations

[0188] Prefilled syringes of the degarelix / organic solvent formulation were prepared as described in Section 3. The samples were not treated with electron beams. The composition of the samples is shown in Table 4. The sealed foil pouches containing the prefilled syringes were placed under accelerated storage conditions (25 ± 2°C for 6 months) and tested for drug determination or recovery and related compounds at each sampling time (0, 1, 3, and 6 months) (see Section 7 for procedures). The results of this study are presented in Figure 1 No drug degradation was observed at 6 months, and the slight increase in percent recovery over time could be attributed to solvent loss / absorption in the prefilled syringes under accelerated conditions.

[0189] Table 4 Composition of the preparation

[0190]

[0191] (“F#” stands for “Formulation Number”)

[0192] Figure 1 Observation results: Degarelix acetate was found to be stable in NMP and DMSO (at the concentration studied) at 25°C for 6 months (accelerated conditions). There was no significant increase in related compounds. At 6 months, the total related compounds were less than 2%. The slight increase in the percent recovery of F1, F2, and F5 formulations during storage can be attributed to the solvent loss over time from the pre-filled syringe or stopper absorption under accelerated storage conditions. No gelation was observed in formulations F1, F2, and F5. The F5 formulation was manufactured at a higher concentration than F2, and it was found that both were stable and did not show any gelation. This supports that higher concentrations, such as 40% w / w, are also feasible.

[0193] 10. Feasibility of terminal sterilization by electron beam or gamma irradiation

[0194] Prefilled syringes of degarelix / organic solvent formulations were exposed to different doses of electron beam or gamma radiation, and pre- and post-irradiation samples were tested for drug concentration or recovery using HPLC (see Section 7), and the results are presented in Table 5.

[0195] Table 5 Results of irradiation feasibility study

[0196]

[0197] (“F#” stands for “Formulation Number”)

[0198] Table 5 Observation results : These results indicate that solutions of degarelix in organic solvents are feasible for terminal sterilization by irradiation, depending on the type of irradiation, irradiation dose, drug concentration, salt form, and stabilizers.

[0199] Compared with degarelix acetate formulation F1-e25-2, degarelix citrate formulation F4-e25-2 showed better stability upon electron beam irradiation.

[0200] 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).

[0201] For total related compounds, formulations F1-e25, F2-e25, F3-e25, and F4-e25 were tested and no significant increase was observed after irradiation of the samples via electron beam.

[0202] 11. Stability of irradiated samples under accelerated storage conditions

[0203] Irradiated pre-filled syringes of the degarelix / organic solvent formulation were stored at different accelerated storage conditions (25°C) and tested using the HPLC method (see Section 7) at 30 and 120 days. The results are presented in Table 6.

[0204] Table 6 Accelerated Storage Stability Testing of Irradiated Prefilled Syringes of Degarelix Solution Formulations

[0205]

[0206] (“F#” stands for “Formulation Number”)

[0207] "NA" means: Not available

[0208] Table 6 Observation resultsNo significant degradation of degarelix was observed in the irradiated samples over the study period, and the slight increase in percent recovery over time can be attributed to solvent loss or absorption from the prefilled syringes under accelerated storage conditions.

[0209] 12. Viscosity of the formulation

[0210] 500 µL of the formulation was transferred into a Hamilton syringe, and the viscosity of the formulation was measured using the RheoSense. Prior to the measurement, the instrument was equilibrated to determine optimal instrument parameters, and then the test was run. The results are presented in Table 7. The viscosity of the formulation ranged from 100 to 250 cP.

[0211] Table 7 Viscosity of formulations after electron beam irradiation of pre-filled syringes

[0212]

[0213] (“F#” stands for “Formulation Number”)

[0214] 13. Nonclinical Evaluation of Drug Release Formulations

[0215] Prefilled syringes of the degarelix / organic solvent formulations were prepared as described in Section 3. The samples were not treated with an electron 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. The composition and dosing details of the formulations are listed in Table 8. Formulation F1 investigated the effect of the organic solvent as compared to the control (reconstituted in water); Formulation F2 investigated the effect of the type of organic solvent in the formulation (NMP versus DMSO); Formulation F3 investigated the effect of adding benzyl alcohol to the formulation; and Formulation F4 investigated the effect of different salt forms of degarelix (citrate) on the formulation.

[0216] At predetermined time points, rats were bled and plasma degarelix levels were determined using liquid chromatography with tandem mass spectrometry (LC-MS / MS). Each data point was based on the mean plasma degarelix concentration. Six rats were dosed in each group, and sparse blood sampling was performed at early time points. FIRMAGON® (degarelix for injection) was included in the study as a control. The control was injected at 15 mg / kg on days 0 and 28 to understand steady-state and accumulation, while the test group received a single injection of 15 mg / kg. Dosing was calculated using the amount of degarelix free base in each formulation, which was calculated for the formulation after correction for purity. The dose was calculated by adding 3 mL of FIRMAGON® (degarelix for injection). ® Sterile Water for Injection provided in the kit is used to reconstitute the 120 mg vial of FIRMAGON ® , and the degarelix concentration of the resulting reconstituted solution was 40 mg / mL.

[0217] Table 8: Dosing details in nonclinical studies

[0218]

[0219] Figure 2 and Figure 3 In vivo degarelix release in rats from organic solvent-based formulations of degarelix formulations 28 days after injection is presented in . Figure 2 is a magnified version of the levels from day 0 to day 3 to show the C max level.

[0220] Figure 2 and Figure 3 Observation results All organic solvent-based degarelix formulations (Groups B-TA1, C-TA2, D-TA3, and E-TA4) showed sustained release profiles of the drug, and the drug was detected for at least 28 days.

[0221] All organic solvent-based degarelix formulations (Groups B-TA1, C-TA2, D-TA3, and E-TA4) exhibited lower initial release (Cmax) than the control (Group A-CA1), which can be attributed to i) the solvent used in the formulation (water in the control versus organic solvent in the test formulations) and ii) differences in the gelation kinetics of the drug from the different formulations.

[0222] Three levels of Cmax were observed for this group of test articles:

[0223] Higher Cmax - for water-based control formulation A-CA1

[0224] Medium Cmax - for NMP-based formulations B-TA1, D-TA3, and E-TA4

[0225] Lower Cmax - for DMSO-based C-TA2 formulations

[0226] These results indicate that the primary / major solvent of the formulation has a higher impact on the initial release (Cmax) of the drug than the salt form or the co-solvent.

[0227] Figure 4 In vivo degarelix release from solvent-based degarelix formulations in rats 63 days after injection is presented in . Figure 4 All drug-releasing formulations that resulted in measurable levels of degarelix in vivo for more than 60 days are shown.

[0228] Figure 5 In vivo degarelix release from a solvent-based degarelix formulation in rats 119 days after injection is presented in . Figure 5All drug-releasing formulations that resulted in measurable levels of degarelix in vivo for more than 90 days (at least 119 days) are shown.

[0229] Table 9 shows the PK data for the experiments described above. Compared to the control (A-CA-1), Cmax occurred earlier for the solvent-based formulations B-TA1, D-TA3, and E-TA4; this may result in a faster decline in testosterone levels.

[0230] Table 9 pK data

[0231]

[0232] *Administered once on Day 0 and once on Day 28. Dose normalization parameters are calculated based on the total dose

[0233] Figure 6 In vivo testosterone concentration levels (ng / mL) in rats of the solvent-based formulation of degarelix in this example 105 days after injection are presented in FIG. Figure 5 All formulations were shown to be sustained over the 119-day study duration. Furthermore, the results showed that all formulations achieved plasma concentrations greater than 1 ng / mL, the lowest drug concentration to induce chemical castration. Furthermore, testosterone levels remained below "historical testosterone baseline" levels, and testosterone suppression occurred on Day 4. Finally, a second dose of FIRMAGON® (A-CA1) on Day 28 did not suppress testosterone levels to a greater extent than the other formulations administered once on Day 0.

[0234] Example 2

[0235] This example describes the results of a nonclinical animal study demonstrating the effects of additives to certain extended-release degarelix formulations on in vivo pharmacokinetics (PK) and testosterone levels (pharmacodynamics, PD) in male Sprague Dawley rats following subcutaneous injection of the formulations.

[0236] This study included control formulations (such as FIRMAGON ) and the degarelix formulations listed in Table 10 below. Additives included in the degarelix formulations (if present) were acetic acid (AcOH) or benzyl alcohol (BnOH). After the study, the rats were euthanized and the injection sites were harvested for histology and residual drug analysis. After these degarelix formulations and control formulations were delivered to male rats by subcutaneous injection, the rats were bled regularly to assess plasma degarelix and testosterone levels.

[0237] Table 10

[0238]

[0239] Percentages refer to degarelix acetate, not peptide (degarelix free base) content.

[0240] DgA = degarelix acetate drug substance; AcOH = acetic acid; BnOH = benzyl alcohol; NMP = N-methyl-2-pyrrolidone; DMSO = dimethyl sulfoxide.

[0241] Degarelix bulk solution preparation and syringe filling

[0242] The drug substance (DgA) and solvent (NMP:acetic acid or NMP:benzyl alcohol or DMSO) with or without the indicated additives were mixed in a 40 mL amber scintillation vial and blanketed with nitrogen. The vial was mixed at room temperature until complete dissolution, as indicated by a clear solution with no visible solids. The bulk drug solution was manually filled into labeled male syringes and capped with a female top cap. The syringes were packaged in labeled foil bags with desiccant packs and the bags were sealed. A portion of the syringes were sent for electron beam irradiation for stability testing, as shown in Table 10. The samples were irradiated at a target delivered dose range of 34-34 kGy, and the internal dosimeter on the syringe read 31.7 kGy. The samples were refrigerated at 5°C until use.

[0243] Dosing in nonclinical animal studies

[0244] As described above, pre-filled syringes of the degarelix test formulations were prepared. The degarelix release rates and the resulting testosterone levels of these formulations were obtained using a rat model. Male rats were injected with a single subcutaneous injection of the degarelix test formulation and the control formulation. The composition and dosing details of the formulations are listed in Table 11. At predetermined time points, blood was collected from the rats and plasma degarelix levels were determined using liquid chromatography with tandem mass spectrometry (LC-MS / MS). Testosterone levels were also determined. Each data point was based on the mean plasma degarelix concentration. Six rats were dosed per group and sparse blood sampling was performed at early time points (days 0 to 7). FIRMAGON was included in this study. (degarelix for injection, Ferring) served as a control. The control was injected at 45 mg / kg on days 0 and 28 to understand steady-state and accumulation, while the test group received a single injection of 45 mg / kg. Dosage of the test formulations was calculated using the amount of degarelix acetate in each formulation (at this dose volume, if dosing was alternatively calculated based on the degarelix free base in the formulation after correction for purity, there was no significant difference in the amount of formulation given). One bottle of FIRMAGON The 240 mg kit contains two 120 mg vials of degarelix. Each vial is reconstituted with 2 mL of water from a prefilled syringe containing 3 mL of sterile water for injection (provided in the kit). The final API concentration is 60 mg / mL.

[0245] Table 11 Nonclinical study dosage details

[0246]

[0247] 35% or 24% wt% degarelix acetate (DgA) drug substance, as indicated for each formulation. NMP = N-methyl-2-pyrrolidone; DMSO = dimethyl sulfoxide; AcOH = acetic acid; BnOH = benzyl alcohol.

[0248] , the actual amount of degarelix in the formulation as degarelix free base (degarelix free base equivalent).

[0249] Figure 7 In vivo degarelix release from an organic solvent-based degarelix formulation in rats 28 days after injection is presented in .

[0250] Figure 8 In vivo testosterone levels in rats 28 days after injection of an organic solvent-based formulation of degarelix are presented in .

[0251] Figure 9 In vivo degarelix release from solvent-based degarelix formulations in rats 63 days after injection is presented in .

[0252] Figure 10 In vivo degarelix release from solvent-based degarelix formulations in rats 90 days after injection is presented in .

[0253] Figure 11 In vivo testosterone levels in rats 90 days after injection of an organic solvent-based formulation of degarelix are presented in .

[0254] Figure 12 In vivo degarelix release from solvent-based degarelix formulations in rats 140 days after injection is presented in .

[0255] Figure 13 In vivo testosterone levels in rats 140 days after injection of an organic solvent-based formulation of degarelix are presented in .

[0256] The results presented in this example show that all degarelix test formulations tested herein maintained the minimum degarelix concentration of 1 ng / mL required for castration over a period of more than 4 months. In addition, all degarelix test formulations tested herein and controls administered at 45 mg / kg (note, control formulations were administered at day 0 and day 28, while test formulations were administered as a single dose at day 0) experienced testosterone suppression to below castration concentrations on day 1. In addition, testosterone suppression did not appear to be dose-dependent (data not shown). Furthermore, clinical observations did not appear to affect drug release or testosterone suppression, as the control group, formulation B (DgA / NMP / AcOH), formulation I (Dg / DMSO), and formulation J (Dg / NMP / AcOH-without electron beam) had no or minimal observations at 45 mg / kg. Compared to the control group, the gelation over the first 7 days appeared different, and without theoretical constraints, this may be due to the solvent in the test formulation and the resulting gelation strength.

[0257] Example 3

[0258] This example demonstrates the effect of acid additive content on the stability of degarelix formulations.This study aimed to determine the stability of degarelix formulations when different levels of different acids were added as excipients to the degarelix formulations of the present invention.

[0259] pH studies were initiated to investigate the role of pH control as a stability model for degarelix formulations using controls without acid additives or with acid additives of acetic acid, citric acid, or succinic acid added at three ratios and placed on stability to monitor impurity growth. Control samples of degarelix acetate and NMP (DgA / NMP 35% / 65% w / w) without acid additives as excipients were compared to other formulations of the same composition spiked with acid excipients at various molar ratios of degarelix peptide (calculated as free base) to acid (acetic acid, citric acid, or succinic acid) (see Table 12). Samples were placed at 5°C, 25°C, and 40°C and tested for durations of 3-12 months. Testing included determination of recovery, related compounds, and pH analysis.

[0260] Table 12

[0261]

[0262] DgA-DA = degarelix acetate; NMP = N-methyl-2-pyrrolidone.

[0263] in conclusion

[0264] The pH of NMP is approximately 8-9 (National Center for Biotechnology Information, 2023), and in the presence of water, the pH of the formulation decreases as more H+ ions flow freely. It may be beneficial to consider how the subcutaneous environment affects the pH of these formulations. In this experiment, all formulations with all ratios of acid excipients showed better stability at 6 months and 3 months at accelerated conditions of 25°C and 40°C, respectively, compared to the control sample without acid excipient. All three acids in this study lowered the apparent pH of the formulation to a new value that depended on the amount of acid added and its pKa. The 3-month time point at 40°C showed minimal growth in impurities, indicating improved stability of the formulation after the addition of acid (data not shown). Figure 14 Data for impurities at 1, 3, and 6 months from a 25°C stability study are presented, demonstrating that the overall stability of the formulation can be optimized by adding a specific amount of acid as an excipient. The molar ratio of degarelix API (calculated as free base) to acetic acid additive used in the test formulations shown in Example 2 ranged from a 1:1 to about 1:3 molar ratio (e.g., Figure 12 ), or about 1:2. Stability studies at 5°C are expected to show a similar pattern of improved stability by adding an acid excipient to the formulation.

[0265] Overall, this study demonstrates that acid excipients 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 important sources of impurity growth for degarelix acetate.

[0266] Various modifications of the above-described invention will be apparent to those skilled in the art. Such modifications are intended to fall within the scope of the following claims.

Claims

1. A composition comprising: a therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof; and Organic biocompatible solvents, in: The composition is formulated for subcutaneous injection into a subject; A single dose of the composition is about 2.5 mL or less; and After 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.

2. The composition of claim 1, wherein the in situ depot releases degarelix over a period of time 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. 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. 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. 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. 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 wt% to about 40 wt% of degarelix free base equivalents.

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

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

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

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

15. 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, wherein the composition has been terminally sterilized or sterile filtered.

17. The composition of claim 16, wherein the composition has been terminally sterilized by electron beam.

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

19. The composition of claim 18, wherein the additive is selected from the group consisting of polysorbate 20, polysorbate 80, poloxamer 188, sorbitan trioleate, lecithin (e.g., soy or egg), polyethylene glycol (PEG), PEG 300, 2-pyrrolidone, α-tocopherol, vitamin E TPGS, sucrose cocoate, sucrose stearate, sucrose laurate, proline, arginine, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxyquinone, butylated hydroxyanisole, hydroxycoumarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl hydroxybenzoate, trihydroxybutyrophenone, vitamin E, lecithin, ethanolamine, ZnCl2, MgCl2, CaCl2, DL-methionine, citrate, dimethylphenol, dibutylphenol, ethylenediaminetetraacetic 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. The composition of claim 18, wherein the additive is an acid additive.

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-chloropropionic acid, 4-cyanobutyric acid, perchloric acid, phosphoric acid, hydroiodic acid, and combinations thereof.

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

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

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

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

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

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

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

29. The pharmaceutical composition of claim 27 or 28, wherein the therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof is from about 20 wt% to about 40 wt% of degarelix free base equivalents.

30. The pharmaceutical composition of claim 27 or 28, wherein the composition further comprises about 0.1 wt% to 10 wt% of an acid additive.

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. The pharmaceutical composition of claim 27 or 28, wherein the composition further comprises about 1.0 wt% to 30 wt% of an alcohol additive.

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

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

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

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

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

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

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

40. The pharmaceutical composition of claim 38, wherein the amount of NMP is about 62.8 wt% and the amount of AcOH is about 2.2 wt%.

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 wt% to about 34 wt% degarelix free base equivalents, or about 31 wt% to about 33 wt% degarelix free base equivalents, or about 31 wt% to about 32 wt% degarelix free base equivalents.

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

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

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

45. The pharmaceutical composition of claim 43, wherein the amount of NMP is about 73.3% and the amount of AcOH is about 1.7 wt%.

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

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

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

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

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

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

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

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

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

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

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

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

60. The method of any one of claims 47-59, wherein the composition is administered about once every 1 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. E 61. The method of any one of claims 47-59, wherein the composition is administered to the subject approximately once every three months.

62. 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, 2 months, or 3 months after the loading dose has been administered.

63. The method of any of claims 47-59, wherein no loading dose of the composition is administered and the composition is administered about once every 1 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.

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

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

66. The prefilled syringe system of claim 64, wherein the syringe is an autoinjector.

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

68. A product comprising the composition of any one of claims 1-46 for use in a method of treating prostate cancer.

69. A product comprising the composition of any one of claims 1-46 for use in a method of treating CPP.

70. A product comprising the composition of any one of claims 1-46 for use in a method of reducing serum testosterone levels to below castrate levels of at least 50 ng / dL.

71. A product comprising the composition of any one of claims 1-46 for use in a method of suppressing ovarian function in a subject having hormone receptor-positive breast cancer.

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