Gnrh antagonist formulations

Abstract

This invention generally relates to the field of GnRH antagonist formulations. More specifically, this invention relates to pharmaceutical compositions made from microparticles for the slow release of GnRH antagonists (e.g., degarelix), the pharmaceutical use of such pharmaceutical compositions, kits comprising such pharmaceutical compositions, and methods for preparing such pharmaceutical compositions.

Description

[0001] describe Technical Field

[0002] This invention generally relates to the field of GnRH antagonist formulations. More specifically, this invention relates to pharmaceutical compositions made from microparticles for the slow release of GnRH antagonists (e.g., degarelix), the pharmaceutical use of such pharmaceutical compositions, kits comprising such pharmaceutical compositions, and methods for preparing such pharmaceutical compositions. Background Technology

[0003] Gonadotropin-releasing hormone (GnRH) is a peptide hormone composed of 10 amino acids (i.e., a decapeptide) that plays a crucial role in human reproduction. It is produced in neurons of the hypothalamus and induces the production of sex hormones downstream of the gonads. GnRH ultimately regulates the onset of puberty and sexual development in females, as well as the ovulation cycle.

[0004] Prostate cancer is a leading cause of death in men. Many prostate cancers require testosterone (an androgen) to develop. Reducing testicular androgen production is currently the most common hormonal therapy for prostate cancer. GnRH antagonists are a group of compounds used to treat prostate cancer. Unlike GnRH agonists, GnRH antagonists do not cause the so-called testosterone flare, the temporary increase in testosterone levels during the first few weeks of treatment. GnRH antagonists work by competitively occupying GnRH receptors. This blocks the release of two other gonadotropins from the anterior pituitary gland: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

[0005] Degarelix (IUPAC name: N-acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-4-((S)-dihydroorhodoamide)-L-phenylalanyl-4-ureo-D-phenylalanyl-L-leucyl-N6-isopropyl-L-lysyl-L-prolyl-D-alanylamide) is a synthetic decapeptide that acts as a GnRH antagonist. It contains seven non-naturally occurring amino acids: D-2-naphthylalanine, D-4-chlorophenylalanine, D-3-pyridylalanine, 4-aminophenylalanine (L-hydroorhodoamide), 4-aminophenylalanine (carbamoyl), N(ε)-isopropyllysine, and D-alanine.

[0006] The peptide sequence of degarelix can be described as follows (SEQ ID NO.:1): Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(l-Hor)-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2.

[0007] The abbreviations refer to: Ac, acetyl; 2Nal, 2-naphthylalanine; 4Cpa, 4-chlorophenylalanine; 3Pal, 3-pyridylalanine; Ser, serine; 4Aph, 4-aminophenylalanine; Hor, oroticoyl; Cbm, carbamoyl; Leu, leucine; ILYs, N(ε)-isopropyllysine; Pro, proline; Ala, alanine.

[0008] It contains degarelix as the active pharmaceutical ingredient (in the form of degarelix acetate) under the trademark name Firmagon. ® The commercially available formulation is available in two packaging configurations for delivery: a starting dose of 240 mg, administered as an initial dose of 40 mg / ml in two vials (each vial delivering 120 mg of degarelc (equivalent to a median of 126 mg of degarelc acetate)); and a maintenance dose of 80 mg, administered as a subsequent dose of 20 mg / ml in a single vial (each vial delivering 80 mg of degarelc (equivalent to a median of 84 mg of degarelc acetate)). Firmagon® is formulated for subcutaneous injection at 1-month intervals.

[0009] It contains degarelix as the active pharmaceutical ingredient (in the form of degarelix acetate) under the trademark Gonax. ® Another formulation commercially available in Japan is administered as a starting dose of 240 mg, followed by two subcutaneous injections of 120 mg at a dose of 40 mg / ml. After four weeks of the initial dose, the maintenance dose of degarelix is ​​80 mg at a dose of 20 mg / ml, administered subcutaneously every four weeks. Gonax is also available as a maintenance dose of 480 mg, administered subcutaneously at 12-week intervals as two subcutaneous injections of 240 mg at a dose of 60 mg / ml.

[0010] Generally, sustained-release compositions can be used to reduce the number of administrations required over extended treatment periods. However, formulating sustained-release drug compositions with acceptable degarelix release profiles for specific therapeutic applications is challenging.

[0011] Therefore, there is an urgent need to develop new pharmaceutical compositions that can provide sustained release of degarelix, for example, at intervals of at least 3 months (12 weeks) following a single administration. Specifically, there is an urgent need for extended-release degarelix compositions with acceptable release profiles. Furthermore, there is an urgent need for pharmaceutical compositions that are convenient and easy to use, have acceptable shelf lives, are safe and well-tolerated by patients, and minimize patient discomfort (e.g., discomfort caused by repeated administration associated with long-term treatment, and / or by syringe suitability and injectability issues). Summary of the Invention

[0012] Against this background, an object of the present invention is to provide a modified degarelix formulation, namely a pharmaceutical composition comprising degarelix. A further object of the present invention is to provide a modified formulation for pharmaceutical use in the treatment of prostate cancer. A further aspect of the present invention provides a method for preparing a modified degarelix formulation, as well as related kits and apparatus.

[0013] Therefore, in a first aspect, the present invention relates to a pharmaceutical composition comprising degarelic acid in the form of a dihydroxynaphthyl salt, wherein the degarelic acid dihydroxynaphthyl salt is contained in microparticles of a biodegradable copolymer (PLGA) of lactide and glycolide units, and wherein the microparticles comprise at least 50 wt% PLGA and about 20 wt% to about 34 wt% of degarelic acid free base equivalent.

[0014] In another aspect, the present invention relates to the pharmaceutical use of pharmaceutical compositions according to the present invention. Therefore, the present invention relates to pharmaceutical compositions as defined herein for the treatment of prostate cancer, and to methods for treating prostate cancer comprising administering an effective amount of the pharmaceutical composition as defined herein to a subject in need.

[0015] The inventors have unexpectedly discovered that peptide formulations comprising degarelix in the form of dihydroxynaphthyl salt (which is substantially insoluble in water at room temperature) and PLGA can increase the relative bioavailability of degarelix at the same dose level as previous degarelix formulations. Further unexpectedly, among other things, it has been found that, by using degarelix dihydroxynaphthyl salt and PLGA, a high initial burst release in the days immediately following administration of the pharmaceutical composition can be avoided.

[0016] In another aspect, the present invention relates to a method for preparing a pharmaceutical composition as defined herein, comprising: (a) Degarelk in the form of pharmaceutically acceptable dihydroxynaphthyl salt, particularly in powder form, is mixed with a biodegradable copolymer (PLGA) of lactide and glycolide units, particularly in powder form; (b) The mixture is gradually heated and extruded; (c) Granulate the obtained extrudate; (d) Pellets obtained by grinding at low temperature.

[0017] In another aspect, the present invention relates to pharmaceutical compositions as defined herein, which can be obtained by preparation methods as defined herein.

[0018] In another aspect, the present invention relates to a kit comprising a device (e.g., a pre-filled syringe or vial) containing a pharmaceutical composition as defined herein, and instructions for use.

[0019] In another aspect, the present invention relates to a dual chamber device, wherein a pharmaceutical composition as defined herein is in powder form in one chamber and an aqueous carrier is in another chamber; or wherein a pharmaceutical composition as defined herein is in powder form in one chamber and an oily carrier is in another chamber.

[0020] In another aspect, the present invention relates to a single-chamber device comprising a pharmaceutical composition as defined herein in the form of a suspension in an oily carrier. This may also refer to a ready-to-use device that requires no reconfiguration step before administration to a patient. Detailed Implementation

[0021] To facilitate understanding of this disclosure, certain terms are first defined. As used in this application, each of the following terms shall have the meaning set forth below unless expressly provided otherwise herein. Additional definitions will be set forth throughout the application.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0023] The singular forms “a / an” and “the” both include plural references unless the context clearly indicates otherwise. The terms “a / an,” “one or more,” and “at least one” are used interchangeably herein. In some respects, the term “a / an” means “single.” In other respects, the term “a / an” means “two or more” or “multiple.”

[0024] Furthermore, “and / or” as used herein is considered to specifically disclose each of two designated features or components having or not having the other. Therefore, the term “and / or” as used in phrases such as “A and / or B” herein is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0025] The term "about" is used herein to mean approximately, roughly, around, or within a certain range. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated value. Generally, the term "about" can modify a value to be above or below the stated value by, for example, a variation of 10 percentage points above or below (higher or lower). In some aspects of this disclosure, the term "about" covers a deviation (including endpoints) from the enumerated value between 0.001% and 10%. In some aspects, the term "about" covers an increase (including endpoints) from the enumerated value between 0.001% and 10%. In some aspects, the term "about" covers a decrease (including endpoints) from the enumerated value between 0.001% and 10%.

[0026] Units, prefixes, and symbols are represented in their form, which is accepted by the International System of Units (SI).

[0027] A range of numbers includes the numbers that define that range. When listing a range of values, it should be understood that the individual intermediate integer values ​​and fractions between the upper and lower limits listed in that range, along with the individual subranges between these values, should also be specifically disclosed.

[0028] The upper and lower limits of any range may be independently included or excluded from the range, and ranges that include any one limit, have no limit, or have both limits are also covered in this disclosure. Therefore, the ranges listed herein should be understood as abbreviations of all values ​​within that range, including the listed endpoints. For example, the range 1 to 10 should be understood as including any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0029] Every numerical value inherently contains some error that is necessarily caused by the standard deviation present in its respective measurement. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, the range “1 to 10” should be considered as including any and all subranges between the minimum value 1 and the maximum value 10 (and inclusive of 1 and 10); that is, all subranges that begin with a minimum value of 1 or greater (such as 1 to 6.1) and end with a maximum value of 10 or less (such as 5.5 to 10).

[0030] When a value is explicitly listed, it should be understood that values ​​of approximately the same quantity or amount as the listed value are also within the scope of this disclosure. In the case of a disclosed combination, each sub-combination of the components of that combination is also specifically disclosed and within the scope of this disclosure. Conversely, in the case of individually disclosing different components or groups of components, their combinations are also disclosed. Where any component of this disclosure is disclosed as having a plurality of alternatives, instances of this disclosure in which each alternative is excluded individually or in any combination with other alternatives are also disclosed; more than one component of this disclosure may have such exclusions, and all combinations of components having such exclusions are disclosed.

[0031] As described above, the present invention relates to a pharmaceutical composition comprising degarelic acid in the form of a dihydroxynaphthyl salt, wherein the degarelic acid dihydroxynaphthyl salt is contained in microparticles of a biodegradable copolymer (PLGA) of lactide and glycolide units, and wherein the microparticles contain at least 50 wt% PLGA and about 20 wt% to about 34 wt% of degarelic acid free base equivalent.

[0032] According to the present invention, the active pharmaceutical ingredient (API) of the pharmaceutical composition is degarelc, which exists as degarelc bis(3-hydroxynaphthyl-2-carboxylic acid). Bis(hydroxynaphthyl-2-carboxylic acid) is a salt of bis(3-hydroxynaphthyl-2-carboxylic acid) (IUPAC: 4,4'-methylenebis(3-hydroxynaphthyl-2-carboxylic acid)), a dicarboxylic acid that is practically insoluble in water. By forming a salt with bis(hydroxynaphthyl-2-carboxylic acid), the solubility of degarelc in water and aqueous media is significantly reduced. The solubility of degarelc bis(hydroxynaphthyl-2-carboxylic acid) in water at ambient temperature is only 0.004 mg / mL. In some embodiments, degarelc (in its bis(hydroxynaphthyl-2-carboxylic acid) form may be the sole API in the pharmaceutical composition according to the present invention.

[0033] Commercially available formulations based on existing technologies (e.g., Firmagon) ® Gonax ®Degarelc is administered in its highly water-soluble acetate form (100 mg / mL). When administered subcutaneously, the peptide forms a gel at the injection site via fibrillation, allowing for the slow release of degarelc into the bloodstream. Sustained release of degarelc in these commercially available formulations has been described as primarily dependent on the initial concentration of degarelc acetate in the formulation. The underlying mechanism is desegregation or defibrillation of the gel.

[0034] In contrast, the pharmaceutical composition of the present invention is based on a compound that is almost insoluble in water, degarelc bis(hydroxynaphthyl) salt, which is encapsulated in PLGA microparticles. Due to its water insolubility, degarelc bis(hydroxynaphthyl) salt does not form a gel library like water-soluble acetates.

[0035] Previously, the use of PLGA microparticles in the formulation of sustained-release preparations has been described. However, unexpectedly, contrary to expectations, it has now been found that the combination of a water-insoluble salt of the API as specified herein (i.e., degarelix bis(hydroxynaphthyl)ate) and the PLGA polymer does not result in an extremely slow and therefore undesirable release characteristic. On the contrary, the inventors have found that degarelix exhibits good dissolution kinetics and improved relative bioavailability when formulated according to the invention. It appears that the water-insoluble degarelix bis(hydroxynaphthyl)ate in the microparticles according to the invention reduces the hydrolysis of peptides and other unwanted degradation pathways associated with the presence of water. Furthermore, the initial burst release is also significantly reduced (see below). Further, it has been unexpectedly found that the combination of PLGA with degarelix bis(hydroxynaphthyl)ate does not reduce, but rather enhances, the release of degarelix into the bloodstream. This sustained release can be maintained for at least 12 weeks after administration. Therefore, an increase in the relative bioavailability of degarelix can be achieved with the pharmaceutical composition according to the invention, despite using the same dose level of API as commercially available degarelix acetate formulations.

[0036] Therefore, the present invention provides a clearly advantageous pharmaceutical composition. Possible embodiments and additional advantages will now be described in more detail.

[0037] As used herein, the term "microparticle" generally refers to a monolithic particle having a size of about 1 µm to about 1 mm. In some instances, the microparticle has a size of about 1 µm to about 200 µm. The microparticle may have an internal continuous biodegradable polymer matrix. The microparticle may be of any shape, including spherical or irregular shapes. The term encompasses both microspheres and microparticles.

[0038] As used herein, “microgranule” is a subgroup of microparticles and is characterized as a non-spherical, irregularly shaped monolith formed from one or more biodegradable polymers or copolymers. The microgranules described herein typically have a diameter of less than 110 µm. They can be obtained, particularly by dry processes, such as extrusion and milling.

[0039] As used herein, the term "microsphere" is a subgroup of microparticles and is characterized as monoparticles of spherical or substantially spherical regular shape formed from one or more biodegradable polymers or copolymers. They can be obtained, in particular, by wet processes, such as emulsification and precipitation.

[0040] The microparticles according to the invention comprise a biodegradable copolymer (PLGA, also known as poly(lactic-co-glycolic acid)) of lactide and glycolide units. In some embodiments, the PLGA may be a poly(D,L-lactide-co-glycolic acid) copolymer.

[0041] As used herein, the term "biodegradable copolymer" means a copolymer or mixture of copolymers that, upon enzymatic and / or non-enzymatic degradation in vivo, yields biocompatible degradation products that can be further metabolized by humans and animals. Biodegradation can be induced in response to contact with bodily fluids (e.g., after injection into a patient). In some aspects, PLGA copolymers can be degraded via hydrolysis in response to contact with bodily fluids after administration (e.g., injection) into a patient.

[0042] According to the present invention, the microparticles contain at least 50 wt% PLGA. In some embodiments, the microparticles may contain about 55 to about 75 wt% PLGA, about 60 to about 70 wt% PLGA, or about 60 to about 65 wt% PLGA. In some preferred embodiments, the microparticles may contain about 60 to about 65 wt% PLGA.

[0043] PLGA can generally be prepared by varying ratios of its constituent monomers, lactic acid and glycolic acid. Within this copolymer, refer to lactide and glycolide units. The PLGA according to the invention can be linear or branched, hyperbranched, comb-like branched, dendritic branched, T-shaped, star-shaped, or any mixture thereof. Specifically, the PLGA can be a linear PLGA. In some embodiments, the PLGA can be a linear polyester having lactide and glycolide units in a random order. The molar ratio of lactide units to glycolide units is typically in the range of about 70:30 to about 90:10, particularly about 75:25 to about 85:15. In some embodiments, the molar ratio of lactide units to glycolide units can be about 75:25, about 80:20, or about 85:15.

[0044] In some embodiments, the PLGA contains less than about 5% residual lactide and / or glycolide monomers. In some embodiments, the initial residual monomer content is 0% to about 5%, or 0% to about 3%. Specifically, the PLGA may be free of residual lactide and / or glycolide monomers, i.e., it has 0% initial residual lactide and / or glycolide monomer content. In an exemplary embodiment, the PLGA has 0% initial residual lactide and glycolide monomer content.

[0045] The end groups of the PLGA used according to the present invention are not limited. Examples of possible end groups include hydroxyl, ester (e.g., stearoyl), acid (e.g., carboxyl), or similar groups.

[0046] In some embodiments of the present invention, the end groups of the PLGA may be acidic and preferably carboxyl groups, i.e., the PLGA is "acid-capped".

[0047] In some exemplary embodiments, the biodegradable polymeric microparticles of the pharmaceutical compositions described herein comprise PLGA having a molecular weight (Mn) of about 20,000 g / mol to about 50,000 g / mol and / or a molecular weight (Mw) of about 30,000 g / mol to about 80,000 g / mol.

[0048] The molar ratio of lactide to glycolide units in PLGA can be determined using conventional methods, such as nuclear magnetic resonance (NMR). 1 It is measured by HNMR.

[0049] Non-limiting examples of commercially available PLGA sources include Evonik's RESOMER. ® LACTEL ® (Evonik), Evonik's MEDISORB ® Corbion's Purasorb ® and Seqens' Expansorb ® .

[0050] According to the present invention, the pharmaceutical composition comprises the API degarelc, which is in its pharmaceutically acceptable salt form, namely, in the form of bis(hydroxynaphthyl) salt. For ease of calculation, the amounts herein are expressed as "free base equivalents" or the amount corresponding to the free base of degarelc. It should be understood that due to the weight of the bis(hydroxynaphthyl) salt, the actual amount of degarelc in the bis(hydroxynaphthyl) salt form will be higher than the amount of degarelc in the free base form.

[0051] As used herein, “drug loading” (which is sometimes used interchangeably with the term “core loading”) refers to the weight ratio (expressed as a percentage) of degarelk free base to biodegradable polymer microparticles (BPM), as shown in the following equation: Drug loading (DL%) = m(degarelk) / m(BPM) x 100 where m(degarelk) represents the weight of degarelk and m(BPM) represents the weight of biodegradable polymer microparticles.

[0052] The pharmaceutical compositions described herein typically have a drug loading of about 20 wt% to about 34 wt% based on degarelc free base, meaning that the PLGA microparticles contain about 20 wt% to about 34 wt% of degarelc free base equivalent. In some embodiments, the drug loading of degarelc dihydroxynaphthyl salt, based on degarelc free base, may be about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, or about 34 wt%. In some embodiments, the PLGA microparticles may contain about 28 wt% to about 33 wt% of degarelc free base equivalent. In an exemplary embodiment, the PLGA microparticles contain about 28 wt%, about 30 wt%, or about 33 wt% of degarelk free base equivalent. According to a non-limiting example, the PLGA microparticles according to the invention contain about 30 wt% of degarelk free base equivalent.

[0053] When using degarelk bis(hydroxynaphthyl) salt, a pharmaceutically acceptable salt of a GnRH antagonist, the weight ratio can be calculated based on the molar amount of the free degarelk base, which is the same as the molar amount of degarelk bis(hydroxynaphthyl) salt contained in the biodegradable polymer microparticles.

[0054] Drug load can be measured using conventional methods, such as high-performance liquid chromatography (HPLC). For example, an appropriate weight (e.g., 20 mg) of biodegradable polymer microparticles can be weighed, dissolved in dimethyl sulfoxide (DMSO), and the sample can be analyzed by HPLC.

[0055] The present invention further relates to a pharmaceutical composition comprising degarelic acid in a pharmaceutically acceptable form of dihydroxynaphthyl salt as an active pharmaceutical ingredient, wherein the degarelic acid dihydroxynaphthyl salt is contained in a biodegradable copolymer (PLGA) of lactide and glycolide units, wherein the microparticles comprise at least 50 wt% PLGA and about 20 wt% to about 34 wt% of free base equivalent of degarelic acid, and wherein the composition continuously and significantly releases degarelic acid under restricted burst release conditions to achieve a therapeutic effect within 14 days of administration and maintain this effect for at least 12 weeks after administration.

[0056] As used herein, the term "therapeutic effect" refers to the achievement of chemical castration in a patient. Following therapy with a GnRH agonist or antagonist, a serum testosterone level equal to or less than 50 ng / dL, i.e., ≤ 0.5 ng / mL (1.735 nmol / L), is considered chemical castration. These levels should be achieved within 14 days of API administration and maintained until the next API dose. According to the invention, this period is defined as achieving a serum testosterone level ≤ 0.5 ng / mL within 14 days of administration and maintaining it for at least 12 weeks after administration.

[0057] In some examples, serum testosterone levels ≤ 0.5 ng / mL can be achieved within 7 days of administration and maintained for at least 12 weeks after administration. In some examples, serum testosterone levels ≤ 0.5 ng / mL can be achieved within 3 days of administration and maintained for at least 12 weeks after administration.

[0058] In some formulations, serum testosterone levels < 0.5 ng / mL can be achieved within 14 days of administration and maintained for at least 12 weeks. In some formulations, serum testosterone levels < 0.5 ng / mL can be achieved within 7 days of administration and maintained for at least 12 weeks. In some formulations, serum testosterone levels < 0.5 ng / mL can be achieved within 3 days of administration and maintained for at least 12 weeks.

[0059] In some examples, serum testosterone levels of 20 ng / dL (≤ 0.2 ng / mL (0.69 nmol / L)) can be achieved within 14 days of administration and maintained for at least 12 weeks. In some examples, serum testosterone levels of 20 ng / dL (≤ 0.2 ng / mL (0.69 nmol / L)) can be achieved within 7 days of administration and maintained for at least 12 weeks. In some examples, serum testosterone levels of 20 ng / dL (≤ 0.2 ng / mL (0.69 nmol / L) can be achieved within 3 days of administration and maintained for at least 12 weeks.

[0060] As used herein, “continuous release” means that at any time during a period of at least 12 weeks following administration, there is a significant release of degarelix from the composition; there is no release interruption that would be defined as “intermittent release” (i.e., no one or more time intervals during which the release of the composition is zero).

[0061] As used in this article, “significant release” means maintaining a degarelix threshold level of >3.0 ng / mL in plasma for at least 12 weeks.

[0062] In some exemplary embodiments, the pharmaceutical composition according to the invention can release degarelix in plasma at a threshold level higher than 8.0 ng / mL (i.e., > 8.0 ng / mL) or a threshold level higher than 9.0 ng / mL (> 9.0 ng / mL), and maintain this threshold level for at least 12 weeks.

[0063] "Dose standardization" is a common calculation performed using pharmacokinetic parameters. The typical procedure involves dividing the PK parameter by the administered dose. This can be done for individual subjects or treatment groups in a study, and then the dose-standardized parameters can be compared.

[0064] "Burst release" or "initial burst release" is a known release kinetic phenomenon in most PLGA microparticle formulations. It refers to a strong initial release of the API, which may consume up to, for example, 50% of the total API administered within the first few days after administration (e.g., day 1 to day 7, or day 1 to day 3). This poses a particularly serious toxic threat to treated subjects and results in a low residual drug load for the remainder of treatment. The inventors have unexpectedly discovered that the pharmaceutical compositions according to the invention exhibit a dose-normalized burst release relative to commercially available 12-week degarelix acetate formulations (Gonax) after administration. ® ), and the commercially available 1-month Firmagon acetate formulation. ®The observed levels are substantially lower. As used herein, the term "substantially lower" means at least about 25% lower. Burst release can be determined, for example, by measuring the concentration of the API (drug) in plasma. According to the invention, the average degarelix plasma concentration from day 1 to day 7 after administration may be less than 100 ng / mL, corresponding to "restricted burst release" (also known as "low burst release") herein. In certain exemplary embodiments, the average degarelix plasma concentration from day 1 to day 7 after administration may be less than 80 ng / mL, less than 60 ng / mL, less than 50 ng / mL, less than 40 ng / mL, or less than 30 ng / mL. In other exemplary embodiments, the average degarelix plasma concentration from day 1 to day 3 after administration may be less than 100 ng / mL, less than 80 ng / mL, less than 60 ng / mL, less than 50 ng / mL, less than 40 ng / mL, or less than 30 ng / mL.

[0065] In some embodiments of the present invention, the mean maximum concentration (Cmax) of degarelax in plasma after administration may be less than 120 ng / mL, less than 100 ng / mL, less than 80 ng / mL, less than 60 ng / mL, less than 50 ng / mL, less than 40 ng / mL, or less than 30 ng / mL. In exemplary embodiments, the mean Cmax of degarelax in plasma may be less than 40 ng / mL.

[0066] In some embodiments, the PLGA microparticles of the pharmaceutical composition according to the present invention may have the following particle size distribution: - D(v,0.1) is approximately 5 to approximately 22 µm - D(v,0.5) is approximately 25 to approximately 45 µm - D(v,0.9) is approximately 55 to approximately 90 µm.

[0067] In this context, "D(v,X)" refers to the X of the biodegradable polymer microparticle sample. 100% of the volume is below the indicated diameter value. For example, D(v,0.5) of 40 µm means that 50% of the volume of the biodegradable polymer microparticle sample has a diameter below 40 µm, such as 10 µm, 20 µm, or 30 µm. D(v,X) (e.g., D(v,0.5)) can be determined by wet laser diffraction, as described in Chapter 2.9.31 of the European Pharmacopoeia V11.3. Particle size measurements can be performed by wet laser diffraction, for example using a Malvern Mastersizer 3000 equipped with a HydroMedium Volume (MV) dispersion unit. For example, biodegradable polymer microparticles can be suspended (at room temperature, i.e., 20 to 25 °C) in an aqueous medium containing a surfactant (e.g., polysorbate 80 (0.1%)), and then the sample can be dispersed in purified water in a hydro MV dispersion unit (stirring speed 2000 rpm) until the opacity reaches between 10% and 20%. The samples were then subjected to 2 minutes of sonication (with the hydroMV dispersion unit set to medium (50%)), and then analyzed using a Malvern Mastersizer 3000. Calculations were based on Mie theory (the actual particle refractive index is 1.52 while the hypothetical particle refractive index is 0.001). A "general analysis model" can be used. D(v,0.5) is sometimes labeled Dv50, D(v,0.1) is sometimes labeled Dv10, and D(v,0.9) is sometimes labeled Dv90.

[0068] The biodegradable polymer (e.g., biodegradable polymer microparticles) included in the pharmaceutical compositions of the present invention may have a median particle size (i.e., D(v,0.50)) of about 25 to about 45 µm, for example, 25 µm to 45 µm or about 25 µm to about 40 µm.

[0069] The biodegradable polymer microparticles may also additionally have one or more of the following particle size values: D(v,0.9) is about 55 to about 90 µm, such as 55 µm to 90 µm, or about 60 µm to about 90 µm; D(v,0.1) is about 5 to about 22 µm, such as 5 µm to 22 µm, or about 5 µm to about 15 µm.

[0070] In some instances, a pharmaceutical composition may consist of a single group of biodegradable microparticles as defined herein. In this context, "single group" means that all microparticles have substantially the same properties, such as particle size distribution, PLGA polymer properties, etc.

[0071] The "inherent viscosity" of biodegradable polymers (e.g., PLGA) used herein is based on the flow time of the biodegradable polymer (polymer dissolved in a given solvent) through a narrow capillary relative to the flow time of the pure solvent through the same capillary. According to IUPAC, intrinsic viscosity is defined as the ratio of the natural logarithm of the polymer's relative viscosity to the polymer's mass concentration. The intrinsic viscosity of biodegradable polymers (e.g., PLGA) can be measured using conventional methods, such as the capillary viscometer method described in the European Pharmacopoeia, V11.3, Chapter 2.2.9. For example, the intrinsic viscosity of a polymer can be measured, for instance, using a Cannon-Fenske Routine size 25 viscometer at 30°C in chloroform at a concentration of 0.5 g / dL.

[0072] As used herein, the “initial intrinsic viscosity” (iv) of a biodegradable polymer (e.g., PLGA) refers to the viscosity of the biodegradable polymer as a starting material (i.e., inherent before it enters the process for preparing microparticles). According to some embodiments of the invention, the initial intrinsic viscosity (iv) of PLGA can be from about 0.3 dL / g to about 0.5 dL / g. In certain embodiments, the initial iv of PLGA can be from about 0.35 dL / g to about 0.45 dL / g. In certain embodiments, the initial iv of PLGA can be from about 0.39 dL / g to about 0.45 dL / g, for example, with the goal of obtaining an average iv of 0.42 dL / g. According to exemplary embodiments, the initial iv of PLGA is about 0.30 dL / g, or about 0.40 dL / g, or about 0.42 dL / g, or about 0.50 dL / g. Sometimes, “short” PLGA is referred to herein. Short PLGA corresponds to PLGA with low initial iv (such as 0.4 dL / g).

[0073] The inventors have unexpectedly discovered that the use of short PLGA (e.g., initial intrinsic viscosity of about 0.4 dL / g) in the pharmaceutical compositions according to the invention can enhance the release of the peptide over time.

[0074] As understood by those skilled in the art, the inherent viscosity of PLGA and the molar ratio of lactide to glycolide are averages over a range, as indicated in the PLGA manufacturer's specifications.

[0075] Any PLGA having desired properties (e.g., the molar ratio of lactide to glycolide and intrinsic viscosity) as described herein may be included in a biodegradable polymer as defined herein, i.e., a biodegradable polymer used to form biodegradable polymer particles as defined herein and included in the pharmaceutical compositions of the present invention.

[0076] The pharmaceutical compositions described herein may be compositions of dried, biodegradable PLGA microparticles (e.g., PLGA microparticles) prepared for suspension in a liquid carrier prior to administration, as described herein, or the pharmaceutical compositions described herein may further contain a liquid carrier. In some exemplary embodiments, the pharmaceutical compositions described herein may be in the form of a suspension, such as a ready-to-use suspension containing a liquid carrier and the PLGA microparticles described herein. The liquid carrier of the pharmaceutical compositions described herein may be an aqueous (water-based) or oil-based carrier.

[0077] In some embodiments, water is the predominant (≥50% (w / v)) component of the aqueous carrier. In some embodiments, the aqueous carrier contains more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100% water. These percentages are indicated as (w / v) percentages.

[0078] In some embodiments, the aqueous carrier may contain additional pharmaceutical excipients. These additional excipients can be used to ensure isotonicity and improve the wettability and non-settling properties of the microspheres. Examples of pharmaceutical excipients include, but are not limited to, mannitol, sodium chloride, glucose, dextran, sucrose, or glycerol, nonionic surfactants (e.g., poloxamer), poly(ethylene oxide)-sorbitan-fatty acid esters, sodium carboxymethyl cellulose (CMC-Na), sorbitol, poly(vinylpyrrolidone), or aluminum monostearate, and polyethylene glycol (PEG), such as PEG 4000.

[0079] When the carrier is a non-aqueous carrier, particularly an oily or lipid-based carrier, it is substantially free of water or (completely) free of water. The terms "oily carrier" and "lipid-based carrier" are used interchangeably herein. Thus, an oily carrier may, for example, contain 0.25% (w / v) or less water, 0.1% or less water, or 0.05% (w / v) or less water.

[0080] The water content of non-aqueous carriers can be measured using conventional methods, such as the method described in the European Pharmacopoeia, V11.3, Chapter 2.5.32, "Water: Micro Determination".

[0081] The oily carrier may be a pharmaceutically acceptable oil or any mixture thereof. In a preferred embodiment, the oil may be a viscous liquid at ambient temperature (20°C to 25°C) or slightly warmer (up to 30°C or up to standard mammalian body temperature, i.e., 37°C), and simultaneously hydrophobic (immiscible with water) and lipophilic (miscible with other oils). Non-limiting examples of suitable oils include vegetable oils such as coconut oil, palm oil, palm kernel oil, sesame oil, soybean oil, almond oil, rapeseed oil, corn oil, sunflower oil, peanut oil, olive oil, castor oil, soybean oil, safflower oil, cottonseed oil, ethyl oleate, and any combination thereof.

[0082] In some embodiments, the oily carrier may comprise or consist of medium-chain triglycerides (MCTs). In some embodiments, the oily carrier is a mixture of medium-chain triglycerides. As used herein, “MCT” refers to a glycerol ester formed from glycerol and three medium-chain fatty acids; each of the three medium-chain fatty acids is a C6 to C12 fatty acid, i.e., a carboxylic acid with an aliphatic chain having 6 to 12 carbon atoms, such as C6 (e.g., hexanoic acid), C8 (e.g., caprylic acid), C10 (e.g., decanoic acid), and C12 (e.g., dodecanoic acid). The three medium-chain fatty acids forming the triglyceride may be identical, for example, all three may be medium-chain fatty acids with an aliphatic chain having, for example, 8 or 10 carbon atoms, or one or all of these medium-chain fatty acids may be different from the other medium-chain fatty acids. The aliphatic chain of the MCT may be saturated or unsaturated.

[0083] In some embodiments, the oily carrier may consist primarily of C8 and / or C10 medium-chain triglycerides. In some embodiments, the oily carrier may be a mixture of C8 / C10 triglycerides, a mixture of C8 triglycerides, or a mixture of C10 triglycerides. In some embodiments, the pharmaceutical composition comprises at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% saturated MCT.

[0084] In some embodiments, the oily carrier may be a mixture of C8 / C10 triglycerides, a mixture of C8 triglycerides, or a mixture of C10 triglycerides, wherein all present C8 and C10 fatty acids are saturated fatty acids. An exemplary saturated fatty acid used according to the invention is caprylic acid (H3C-(CH2)). 6- COOH) and decanoic acid (H3C-(CH2)) 8- (COOH). In exemplary embodiments, the oily carrier is essentially (e.g., ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%) a mixture of triglycerides of caprylic and capric acids. In some embodiments, the oily carrier is a mixture of triglycerides of caprylic and capric acids.

[0085] In some examples, the oily carrier may consist of 50% to 80% C8 MCT and 20% to 50% C10 MCT, such as 58% C8 MCT and 41% C10 MCT, which are present in MIGLYOL as described below. ® In 812, the MCT content of the oil was measured by GC according to the method described in Chapter 2.4.22 of the European Pharmacopoeia, V11.3, without further conversion.

[0086] Non-limiting examples of MCTs that can be used as oily carriers in pharmaceutical compositions according to the present invention include MIGLYOL. ® 810, 812, 818 (Sasol Germany GmbH, Witten, Germany). In an exemplary embodiment, the oily carrier is MIGLYOL. ® 812, for example, MIGLYOL ® 812 N.

[0087] The inventors have discovered that, compared with other carriers, using an oily carrier with the pharmaceutical composition according to the invention can significantly increase the release of the peptide over time.

[0088] In some embodiments, the pharmaceutical composition described herein may be a suspension in an oily carrier. In some embodiments, the pharmaceutical composition described herein may be a suspension in a mixture of MCTs as defined above. In some embodiments, the pharmaceutical composition described herein may be a suspension in a mixture of C8 and / or C10 triglycerides (C8 / C10 triglycerides) as defined above. In some embodiments, the pharmaceutical composition described herein may be a suspension in a mixture of saturated C8 and / or C10 fatty acid triglycerides as defined above. In some embodiments, the pharmaceutical composition described herein may be a suspension in a mixture consisting essentially of caprylic acid and capric acid or a mixture thereof. In an exemplary embodiment, the pharmaceutical composition described herein may be a suspension in an oily carrier, wherein the oily carrier is MIGLYOL. ® 812, such as MIGLYOL ® 812 N.

[0089] According to the invention, the concentration of microparticles in the suspension may vary to some extent. In some exemplary embodiments, the concentration of microparticles (such as microparticles as defined herein) in the suspension may be from about 150 mg / mL to about 350 mg / mL. In some preferred exemplary embodiments, the concentration of microparticles in the suspension may be from about 180 mg / mL to about 300 mg / mL. Thus, in some exemplary embodiments, the pharmaceutical composition may be a suspension comprising biodegradable PLGA microparticles as defined herein, at a concentration of from about 150 mg / mL to about 350 mg / mL, from about 180 mg / mL to about 300 mg / mL, such as about 180 mg / mL, about 200 mg / mL, about 250 mg / mL, or about 300 mg / mL.

[0090] Furthermore, as covered by this invention, the molar ratio of degarelic acid base to dihydroxynaphthyl salt may vary. Thus, in some exemplary embodiments, the molar ratio of degarelic acid base to dihydroxynaphthyl salt may be from about 1:1 to about 2:1.

[0091] The pharmaceutical compositions described herein may additionally include one or more other pharmaceutical excipients, such as those commonly included in the formulation types described herein. These pharmaceutical excipients include, but are not limited to, diluents, surfactants, stabilizers, release modifiers, preservatives, antioxidants, buffers, anti-aggregators, etc.

[0092] Non-limiting examples of other pharmaceutical excipients that may be included in the pharmaceutical compositions described herein include polyvinyl alcohol; polyvinylpyrrolidone; sodium carboxymethyl cellulose (CMC-Na); dextrin; polyethylene glycol; suitable surfactants such as poloxamer (also known as poly(ethylene oxide-block-propylene oxide)) and poly(ethylene oxide)-sorbitan-fatty acid esters, which are known and can be traded under the name TWEEN. ® (e.g., Tween 20, Tween 40, Tween 60, Tween 80, Tween 65, Tween 85, Tween 21, Tween 61, Tween 81) Commercially available sorbitan fatty acid esters, such as those known and trademarked as SPAN. ® Commercially available types; lecithin; inorganic salts such as zinc carbonate, magnesium hydroxide, magnesium carbonate; or protamine, such as human protamine or salmon protamine; or natural or synthetic polymers with amine residues, such as polylysine; hydroxyethyl cellulose (HEC) and / or hydroxypropyl cellulose (HPC); polyvinylpyrrolidone; and gelatin, such as porcine or fish gelatin. Suitable anti-aggregating agents include, for example, mannitol, glucose, dextrose, sucrose, sodium chloride, or water-soluble polymers such as polyvinyl alcohol, polyvinylpyrrolidone, or polyethylene glycol.

[0093] According to the present invention, it is preferred that the pharmaceutical composition does not contain trehalose as an excipient, that is, it does not contain trehalose.

[0094] The term "administration," as used herein, refers to any mode of transferring, delivering, introducing, or transporting a therapeutic agent to a subject who requires treatment with such agent. Such modes of administration include, but are not limited to, parenteral administration.

[0095] In some respects, the pharmaceutical compositions described herein may be administered parenterally to a subject (e.g., a human). As used herein, the term “subject” refers to an animal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used interchangeably herein and refer to, for example, a mammalian subject, such as a human subject.

[0096] In the context of this invention, parenteral administration can be subcutaneous (abbreviated herein as sc or SC) or intramuscular (abbreviated herein as im or IM). In some exemplary embodiments, parenteral administration can be via injection, specifically subcutaneous or intramuscular injection. In an exemplary embodiment, the pharmaceutical composition according to the invention is administered via intramuscular injection.

[0097] The inventors have discovered that better API exposure can be achieved by administering the pharmaceutical composition according to the invention via immobilization.

[0098] The pharmaceutical compositions described herein contain degarelix dihydroxynaphthyl salt, i.e., the dihydroxynaphthyl salt of the API. According to the invention, it is preferred that the pharmaceutical compositions do not contain metal salts of dihydroxynaphthyl salts, such as alkali metal dihydroxynaphthyl salts and alkaline earth metal dihydroxynaphthyl salts. Therefore, it is preferred that the pharmaceutical compositions according to the invention do not contain alkali metal dihydroxynaphthyl salts and alkaline earth metal dihydroxynaphthyl salts, i.e., they contain less than 0.01 wt%, less than 0.001 wt%, or less than 0.001 wt% of any such salts.

[0099] As described, the pharmaceutical composition according to the invention is formulated such that degarelix is ​​continuously and significantly released from the microparticles for a period of at least 12 weeks. In some exemplary embodiments, degarelix is ​​continuously and significantly released from the microparticles for even longer periods, such as at least 16 weeks, at least 20 weeks, or at least 24 weeks.

[0100] In a particular exemplary embodiment, the pharmaceutical composition according to the invention comprises degarelic acid in the form of a dihydroxynaphthyl salt, wherein the degarelic acid dihydroxynaphthyl salt is contained in a PLGA, wherein the microparticles comprise about 60 to about 65 wt% of the PLGA and about 28 to about 33 wt% of the degarelic acid base equivalent, wherein the PLGA has a lactide to glycolide molar ratio of about 75:25 and an initial intrinsic viscosity of about 0.35 to 0.45 dL / g, such as about 0.42 dL / g, wherein these are microparticles having a particle size distribution as defined below: -D(v,0.1) is approximately 5 to approximately 15 µm -D(v,0.5) is approximately 25 to approximately 40 µm -D(v,0.9) is approximately 60 to approximately 90 µm.

[0101] A further advantage of the sustained-release pharmaceutical composition of the present invention is that, with the aid of only biodegradable PLGA microparticles as defined herein, one or more of the following can be achieved upon administration to a subject: Sustained release over a period of 12 weeks or longer, or even 16 weeks or longer. Low initial release (burst release), and For sustained-release formulations, degarelix dihydroxynaphthol has surprisingly high bioavailability.

[0102] This invention also relates to the pharmaceutical use of a pharmaceutical composition comprising degarelic acid in the form of a dihydroxynaphthyl salt, wherein the degarelic acid dihydroxynaphthyl salt is contained in microparticles of a biodegradable copolymer (PLGA) of lactide and glycolide units, and wherein the microparticles comprise at least 50 wt% PLGA and about 20 wt% to about 34 wt% of the free base equivalent of degarelic acid. Specific examples of pharmaceutical compositions according to the invention have been described above.

[0103] As used herein, the term "treatment" refers to both therapeutic treatment and preventative or deterrent measures aimed at stopping or mitigating (alleviating) an unwanted physical condition, symptom, or disease, or achieving a beneficial or desired clinical outcome. Therefore, those requiring treatment include those already diagnosed with or suspected of having the condition. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction in the severity of the condition, symptom, or disease; a stable (i.e., non-deteriorating) state of the condition, symptom, or disease; a delay in the onset or slowing of the progression of the condition, symptom, or disease; improvement or relief of the condition, symptom, or disease state (whether partial or complete), whether detectable or undetectable; improvement in at least one measurable bodily parameter (not necessarily identifiable by the patient); or enhancement or improvement of the condition, symptom, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival without treatment.

[0104] Therefore, the present invention relates to pharmaceutical compositions as described herein for the treatment of prostate cancer.

[0105] The pharmaceutical compositions according to the invention are particularly suitable for treating prostate cancer. "Prostate cancer" is specifically understood to mean adenocarcinoma of the prostate gland. Treatment can be performed at any stage after a diagnosis of prostate cancer. In some embodiments, treatment may be associated with advanced prostate cancer with the aim of delaying or stopping cancer growth. In some embodiments, treatment may be associated with locally advanced / metastatic prostate cancer.

[0106] The present invention further relates to pharmaceutical compositions comprising degarelix bis(hydroxynaphthyl) salt in PLGA microparticles as defined herein, for use in treating patients with prostate cancer to prolong the duration of exposure to degarelix. In this context, "prolonged exposure duration" means that a single administration of the pharmaceutical composition of degarelix according to the invention may have a longer therapeutic effect than when using other degarelix formulations (e.g., commercially available 1-month and / or 3-month formulations).

[0107] The present invention also relates to a method for treating prostate cancer, comprising administering an effective amount of a pharmaceutical composition as described herein to a subject in need.

[0108] In the context of the pharmaceutical use of the pharmaceutical composition according to the invention, i.e., a pharmaceutical composition for treating prostate cancer or a method for treating prostate cancer, the composition may be prepared in a manner suitable for parenteral administration. As described, parenteral administration may be subcutaneous (sc) or intramuscular (im) administration. In some exemplary embodiments, parenteral administration may be via injection, specifically subcutaneous or intramuscular injection. In exemplary embodiments, the pharmaceutical composition according to the invention for treating prostate cancer or for prolonging the duration of exposure to degarelix in the treatment of prostate cancer is administered via intramuscular injection. In some exemplary embodiments, im injection is selected as the route of administration and combined with the pharmaceutical composition according to the invention suspended in an oily carrier. Surprisingly, this combination has been found to provide additional advantages in terms of pharmacokinetic performance (e.g., compared to other routes of administration and / or other carriers).

[0109] Pharmaceutical compositions for pharmaceutical use as described herein may be provided in an injection device (e.g., a syringe) prepared for injection (e.g., intramuscular injection). For subcutaneous and intramuscular administration (e.g., injection) of PLGA microparticles, relatively large needle diameters are conventionally used due to their broad particle size distribution. In exemplary embodiments of the invention, pharmaceutical compositions for pharmaceutical use as described herein may be administered intramuscularly via needles of sizes G18 to G21. Needle size is also referred to as “needle gauge”. In some preferred embodiments, needle sizes for pharmaceutical use of pharmaceutical compositions as described herein may be G18 to G20, corresponding to a nominal inner diameter of about 0.8 mm (G18) to about 0.6 mm (G20).

[0110] According to the present invention, the amount of API administered per dose can also vary within certain limits. According to some examples, degarelix can be administered in doses of about 200 mg to about 360 mg of free base equivalent. In some examples, degarelix can be administered in doses of about 200 mg to about 300 mg of free base equivalent. For example, the amount of free base equivalent per dose of degarelix can be about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg.

[0111] According to some exemplary embodiments, the target amount of degarelc free base equivalent to be administered may exceed the maximum amount of free base equivalent available per dose. Therefore, in some exemplary embodiments, degarelc may be administered in two administration steps, such as two injections, like two intramuscular injections. In an exemplary embodiment, degarelc may be administered in two injections with a maximum total amount of 600 mg free base equivalent. In another exemplary embodiment, degarelc may be administered in two injections with a maximum total amount of 400 mg free base equivalent.

[0112] For administration, the API-containing microparticles (degarelix dihydroxynaphthyl salt) can be suspended in a liquid carrier (e.g., an oily carrier) as described above. For patient compliance reasons, smaller administration (e.g., injection) volumes are desirable. Therefore, as covered by this invention, in some instances, the administration volume may be less than or equal to about 6 mL, specifically less than about 4 mL, such as less than about 4.0 mL. In some exemplary embodiments, the administration volume of the pharmaceutical composition as described herein may be from about 2.0 mL to about 3.5 mL. In exemplary embodiments, the administration volume of the pharmaceutical composition as described herein is about 2.2 mL, or about 3.0 mL, or about 3.3 mL.

[0113] For example, according to some exemplary methods, a pharmaceutical composition for medicinal use as described herein may contain about 200 mg or 300 mg of degarelix free base equivalent per milliliter of suspension.

[0114] The pharmaceutical compositions described herein may be administered to subjects (e.g., humans) in need of treatment for a disease or condition (e.g., prostate cancer) that has not previously been treated with the pharmaceutical compositions, i.e., the patient is a previously untreated patient.

[0115] Alternatively, the pharmaceutical compositions described herein may be administered to subjects (e.g., humans) in need who have previously been treated for the disease or condition (e.g., prostate cancer).

[0116] In some aspects, subjects (e.g., humans) in need who have previously been treated for a disease or condition (e.g., prostate cancer) with the pharmaceutical composition have been treated with a pre-loading dose. In some aspects, subjects (e.g., humans) in need who have previously been treated for a disease or condition (e.g., prostate cancer) with the pharmaceutical composition have, for example, been treated for at least one month, at least two months, at least three months, at least four months, at least six months, or at least one year. The subjects may have previously been treated, for example, with a GnRH agonist, a GnRH antagonist, or a GnRH analogue.

[0117] In some respects, subjects (e.g., humans) in need who have previously been treated for a disease or condition (e.g., prostate cancer) with this pharmaceutical composition may be those who have previously undergone androgen deprivation therapy (ADT). ADTs are known to block the production of testosterone. Exemplary active pharmaceutical ingredients that may be used in ADTs are LHRH agonists and antagonists, including leuprorelin, goserelin, triptorelin, histrelin, buserelin, and degarelin. Therefore, subjects (e.g., humans) in need who have previously been treated for a disease or condition (e.g., prostate cancer) with this pharmaceutical composition may be those who have previously been treated with leuprorelin, goserelin, triptorelin, histrelin, buserelin, or degarelin. ADTs may be administered according to a protocol established in accordance with the terms of the marketing authorization.

[0118] In some respects, subjects (e.g., humans) in need of treatment for a disease or condition (e.g., prostate cancer) previously treated with this pharmaceutical composition may be those previously treated with an androgen receptor inhibitor (ARI). ARIs disrupt the interaction between testosterone and cancer cells. Exemplary ARIs are enzalutamide, abiraterone, apalutamide, darolutamide, bicalutamide, clascoterone, flutamide, and nilutamide. Therefore, subjects (e.g., humans) in need of treatment for a disease or condition (e.g., prostate cancer) previously treated with this pharmaceutical composition may be those previously treated with enzalutamide, abiraterone, apalutamide, darolutamide, bicalutamide, clascoterone, flutamide, and nilutamide. ARI treatment can be performed according to the administration protocol established in accordance with the terms of the marketing authorization.

[0119] In this exemplary instance, the subject is a human subject with prostate cancer who has previously been treated with enzalutamide. Enzalutamide is a nonsteroidal anti-androgen drug used to treat prostate cancer. The chemical structure of enzalutamide is shown below:

[0120] In some aspects, ARIs may also be used in combination with the pharmaceutical compositions of the present invention. According to certain exemplary embodiments, the pharmaceutical compositions described herein are used in combination therapy with ARIs, particularly ARIs selected from the group consisting of: enzalutamide, abiraterone, apalutamide, darotamide, bicalutamide, clavusone, flutamide, and nilumet. In exemplary embodiments, the pharmaceutical compositions described herein are used in combination therapy with enzalutamide, wherein, specifically, enzalutamide is administered according to an administration protocol established in accordance with the terms of the marketing authorization.

[0121] The pharmaceutical composition described herein can be administered frequently as needed, for example, depending on the duration of sustained release of the composition. Due to its advantageous release properties, the pharmaceutical composition can be administered once every 12 weeks (three months).

[0122] In an exemplary embodiment, the pharmaceutical composition described herein is administered via intramuscular (IM), particularly by intramuscular injection, in a single dose every 12 weeks (3 months), at a dose of about 200 mg of degarelix free base equivalent, particularly a total of 200 mg of degarelix free base equivalent. In a further exemplary embodiment, the pharmaceutical composition described herein is administered via intramuscular (IM), particularly by intramuscular injection, in a single dose every 12 weeks (3 months), at a dose of about 300 mg of degarelix free base equivalent, particularly a total of 300 mg of degarelix free base equivalent.

[0123] In a further exemplary embodiment, the pharmaceutical composition described herein is administered as a loading dose via immediacy, particularly by intramuscular injection, in a total amount of about 400 mg (particularly two doses of 200 mg each). It should be understood that the loading dose is intended for a single administration at the start of treatment. Subsequently, i.e., after the administration of the loading dose, according to these exemplary embodiments, the pharmaceutical composition described herein is administered as a maintenance dose, in a single dose via immediacy, particularly by intramuscular injection, every 12 weeks (3 months), in a total amount of about 200 mg of the degarelix free base equivalent, particularly 200 mg of the degarelix free base equivalent.

[0124] This also includes the possibility that the pharmaceutical compositions described herein can be used as a maintenance dose following a loading dose administration of another formulation comprising degarelix acetate as the active pharmaceutical ingredient. For example, the pharmaceutical compositions described herein can be used as a maintenance dose following a loading dose administration of a product marketed under the trade name Firmagon. ® Or Gonax ®The commercially available degarelix acetate formulation is administered after a loading dose. Thus, in an exemplary embodiment, degarelix acetate is administered as a loading dose via subcutaneous (SC) administration, particularly by SC injection, of a total amount of 240 mg (particularly two doses of 120 mg each), of the degarelix free base equivalent. Subsequently, the pharmaceutical composition described herein is administered as a maintenance dose via intramuscular (IM) administration, particularly by IM injection, of a single dose every 12 weeks (3 months), of a total amount of about 200 mg of the degarelix free base equivalent, particularly a total amount of 200 mg of the degarelix free base equivalent.

[0125] The pharmaceutical compositions described herein may be administered in a dosing regimen to achieve desired hormone suppression, which is compared to subjects who have not received the pharmaceutical compositions described herein, or to subjects before receiving the pharmaceutical compositions. Hormone suppression can be assessed in different ways. For example, it can be determined whether a threshold for chemical castration has been reached. In some instances for patients with prostate cancer, hormone suppression may be characterized by testosterone suppression to castration levels (defined as serum testosterone ≤ 0.5 ng / mL). In some instances, hormone suppression may be characterized by serum testosterone suppression to ≤ 0.2 ng / mL.

[0126] Following administration (e.g., subcutaneous or intramuscular administration, such as injection), the API degarelix can be continuously released from microparticles to achieve the desired therapeutic effect. In some exemplary embodiments, degarelix can be continuously released from microparticles to achieve and maintain a mean plasma concentration above a threshold of 3.0 ng / mL for at least 12 weeks, or in some exemplary embodiments, above a threshold of 8.0 ng / mL or 9.0 ng / mL for at least 12 weeks. It should be understood that higher mean plasma concentrations (Cmax) may be observed primarily within the days immediately following administration.

[0127] In some embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels and maintaining them at castration levels for at least 12 weeks. In some embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to less than or equal to 0.5 ng / mL (≤ 0.5 ng / mL) within 14 days of administration and maintaining serum testosterone levels ≤ 0.5 ng / mL for at least 12 weeks from the date of administration. In some embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to less than or equal to 0.5 ng / mL (≤ 0.5 ng / mL) within 7 days of administration and maintaining serum testosterone levels ≤ 0.5 ng / mL for at least 12 weeks from the date of administration. In certain embodiments, degarelix can be continuously released from microparticles to reduce serum testosterone levels to less than or equal to 0.5 ng / mL (≤ 0.5 ng / mL) within 3 days of administration and maintain serum testosterone levels ≤ 0.5 ng / mL for at least 12 weeks from the date of administration.

[0128] In further embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to less than 0.5 ng / mL (< 0.5 ng / mL) within 14 days of administration and maintaining serum testosterone levels < 0.5 ng / mL for at least 12 weeks from the time of administration. In some embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to less than 0.5 ng / mL (< 0.5 ng / mL) within 7 days of administration and maintaining serum testosterone levels < 0.5 ng / mL for at least 12 weeks from the time of administration. In some embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to less than 0.5 ng / mL (< 0.5 ng / mL) within 3 days of administration and maintaining serum testosterone levels < 0.5 ng / mL for at least 12 weeks from the time of administration.

[0129] In further embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to less than or equal to 0.2 ng / mL (≤ 0.2 ng / mL) within 14 days of administration and maintaining serum testosterone levels ≤ 0.2 ng / mL for at least 12 weeks from the date of administration. In some embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to less than or equal to 0.2 ng / mL (≤ 0.2 ng / mL) within 7 days of administration and maintaining serum testosterone levels ≤ 0.2 ng / mL for at least 12 weeks from the date of administration. In some embodiments, degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to less than or equal to 0.2 ng / mL (≤ 0.2 ng / mL) within 3 days of administration and maintaining serum testosterone levels ≤ 0.2 ng / mL for at least 12 weeks from the date of administration.

[0130] As mentioned above, the inventors unexpectedly discovered that the pharmaceutical compositions described herein exhibit strong sustained release and low burst release upon administration to subjects. Specifically, this dose-normalized burst release is significantly lower than that of commercially available 3-month degarelix acetate formulations (Gonax). ® ) and commercially available 1-month dermalin acetate preparation (Firmagon) ® As observed herein, the pharmaceutical composition as described herein for the treatment of prostate cancer, or a method of treating prostate cancer including the administration of the pharmaceutical composition described herein, may result in mean degarelix plasma concentrations of less than 100 ng / mL, less than 80 ng / mL, less than 60 ng / mL, less than 50 ng / mL, less than 40 ng / mL, or less than 30 ng / mL from day 1 to day 7 after administration.

[0131] This invention further relates to a method for preparing a pharmaceutical composition as described herein (also referred to herein as a “preparation method”). This preparation method comprises mixing degarelic acid in a pharmaceutically acceptable form of a dihydroxynaphthyl salt with a biodegradable copolymer (PLGA) of lactide and glycolide units. This mixing is also referred to herein as (a). Both components are weighed prior to mixing. This ensures, for example, that the degarelic acid dihydroxynaphthyl salt starting material is free of metal salts of dihydroxynaphthyl acid. It also encompasses milling, crushing, and / or sieving to begin the method with more uniform particle size. If sieving is required, the components may be sieved, for example, using a sieve with a 180 µm aperture. Both the degarelic acid dihydroxynaphthyl salt and the PLGA polymer may be in powder form to facilitate mixing. Mixing continues until a homogeneous mixture of the two components is obtained.

[0132] The resulting mixture is then subjected to gradual heating and extrusion. This heating and extrusion is also referred to herein as (b). An exemplary method for performing (b) is hot melt extrusion. Commercially available extruders, such as those comprising a single screw or twin screws, can be used. Screw speed and temperature conditions can be adjusted to obtain a processable extrudate. For example, in the context of this invention, the temperature range may be from about 50°C to about 100°C, such as from about 80°C to about 90°C, and / or the screw speed range may be from about 50 to about 500 rpm, such as about 100 rpm.

[0133] The extrudate obtained after (b) will then be granulated into pellets. Granulation is also referred to herein as (c). For granulation, a commercially available pelletizer can be used. During processing, the pellet size can be adjusted to, for example, 0.5 to 10 mm.

[0134] The granules obtained after (c) are ground at a low temperature. Specifically, a low temperature can be a temperature below 0°C, such as 0°C to approximately -100°C, for example, approximately -80°C or approximately -100°C. Low-temperature grinding is also referred to herein as (d). If necessary, the microparticles obtained after grinding may be dried before further processing.

[0135] After grinding, the obtained particles can be sieved to obtain a size less than or equal to about 150 µm. Sieving is also referred to herein as (e). It should be understood that in the preparation method according to the invention, (a) to (d) are mandatory, while (e) to (h) are each optional, but may be advantageous. Sieving can be carried out using a sieve with an aperture size that produces the desired particle size. In some exemplary embodiments, the sieve is a 106 µm sieve, although smaller or larger aperture sizes can be used, such as about 50 µm or about 150 µm, or any other value in the range of about 75 µm to about 106 µm.

[0136] In a specific example embodiment, the microparticles produced by the preparation method may, for example, have a particle size D(v,0.5) of about 25 to about 45 µm, such as about 25 to 40 µm. In a specific example embodiment, the particle size distribution may be as follows: - D(v,0.1) is approximately 5 to approximately 22 µm - D(v,0.5) is approximately 25 to approximately 45 µm - D(v,0.9) is approximately 55 to approximately 90 µm.

[0137] In a further example, the particle size distribution can be as follows: - D(v,0.1) is approximately 5 to approximately 15 µm - D(v,0.5) is approximately 30 to approximately 40 µm - D(v,0.9) is approximately 60 to approximately 90 µm.

[0138] In some examples, the encapsulation efficiency of degarelk bis(hydroxynaphthyl) salt in the microparticles prepared by the methods described herein may be about 80% to about 99%, about 80% to about 95%, about 80% to about 90%, about 85% to about 99%, about 85% and about 95%, or about 90% and about 99%. In some examples, the encapsulation efficiency of degarelk bis(hydroxynaphthyl) salt in the microparticles prepared by the methods described herein is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

[0139] In some exemplary embodiments, the preparation method may further include drying the obtained microparticles after (d) or after (e), and / or after (f). Drying may be carried out at high temperature and under reduced pressure, and / or using convection. For example, drying may be carried out at a temperature of about 20 to about 50°C. Furthermore, specific pressures may be applied, such as from below 1 mbar to 1000 mbar. In some exemplary embodiments, alternating pressures may be used, such as 10 mbar for 55 min / 1000 mbar for 5 min, and so on for several hours, or 50 mbar for 3 h / below 1 mbar for 12.5 h. Drying may include primary drying and secondary drying.

[0140] In an exemplary embodiment, the preparation method may further include filling optionally dried or partially (e.g., primary) dried, and / or optionally sieved microparticles into vials (e.g., glass vials) or syringes (e.g., glass or polymer syringes). An exemplary vial size used according to the invention is 6 ml. The vial or syringe used herein is also referred to as (f).

[0141] In the example embodiment, the filled vial obtained after (f) can then be sealed, for example by crimping with a metal cap. In the example embodiment, the filled syringe obtained after (f) can then be sealed, for example via a plunger / stopper, such as a rubber plunger. Sealing the vial or syringe is also referred to herein as (g).

[0142] In some exemplary embodiments, the sealed vials or syringes obtained after (g) can be sterilized. Sterilization is also referred to herein as (h). Several known sterilization methods are available. In some exemplary embodiments, the filled and sealed vials containing the microparticles according to the invention can be sterilized by irradiation, such as X-ray or gamma-ray irradiation, for example using a dose of about 25 to about 40 kGy. In some exemplary embodiments, sterilization is performed via X-ray irradiation using a dose of about 25 to about 40 kGy.

[0143] In some examples, the preparation method does not include freeze-drying of any intermediates or final product. In some examples, the preparation method does not include milling prior to extrusion (b)). In some examples, the preparation method does not involve supercritical fluid treatment.

[0144] In some preferred embodiments, the preparation method does not involve any freeze-drying or supercritical fluid treatment.

[0145] The product obtained after sterilization can be used as a pharmaceutical composition as described herein, for example, for the pharmaceutical uses described above. In some exemplary embodiments, the obtained microparticles can be suspended in an oily carrier as described herein, such as a mixture of C8 / C10 triglycerides, a mixture of C8 triglycerides, or a mixture of C10 triglycerides, for example, MIGLYOL. ® 812. For example, suspending microparticles in an oily carrier can be done in vials already filled with microparticles.

[0146] This invention further relates to pharmaceutical compositions as described herein, which can be obtained by the preparation methods described herein. Specifically, this invention relates to pharmaceutical compositions comprising degarelic acid in the form of a dihydroxynaphthyl salt, wherein the degarelic acid dihydroxynaphthyl salt is contained in microparticles of a biodegradable copolymer (PLGA) of lactide and glycolide units, and wherein the microparticles contain at least 50 wt% PLGA and about 20 wt% to about 34 wt% of free base equivalent of degarelic acid, which can be obtained by methods comprising: (a) Degarelk in the form of pharmaceutically acceptable dihydroxynaphthyl salt, particularly in powder form, is mixed with a biodegradable copolymer (PLGA) of lactide and glycolide units, particularly in powder form; (b) The mixture is gradually heated and extruded; (c) Granulate the resulting extrudate; (d) Granules obtained by grinding at low temperature.

[0147] Furthermore, the present invention relates to a kit comprising a device containing a pharmaceutical composition according to the invention and instructions for use. In some embodiments, the device may be a pre-filled syringe or vial. The syringe may contain needles of G18 to G21, particularly G18 to G20.

[0148] This invention further relates to a dual chamber device (DCD). The DCD can be provided, in particular, in a pre-filled form. The DCD is a combination product containing a pharmaceutical composition and a diluent in a dry (or pre-dried) form in two separate chambers of the device. It provides patients and healthcare professionals with high stability and convenience, thereby significantly improving product quality and patient compliance. Administration via the dual chamber device first requires a reconstitution stage in which the pharmaceutical composition is contacted with a diluent (e.g., an aqueous or oil-based carrier) to suspend it. Subsequently, the reconstituted composition (e.g., a suspension) is ready for administration. In some exemplary embodiments, the DCD according to the invention may contain a pharmaceutical composition in powder form as described herein in one chamber and an aqueous carrier in the other chamber. In other exemplary embodiments, the DCD according to the invention may contain a pharmaceutical composition in powder form as described herein in one chamber and an oil-based carrier in the other chamber.

[0149] The present invention further relates to a single-compartment device comprising a pharmaceutical composition as described herein in the form of a suspension in an oily carrier. This may also be referred to as a ready-to-use device. An exemplary single-compartment device is a pre-filled syringe comprising a suspension of degarelix dihydroxynaphthyl salt, which is contained in microparticles of PLGA as described herein. For example, the pre-filled syringe may comprise a suspension in an oily carrier as described herein (e.g., MIGLYOL). ® The microparticles in 812 contain at least 50 wt% PLGA and about 20 wt% to about 34 wt% degarelix free base equivalent. This pre-filled single-chamber device offers easier operation as no reconfiguration is required before administration to the patient.

[0150] In some embodiments, the kit, the aforementioned dual-chamber device, and / or single-chamber device may be suitable for storage at room temperature. As used herein, “storage” specifically means storage for at least 6 months, at least 12 months, or at least 24 months after the manufacturing date without significant deterioration. In this context, “without significant deterioration” should be understood as a loss of less than 5%, less than 3%, less than 1%, or even less than 0.5% due to degradation of the PLGA microparticles containing degarelic bis(hydroxynaphthyl) salt according to the invention.

[0151] The present invention is further described by the following items.

[0152] Item 1. A pharmaceutical composition comprising degarelic acid in the form of a dihydroxynaphthyl salt, wherein the degarelic acid dihydroxynaphthyl salt is contained in microparticles of a biodegradable copolymer (PLGA) of lactide and glycolide units, and wherein the microparticles comprise at least 50 wt% PLGA and about 20 wt% to about 34 wt% of free base equivalent of degarelic acid.

[0153] Item 2. A pharmaceutical composition comprising degarelic acid in a pharmaceutically acceptable form of dihydroxynaphthyl salt as an active pharmaceutical ingredient, wherein the degarelic acid dihydroxynaphthyl salt is contained in microparticles of a biodegradable copolymer (PLGA) of lactide and glycolide units, wherein the microparticles comprise at least 50 wt% PLGA and about 20 wt% to about 34 wt% free base equivalent of degarelic acid, and wherein the composition continuously and significantly releases degarelic acid under restricted burst release conditions to achieve a therapeutic effect within 14 days of administration and maintain such effect for at least 12 weeks after administration.

[0154] Project 3. The pharmaceutical composition as described in Project 2, wherein the composition continuously and significantly releases degarelix under restricted burst release conditions to achieve a therapeutic effect within 7 days of administration or within 3 days of administration.

[0155] Item 4. The pharmaceutical composition as described in any of the preceding items, wherein the PLGA has a molar ratio of lactide units to glycolide units of about 75:25 to about 85:15.

[0156] Item 5. The pharmaceutical composition as described in any of the preceding items, wherein the PLGA has a molar ratio of lactide units to glycolide units of about 75:25, about 80:20, or about 85:15.

[0157] Item 6. The pharmaceutical composition as described in any of the preceding items, wherein the microparticles have a particle size distribution as defined below: - D(v,0.1) is approximately 5 to approximately 22 µm - D(v,0.5) is approximately 25 to approximately 45 µm - D(v,0.9) is approximately 55 to approximately 90 µm.

[0158] Item 7. The pharmaceutical composition as described in any of the preceding items, wherein the microparticles have a particle size distribution as defined below: - D(v,0.1) is approximately 5 to approximately 15 µm - D(v,0.5) is approximately 25 to approximately 40 µm - D(v,0.9) is approximately 60 to approximately 90 µm.

[0159] Item 8. The pharmaceutical composition as described in any of the preceding items, wherein the PLGA is a linear polyester having a random arrangement of lactide and glycolide units.

[0160] Item 9. The pharmaceutical composition as described in any of the preceding items, wherein the PLGA is acid-terminated.

[0161] Item 10. The pharmaceutical composition of any one of the preceding items, wherein the microparticles comprise about 55 to about 75 wt% PLGA, about 60 to about 70 wt% PLGA, or about 60 to about 65 wt% PLGA.

[0162] Item 11. The pharmaceutical composition of any one of the preceding items, wherein the microparticles comprise about 60 to about 65 wt% PLGA.

[0163] Item 12. The pharmaceutical composition as described in any of the preceding items, wherein the initial intrinsic viscosity (iv) of the PLGA is about 0.3 dL / g to about 0.5 dL / g, or about 0.35 dL / g to about 0.45 dL / g.

[0164] Item 13. The pharmaceutical composition as described in Item 12, wherein the initial intravenous dose of the PLGA is about 0.30 dL / g, or about 0.40 dL / g, or about 0.50 dL / g.

[0165] Item 14. The pharmaceutical composition as described in Item 12, wherein the initial intravenous dose of the PLGA is about 0.42 dL / g.

[0166] Item 15. The pharmaceutical composition of any one of the preceding items further comprises a carrier, which is an aqueous carrier or an oily carrier.

[0167] Item 16. The pharmaceutical composition as described in Item 15, wherein the carrier is an oily carrier, particularly a mixture of medium-chain triglycerides.

[0168] Item 17. The pharmaceutical composition as described in Item 16, wherein the oily carrier is a mixture of C8 / C10 triglycerides, particularly a mixture of triglycerides of saturated C8 / C10 fatty acids.

[0169] Item 18. The pharmaceutical composition as described in Item 16 or 17, wherein the oily carrier is a mixture consisting essentially of triglycerides of caprylic and capric acids.

[0170] Item 19. The pharmaceutical composition as described in any of the preceding items, wherein the pharmaceutical composition is in the form of a suspension.

[0171] Item 20. The pharmaceutical composition of Item 19, wherein the suspension is a suspension of an oily carrier as defined in any one of Items 16 to 18.

[0172] Item 21. The pharmaceutical composition of Item 19 or 20, wherein the concentration of microspheres in the suspension is from about 150 mg / mL to about 350 mg / mL, or from about 180 mg / mL to about 300 mg / mL.

[0173] Item 22. The pharmaceutical composition of any one of the preceding items, wherein the molar ratio of degarelic acid to dihydroxynaphthyl salt is about 1:1 to about 2:1.

[0174] Item 23. The pharmaceutical composition of any of the preceding items, wherein the microparticles comprise about 28 wt% to about 33 wt% of degarelix free base equivalent.

[0175] Item 24. The pharmaceutical composition as described in any of the preceding items, wherein the microparticles comprise about 28 wt%, about 30 wt%, or about 33 wt% of degarelix free base equivalent.

[0176] Item 25. The pharmaceutical composition as described in any of the preceding items, wherein the microparticles are microparticles.

[0177] Item 26. The pharmaceutical composition as described in any of the preceding items, which is suitable for parenteral administration.

[0178] Item 27. The pharmaceutical composition as described in any of the preceding items, which is suitable for subcutaneous or intramuscular administration.

[0179] Item 28. The pharmaceutical composition as described in any of the preceding items, which is suitable for intramuscular administration.

[0180] Item 29. The pharmaceutical composition of any one of the preceding items, which is a suspension of PLGA microparticles in a mixture of saturated C8 / C10 fatty acid triglycerides, the microparticles comprising degarelic acid dihydroxynaphthyl salt having a molar ratio of lactide units to glycolide units of about 75:25.

[0181] Item 30. The pharmaceutical composition of Item 29, wherein the microparticles comprise about 28 wt% to about 33 wt% of degarelix free base equivalent.

[0182] Item 31. The pharmaceutical composition as described in Item 29 or 30, wherein the initial intravenous dose of the PLGA is about 0.35 dL / g to about 0.45 dL / g.

[0183] Item 32. The pharmaceutical composition as described in any of the preceding items, wherein the pharmaceutical composition is free of alkali metal dihydroxynaphthate and alkaline earth metal dihydroxynaphthate.

[0184] Item 33. The pharmaceutical composition of any of the preceding items, wherein degarelix is ​​continuously and significantly released from the microparticles for a period of at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks.

[0185] Item 34. A pharmaceutical composition as described in any one of items 1 to 33, for the treatment of prostate cancer.

[0186] Item 35. A pharmaceutical composition comprising degarelix dihydroxynaphthyl salt in PLGA microparticles for prolonging the duration of exposure to degarelix in the treatment of patients with prostate cancer.

[0187] Item 36. Pharmaceutical compositions as used in Items 34 or 35, wherein the composition is intended for parenteral administration, particularly for subcutaneous or intramuscular administration.

[0188] Item 37. The pharmaceutical composition used in any of Items 34 to 36, wherein the composition is to be administered once every 12 weeks.

[0189] Item 38. A pharmaceutical composition used in any of Items 34 to 37, wherein the composition is for intramuscular administration.

[0190] Item 39. The pharmaceutical composition used in Item 38, wherein the composition is administered intramuscularly via a needle of size G18 to G21, particularly G18 to G20.

[0191] Item 40. The pharmaceutical composition used in any of Items 34 to 39, wherein degarelix is ​​administered in an amount of about 200 mg to about 360 mg free base equivalent per dose, particularly about 200 mg to about 300 mg free base equivalent per dose.

[0192] Item 41. The pharmaceutical composition used in any of Items 34 to 40, wherein degarelix is ​​administered in two injections at a maximum total amount of 600 mg free base equivalent, or in two injections at a maximum total amount of 400 mg free base equivalent.

[0193] Item 42. The pharmaceutical composition used in any of Items 34 to 41, wherein the administration volume is less than or equal to about 6 mL, particularly less than 4 mL, more particularly about 2.0 mL to about 3.5 mL.

[0194] Item 43. A pharmaceutical composition used in any of Items 34 to 42, wherein degarelix is ​​continuously released from the microparticle, thereby reducing and maintaining serum testosterone levels to castration levels for at least 12 weeks.

[0195] Item 44. A pharmaceutical composition used in any of Items 34 to 43, wherein degarelix is ​​continuously released from microparticles, thereby reducing serum testosterone levels to ≤ 0.5 ng / mL within 14 days of administration and maintaining such levels for at least 12 weeks from the date of administration.

[0196] Item 45. A pharmaceutical composition used in any of Items 34 to 44, wherein degarelix is ​​continuously released from microparticles, thereby causing the mean plasma concentration of degarelix to reach and be maintained above a threshold of 3.0 ng / mL for at least 12 weeks.

[0197] Item 46. A pharmaceutical composition used in any of Items 34 to 44, wherein degarelix is ​​continuously released from the microparticle, thereby achieving and maintaining a mean plasma concentration of degarelix at and above a threshold of 8.0 ng / mL or above a threshold of 9.0 ng / mL for at least 12 weeks.

[0198] Item 47. The pharmaceutical composition used in any of Items 34 to 46, wherein the mean degarelix plasma concentration on day 1 to day 7 after administration is less than 100 ng / mL, less than 80 ng / mL, less than 60 ng / mL, less than 50 ng / mL, less than 40 ng / mL, or less than 30 ng / mL.

[0199] Item 48. A method for treating prostate cancer, comprising administering to a subject in need an effective amount of a pharmaceutical composition such as any one of items 1 to 33.

[0200] Item 49. The method as described in Item 48, wherein the pharmaceutical composition is administered once every 12 weeks.

[0201] Item 50. The method as described in Item 48 or 49, wherein the pharmaceutical composition is administered by intramuscular injection, particularly by a single injection.

[0202] Item 51. The method as described in Item 50, wherein the intramuscular injection is performed using a needle of size G18 to G21, particularly G18 to G20.

[0203] Item 52. The method of any one of Items 48 to 51, wherein degarelix is ​​administered in an amount of about 200 mg to about 360 mg free base equivalent per administration, or in an amount of about 200 mg to about 300 mg free base equivalent per administration.

[0204] Item 53. The method of any one of items 48 to 52, wherein the application volume is less than or equal to about 6 ml, particularly less than 4 ml, more particularly about 2.0 to about 3.5 ml.

[0205] Item 54. The method of any one of Items 48 to 53, wherein degarelix is ​​continuously released from the microparticles, thereby causing the mean plasma concentration of degarelix to reach and be maintained above a threshold of 3.0 ng / mL for at least 12 weeks.

[0206] Item 55. The method of any one of Items 48 to 54, wherein the average degarelix plasma concentration from day 1 to day 7 after administration is less than 100 ng / mL, less than 80 ng / mL, less than 60 ng / mL, less than 50 ng / mL, less than 40 ng / mL, or less than 30 ng / mL.

[0207] Item 56. A method for preparing a pharmaceutical composition as described in any one of Items 1 to 33, comprising: (a) Degarelk in the form of pharmaceutically acceptable dihydroxynaphthyl salt, particularly in powder form, is mixed with a biodegradable copolymer (PLGA) of lactide and glycolide units, particularly in powder form; (b) subject the mixture to gradual heating and extrusion; (c) Granulate the resulting extrudate; (d) Granules obtained by grinding at low temperature.

[0208] Item 57. The method of Item 56 further includes: (e) The obtained particles are sieved to a size of less than or equal to about 150 µm.

[0209] Item 58. The method of Items 56 or 57 further includes: (f) Fill the microparticles into a vial or syringe; (g) Seal the vial or syringe.

[0210] Item 59. The method of Item 58 further includes: (h) Sterilize the filled and sealed vials or syringes by X-ray or gamma-ray irradiation.

[0211] Project 60. The method of Project 58 further includes: (h) Sterilize the filled and sealed vials by X-ray irradiation.

[0212] Item 61. The method of any one of items 56 to 60, further comprising: drying the particles after (d) or after (e) and / or after (f).

[0213] Item 62. The method of any one of items 56 to 61, further comprising suspending the particles in an oily carrier.

[0214] Item 63. The method of any one of items 56 to 62, wherein the method does not include freeze drying.

[0215] Item 64. The method of any one of items 56 to 63, wherein the method does not include milling prior to extrusion.

[0216] Item 65. The method of any one of items 56 to 64, wherein the method does not include supercritical fluid processing.

[0217] Item 66. A pharmaceutical composition as described in any one of items 1 to 33, which can be obtained by any one of the methods described in items 56 to 65.

[0218] Item 67. A kit comprising a device, such as a pre-filled syringe, comprising a pharmaceutical composition as described in any one of items 1 to 33 and instructions for use.

[0219] Item 68. A dual-chamber device comprising

[0220] a. A pharmaceutical composition in powder form, such as any of items 1 to 33, in one chamber and an aqueous carrier in another chamber, or

[0221] b. A pharmaceutical composition in powder form, such as any of items 1 to 33, in one compartment and an oily carrier in another compartment.

[0222] Item 69. A single-chamber device comprising a pharmaceutical composition, such as any one of items 1 to 33, in the form of a suspension in an oily carrier.

[0223] Item 70. The kit as described in Item 67, the device as described in Item 68, or the device as described in Item 69, which is suitable for storage at room temperature.

[0224] Item 71. The pharmaceutical composition used in any of Items 34 to 47, wherein degarelix is ​​administered in an amount of about 200 mg of degarelix free base equivalent, particularly 200 mg of degarelix free base equivalent, and wherein the pharmaceutical composition is administered once every 12 weeks in a single intramuscular dose.

[0225] Item 72. The pharmaceutical composition used in any of Items 34 to 47, wherein degarelix is ​​administered in an amount of about 300 mg of degarelix free base equivalent, particularly 300 mg of degarelix free base equivalent, and wherein the pharmaceutical composition is administered once every 12 weeks in a single intramuscular dose.

[0226] Item 73. The pharmaceutical composition used in any of Items 34 to 47, wherein degarelix is ​​(i) for initial intramuscular administration in an amount of about 400 mg of degarelix free base equivalent, particularly 400 mg of degarelix free base equivalent, and (ii) for subsequent intramuscular administration in a single dose every 12 weeks in an amount of about 200 mg of degarelix free base equivalent, particularly 200 mg of degarelix free base equivalent.

[0227] Item 74. The pharmaceutical composition used in Item 73, wherein a total amount of 400 mg of degarelix free base equivalent is used to administer the drug in two injections of 200 mg each of degarelix free base equivalent.

[0228] Item 75. The pharmaceutical composition used in Item 71, which is administered via subcutaneous (SC) administration, particularly via SC injection, and more particularly via two SC injections of 120 mg degarelix free base equivalent, to a patient who has previously received degarelix acetate.

[0229] Item 76. The pharmaceutical composition used in any of Items 71 to 75, wherein intramuscular administration is intramuscular injection.

[0230] Item 77. The method of any one of Items 48 to 55, wherein degarelix is ​​administered in an amount of about 200 mg of degarelix free base equivalent, particularly 200 mg of degarelix free base equivalent, and wherein the pharmaceutical composition is administered by a single intramuscular dose once every 12 weeks.

[0231] Item 78. The method of any one of items 48 to 55, wherein degarelix is ​​administered in an amount of about 300 mg of degarelix free base equivalent, particularly 300 mg of degarelix free base equivalent, and wherein the pharmaceutical composition is administered by a single intramuscular dose once every 12 weeks.

[0232] Item 79. The method of any one of Items 48 to 55, comprising (i) an initial intramuscular administration of the pharmaceutical composition of any one of Items 1 to 33, the total amount of which is about 400 mg of degarelix free base equivalent, particularly 400 mg of degarelix free base equivalent, and (ii) subsequent intramuscular administrations in a single dose every 12 weeks, the amount of which is about 200 mg of degarelix free base equivalent, particularly 200 mg of degarelix free base equivalent.

[0233] Item 80. As described in Item 79, wherein a total of 400 mg of degarelk free base equivalent is administered by two injections of 200 mg each of degarelk free base equivalent.

[0234] Item 81. The method of Item 77, wherein the pharmaceutical composition of any one of Items 1 to 33 is administered via subcutaneous administration, particularly via subcutaneous injection, and more particularly via two subcutaneous injections of 120 mg of degarelix free base equivalent to a patient who has previously received degarelix acetate, in an amount of 240 mg of degarelix free base equivalent.

[0235] Item 82. The method of any one of items 77 to 81, wherein intramuscular administration is intramuscular injection. Attached Figure Description

[0236] Figure 1 : A graph showing the mean plasma concentration (ng / mL) of degarelix in rats after administration of composition A (TF8) and composition Y (TF4) suspended in an aqueous carrier and after administration of the reference product, as described in Example 3a (PK3).

[0237] Figure 2 Display and Figure 1 Same data, but focusing on the graph of the first 10 days after application.

[0238] Figure 3 Graph of mean plasma concentrations (ng / mL) of degarelix in rats after administration of composition B (TF6) and composition Z (TF9) suspended in an aqueous carrier and after administration of the reference product, as described in Example 3b (PK4).

[0239] Figure 4 Display and Figure 3 The same data, but focusing on the graph of the first 7 days after application.

[0240] Figure 5 Graph of mean plasma concentrations (ng / mL) of degarelix in rats after administration of composition B (TF6) and composition W (TF8) suspended in an aqueous carrier and after administration of the reference product, as described in Example 3b (PK4).

[0241] Figure 6 : A graph showing the mean plasma concentration (ng / mL) of degarelk in rats after administration of composition X (PK3-TF5) suspended in an aqueous carrier as described in Example 3 a) and composition A (PK4-TF5) suspended in an aqueous carrier as described in Example 3 b).

[0242] Figure 7: A graph showing the mean plasma concentration (ng / mL) of degarelix in rats after administration of composition C suspended in an oily carrier in IM (TF2) or SC (TF3), and after administration of the reference product, as described in Example 3 c)(PK5).

[0243] Figure 8 : A graph showing the mean plasma concentration (ng / mL) of degarelix in rats after administration of composition C suspended in an oily carrier (TF2) or an aqueous carrier (TF4) and after administration of the reference product, as described in Example 3 c)(PK5).

[0244] Figure 9 Graph of mean plasma concentrations (ng / mL) of degarelix in rats after administration of IM to compositions D (TF6) and E (TF7) suspended in an oily carrier, and after administration of a reference product, as described in Example 3 c (PK5).

[0245] Figure 10 Graph of mean plasma concentrations (ng / mL) of degarelk in rats after administration of compositions F (TF1), G (TF3), and H (TF4) suspended in an oily carrier in IM, as described in Example 3 d (PK8).

[0246] Figure 11 Graph of mean plasma concentrations (ng / mL) of degarelk in rats after administration of composition F (TF1) and composition I (TF6) suspended in an oily carrier in IM, as described in Example 3 d (PK8).

[0247] Figure 12 : A graph showing the mean plasma concentration (ng / mL) of degarelk in rats after administration of compositions F (TF1) and J (TF7) suspended in an oily carrier, as described in Example 3 d (PK8).

[0248] Example

[0249] Characterization methods used in the microparticle preparation examples

[0250] Molecular weight determination

[0251] In the following examples, the molecular weight of the polymer starting material was measured using gel permeation chromatography (GPC) as follows. The sample was dissolved in tetrahydrofuran (THF) and analyzed using isocratic elution at 1 mL / min on tandem Styragel® columns HR 5, HR4, HR 3, and HR 2 at 40°C with a refractive index detector. The number-average molecular weight (Mn), weight-average molecular weight (Mw), and polydispersity index (Ip = Mw / Mn) were determined based on calibration curves using narrow molecular weight polystyrene from Sigma Aldrich as a standard, as shown in Table 1. Table 1

[0252] Drug loading and purity determination

[0253] In the following examples, drug loading and purity were measured using (ultra)high performance liquid chromatography ((U)HPLC) as follows: 2 to 15 mg of biodegradable polymer microparticles were weighed, dissolved in dimethyl sulfoxide (DMSO) or dimethylformamide (DMF), and analyzed using a C18 column, a water-TFA / acetonitrile-TFA mobile phase, and 280 nm UV detection in gradient elution mode. More specifically, the drug loading and purity of the compositions tested in PK3, PK4, and PK5 were measured using 2 to 4 mg of the sample in DMF using the above method; the drug loading and purity of the composition tested in PK8 were measured using 15 mg of the sample in DMSO using the above method. The drug loading and purity of composition K were measured using 15 mg of the sample in DMSO using the above method.

[0254] Determination of particle size

[0255] PLGA microparticles after granulation

[0256] In the following examples, the size of the milled PLGA particles was determined by wet laser diffraction using a Malvernmastersizer 3000, as follows: 40 to 80 mg of sample was suspended in an aqueous solution of sodium carboxymethyl cellulose (1.5% w / w), mannitol (4.25% w / w), and polysorbate 80 (0.1% w / w), and then introduced into a hydroMV dispersion unit containing purified water (stirred at 2000 rpm) until a stable laser opacity of 5% to 20% was achieved. The sample was then subjected to sonication for 3 min (MV dispersion unit set to medium (50%)). The volume-weighted size distribution was calculated according to the Mie theory using the following parameters: dispersant refractive index 1.33; true particle refractive index 1.52; absorption index 0.001.

[0257] Microparticles of degarelk salt in PLGA

[0258] In the following examples, the particle size distribution of the different compositions prepared was determined by wet laser diffraction using a Malvern mastersizer 3000, as follows: Approximately 50 mg of sample was suspended in an aqueous solution of sodium carboxymethyl cellulose (1.5% w / w), mannitol (4.25% w / w), and polysorbate 80 (0.1% w / w), and then introduced into a hydroMV dispersion unit containing purified water (stirred at 2000 rpm) until a stable laser opacity of 10% to 20% was achieved. The sample was then subjected to sonication for 3 min (MV dispersion unit set to medium (50%)). The volume-weighted size distribution was calculated according to the Mie theory using the following parameters: dispersant refractive index 1.33; true particle refractive index 1.56; absorption index 0.015.

[0259] Degarelix dihydroxynaphthol nanoparticles

[0260] The particle size distribution of degarelic bis(hydroxynaphthyl)ate after crushing and sieving was determined by wet laser diffraction using a Malvernmastersizer 3000. Approximately 2 mg of the sample was suspended in 2 mL of dichloromethane (DCM). Then, approximately 0.5 mL of the suspension was introduced into a hydro-SV dispersion unit containing DCM (stirred at 1500 rpm) until a stable laser opacity of 3% to 15% was achieved. The volume-weighted size distribution was calculated according to the Mie theory using the following parameters: dispersant refractive index 1.42; true particle refractive index 1.56; absorption index 0.010.

[0261] Supporting Tables for Microparticle Formulation Examples

[0262] Table 2 summarizes the starting materials and process parameters used in the methods further described in Examples 1 and 2. Table 3 summarizes the characterization of the compositions prepared according to Examples 1 and 2.

[0263] Table 2: Starting materials and process parameters for microparticle preparation

[0264] Table 3: Characterization of Particles

[0265] Example 1: Preparation of degarelix dihydroxynaphthol salt microparticles (compositions A to K)

[0266] The following methods are used to manufacture degarelck bis(hydroxynaphthyl) salt microparticles (compositions A to J): 1. Suitable PLGA particles were milled at -80°C using a cryogenic milling apparatus (ring milling) with a pore size of 250 μm (Table 2, “PLGA” and “Initial iv” columns). The Dv50 (or D(v, 0.5)) of the resulting PLGA particles was approximately 100 µm, as determined by wet laser diffraction. The polymer weight was determined by GPC (see Mw and Mn values ​​in Table 2).

[0267] 2. The appropriate amount of degarelic bis(hydroxynaphthalate) was pulverized and sieved through a 180-micron sieve. The Dv50 of the resulting particles was determined to be approximately 50 µm by wet laser diffraction.

[0268] 3. Mix an appropriate amount of degarelic bis(hydroxynaphthyl) salt (Table 2, "Degarelic Salt Amount" column) and an appropriate amount of PLGA polymer (Table 2, "PLGA Amount" column) using a three-dimensional shaking device at 101 min. -1 Mix at rpm for 1 minute to obtain the target drug load of degarelk free base (Table 2, “Target Drug Load” column).

[0269] 4. The resulting mixture is then extruded using an automatic feeder and an extruder, with the speed and temperature as shown in the "Extrusion Parameters" column of Table 2.

[0270] 5. Use a pelletizer to cut the extrudate into 0.5 mm or 2 mm pellets.

[0271] 6. Grind the granules into microparticles at -80°C using a low-temperature grinding equipment (ring mill).

[0272] 7. The microparticles were sieved through a 106 µm mesh. The particle size distribution was measured by wet laser diffraction (see Table 3).

[0273] 8. The microparticles were then initially dried at 30°C using alternating pressure for 15.5 h, as follows: 10 mbar for 55 min / 1000 mbar for 5 min, etc. The microparticles were subjected to drug loading tests (see Table 3) and filled into vials.

[0274] 9. Perform secondary drying at 30℃ for 24 h, followed by nitrogen inerting.

[0275] 10. The microparticles are then sterilized by irradiation with gamma or X-rays at a dose of 25 to 40 kGy.

[0276] The degarelix bis(hydroxynaphthyl)naphthyl acid microparticles of composition K (to be used in the clinical trial batch in Example 4) were manufactured using the following method: 1. Suitable PLGA particles were milled at -70°C using a cryogenic milling apparatus (ring milling) with a pore size of 250 μm (Table 2, “PLGA” and “Initial iv” columns). The Dv50 of the resulting PLGA particles was determined to be approximately 100 µm by wet laser diffraction. The polymer weight was determined by GPC (see Mw and Mn values ​​in Table 2).

[0277] 2. The appropriate amount of degarelic bis(hydroxynaphthalate) was pulverized and sieved through a 180 µm sieve. The Dv50 of the obtained particles was determined to be 105.7 µm by wet laser diffraction.

[0278] 3. Mix an appropriate amount of degarelix dihydroxynaphthyl salt (Table 2, “Degarelix Salt Amount” column) with an appropriate amount of PLGA polymer (Table 2, “PLGA Amount” column) using a three-dimensional shaker at 20 min-1 rpm for 1 minute to obtain the target drug load of the degarelix free base (Table 2, “Target Drug Loading” column).

[0279] 4. The resulting mixture is then extruded using an automatic feeder and an extruder, with the speed and temperature as shown in the "Extrusion Parameters" column of Table 2.

[0280] 5. Use a granulator to cut the extrudate into 0.5 mm pellets.

[0281] 6. Grind the granules into microparticles using a low-temperature grinding device (ring-shaped) at -100°C.

[0282] 7. The microparticles were sieved through a 106 µm sieve. The particle size distribution was measured by wet laser diffraction (see Table 3).

[0283] 8. The microparticles were then initially dried at room temperature (17 to 24 °C) using alternating pressure for 15.5 h, as follows: 3 h at 50 mbar / 12.5 h at less than 1 mbar. The microparticles were subjected to drug loading assays (see Table 3) and filled into vials.

[0284] 9. Perform secondary drying at room temperature (17 to 24°C) for 15 h, followed by nitrogen inerting.

[0285] 10. The microparticles are then sterilized by X-ray irradiation at a dose of 31.6 to 32.2 kGy.

[0286] Example 2 (Comparative): Microparticles of degarelix soluble salt (hydrochloride and acetate) formulations, and microparticles of degarelix dihydroxynaphthyl salt formulations.

[0287] Degarelcke acetate microparticles (compositions X and Y) were manufactured using the following method: 1. Suitable PLGA particles were ground at -80°C using a cryogenic grinding apparatus (ring grinding) with a pore size of 250 μm (Table 2, “PLGA” and “Initial iv” columns). The Dv50 of the resulting PLGA particles was approximately 100 µm as measured by wet laser diffraction.

[0288] 2. Mix an appropriate amount of degarelic acetate (Table 2, “Degarelic Salt Amount” column) with an appropriate amount of PLGA polymer (Table 2, “PLGA Amount” column) using a planetary ball mill for 3 min to obtain the target drug load of the degarelic free base (Table 2, “Target Drug Load” column).

[0289] 3. The resulting mixture is then extruded using an automatic feeder and an extruder, with the speed and temperature as shown in the "Extrusion Parameters" column of Table 2.

[0290] 4. Use a granulator to cut the extrudate into 2 mm pellets.

[0291] 5. Grind the granules into microparticles using a low-temperature grinding device (ring-shaped) at -80°C.

[0292] 6. The microparticles were sieved on a 106 µm sieve. The particle size was measured by wet laser diffraction (see Table 3).

[0293] 7. The microparticles were then initially dried at 30°C using alternating pressure for 15.5 h, as follows: 10 mbar for 55 min / 1000 mbar for 5 min, etc. The microparticles were subjected to drug loading tests (see Table 3) and filled into vials.

[0294] 8. Perform secondary drying at 30℃ for 24 h, followed by nitrogen inerting.

[0295] 9. Sterilize the microparticles by irradiation with gamma or X-rays at doses of 25 to 40 kGy.

[0296] Degarelk hydrochloride microparticles (composition Z) were manufactured using the following method: 1. PLGA (PLGA75 / 25 acid-terminated, iv 4.2 dL / g) particles were ground at -80°C using a cryogenic grinding apparatus (ring grinding) with a pore size of 250 μm. The Dv50 of the obtained PLGA particles was approximately 100 µm as measured by wet laser diffraction.

[0297] 2. Mix 1.6 g of degarelix hydrochloride with 3.4 g of PLGA using a three-dimensional shaker with 10 g of 5 mm stainless steel balls at 101 min-1 rpm for 1 minute to obtain a target drug loading of 33%, based on degarelix free base.

[0298] 3. The resulting mixture is then manually fed and extruded using an extruder, with the speed and temperature as shown in the "Extrusion Parameters" column of Table 2.

[0299] 4. Use a granulator to cut the extrudate into 2 mm pellets.

[0300] 5. Grind the granules into microparticles at -80°C using a low-temperature grinding equipment (ring mill).

[0301] 6. The microparticles were sieved through a 106 µm sieve. The particle size was measured by wet laser diffraction (see Table 3).

[0302] 7. The microparticles were then initially dried at 30°C using alternating pressure for 15.5 h, as follows: 10 mbar for 55 min / 1000 mbar for 5 min, etc. The microparticles were subjected to drug loading tests (see Table 3) and filled into vials.

[0303] 8. Perform secondary drying at 30℃ for 24 h, followed by nitrogen inerting.

[0304] 9. Sterilize microparticles by X-ray irradiation at doses of 25 k to 40 kGy.

[0305] Degarelix bis(hydroxynaphthyl) nanoparticles of composition W were prepared using the following method: 1. Degarelk dihydroxynaphthalate was pulverized and sieved through a 106 µm sieve. Particle size was measured by wet laser diffraction (see Table 3).

[0306] 2. Microparticles are sterilized by X-ray irradiation at doses of 25 to 40 kGy.

[0307] Example 3: In vivo pharmacokinetic profile of compositions A to J and W to Z in rats

[0308] In all the PK studies in this paper, sample analysis of degarelk concentration was performed as follows: degarelk was extracted from rat plasma using solid-phase extraction and the concentration was determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0309] All PK results tables (whether for individual concentrations or averages) are presented in a standard 3-digit format. "SD" stands for Standard Deviation (a statistical measure of the dispersion of a measurement dataset relative to its mean), while "CV%" stands for Coefficient of Variation (the ratio of the standard deviation to the mean), expressed as a percentage. CV shows the degree of variation relative to the population mean.

[0310] It should be understood that, in the context of this invention, the release of degarelix within the first 84 days (12 weeks) after administration is of particular interest.

[0311] a) PK Research 3 (PK3)

[0312] The microparticles of compositions A, X, and Y were suspended in physiologically acceptable aqueous carriers, as shown in Table 4 below.

[0313] In this study, a generic version of Gonax® for 12 weeks was used as a reference product, prepared as follows: 120 mg of degarelix acetate and mannitol lyophilized (in one vial of commercially available Firmagon starting dose) was reconstituted in water for injection to obtain a degarelix concentration of 60 mg / ml.

[0314] Table 4 CMC-Na: Sodium carboxymethyl cellulose; Tw80: Tween 80 On the day of treatment, the resulting suspension (aqueous carrier) was injected subcutaneously (SC) (TF4, TF8, and reference products) or intramuscularly (IM) (TF5) into male Sprague Dawley rats (5 to 6 weeks old) weighing 200 to 250 g at a single dose of degarelc at a concentration equal to 50 mg / kg. Plasma samples were collected after a specified time period, and degarelc concentrations were analyzed. The results are shown in Tables 8 and 9 of this paper. Figure 1 , Figure 2 and Figure 6 middle.

[0315] Data shows that, compared with the reference product, both test formulations (TF4 and TF8) have lower C-values. max Value. Please see in particular. Figure 2 Its display is the same as Figure 1 Same data, but focusing on the first 10 days after application.

[0316] Compared to TF4 (PLGA microparticles containing degarelix acetate) and the reference product, TF8 (PLGA microparticles containing degarelix dihydroxynaphthyl salt) showed higher plasma concentrations (after approximately 7 days) and longer release.

[0317] b) PK Research 4 (PK4)

[0318] Compositions A, B, W, and Z were suspended in physiologically acceptable aqueous carriers, as shown in Table 5 below.

[0319] In this study, commercially available Gonax® 12-week was used as a reference product. The contents of one vial (i.e., 240 mg lyophilized degarelix acetate and mannitol) were reconstituted and dissolved in water for injection to obtain a degarelix concentration of 60 mg / mL.

[0320] Table 5

[0321] On the day of treatment, the resulting suspension was injected subcutaneously (reference product) or intramuscularly (TF6, 8, 9) into male Sprague Dawley rats (5 to 6 weeks old) weighing 200 to 250 g at a single dose equal to 50 mg / kg degarelc. Due to technical issues, TF5 was administered at a dose of 25 mg / kg degarelc. Plasma samples were collected at specified time intervals and degarelc concentrations were analyzed. Assuming dose-proportionality, the concentrations measured with TF5 were multiplied by 2. The results are shown in Tables 10 to 15 of this paper. Figure 3 , Figure 4 , Figure 5 and Figure 6 middle.

[0322] Data shows that, compared to the reference product, C max Compared to the values, the C values ​​of the tested formulations TF6, TF8, and TF9 were... max The value is low. Please refer to the following for details. Figure 4 Its display is the same as Figure 3 Same data, but focusing on the first 7 days after application.

[0323] TF6 (Composition B: PLGA microparticles containing degarelix dihydroxynaphthyl salt) showed higher plasma concentration profile and exposure compared to TF9 (Composition Z: PLGA microparticles containing degarelix HCl salt), which had a similar concentration profile to the reference product.

[0324] Compared to TF8 (composition W: PLGA-free degarelix dihydroxynaphthyl acid microparticles), TF6 (composition B: PLGA microparticles containing degarelix dihydroxynaphthyl acid) also showed higher plasma concentration profiles and exposure over the first 84 days.

[0325] Figure 6 This study compares two PK groups from the PK3 and PK4 studies: PK3-TF5 (PLGA microparticles containing degarelc acetate, aqueous carrier, intramural administration) and PK4-TF5 (PLGA microparticles containing degarelc bis(hydroxynaphthyl)ate, aqueous carrier, intramural administration). Data show that PK4-TF5 had a lower Cmax value than PK3-TF5, but compared to PK3-TF5, PK4-TF5 showed lower Cmax values ​​at approximately day 34 and day 84 (Cmax values ​​were lower). 84 (It shows a higher plasma concentration at this time.)

[0326] c) PK Research 5 (PK5)

[0327] Compositions C, D, and E were suspended in physiologically acceptable aqueous or oily carriers, as shown in Table 6 below.

[0328] Commercially available Firmagon® was used as a reference product in this study. The contents of one vial of the starting dose (i.e., 120 mg lyophilized degarelix acetate and mannitol) were reconstituted and dissolved in water for injection to obtain a starting dose of 40 mg / mL for animals. The contents of one vial of the maintenance dose (i.e., 80 mg lyophilized degarelix acetate and mannitol) were reconstituted and dissolved in water for injection to obtain a maintenance dose of 20 mg / mL for animals. See also Table 6.

[0329] Table 6

[0330] On the day of treatment, the resulting suspension was injected intramuscularly (TF2, TF4, TF6 and TF7) or subcutaneously (reference product and TF3) into male Sprague Dawley rats (5 to 6 weeks old) weighing 200 to 250 g at a single dose of 50 mg / kg of degarelix.

[0331] The reference product was administered subcutaneously on day 1 (30 mg / kg), day 28 (10 mg / kg), and day 56 (10 mg / kg) to simulate the starting and maintenance doses of the commercially available product Firmagon®.

[0332] For the reference product, because the animals in the Firmagon® group gained weight between the first and last administrations, and the dosage was based on mg / kg, the degarelix concentration was adjusted to ensure that the total dose per animal over 12 weeks (84 days) was equal to the total dose in the test formulation group. (The concentration of the first dose was not adjusted, while the concentrations of the second and third doses were adjusted based on the initial animal weight to ensure that the total amount of degarelix was the same for each animal.)

[0333] Plasma samples were collected and degarelic concentrations were analyzed after a specified time period. Results are shown in Tables 16 to 19 of this paper. Figure 7 , Figure 8 and Figure 9 middle.

[0334] In this embodiment, special attention should be paid to Cmax when using Firmagon® as a reference product. In fact, because Firmagon® is formulated for administration at 1-month intervals, it must be administered three times, while the test formulation maintains release for 3 months (12 weeks, 84 days) with a single administration.

[0335] As stated above, the total dose over 12 weeks was the same for both the reference product Firmagon® and the test formulation (i.e., 50 mg / kg). However, the initial dose of Firmagon (30 mg / kg) was relatively lower than that of the test formulation (50 mg / kg). Consequently, the burst releases observed in the first few days, including the maximum concentration (Cmax) values, were substantially significantly lower for the test formulations TF2, TF3, TF4, and TF6 (when dose-normalized).

[0336] TF2 (PLGA microparticles containing degarelix dihydroxynaphthyl salt of composition C, DL 32.9%, in an oily carrier, administered IM) showed higher plasma concentrations than TF3 (composition C, in an oily carrier, administered SC) and TF4 (composition C, in an aqueous carrier, administered IM). Within 84 days post-administration, the exposure (expressed as area under the curve (AUC)) of TF2 was higher than that of the reference product. The exposure (AUC) of TF3 was similar to that of the reference product. TF4 showed a lower AUC than both TF2 and the reference product.

[0337] TF6 (Composition D: PLGA microparticles containing degarelic bis(hydroxynaphthyl) salt, DL 28%, in an oily carrier, IM application) showed a particularly favorable PK profile.

[0338] Within the first 84 days after application, TF6 and TF7 showed higher exposures than the reference product.

[0339] TF7 (Composition E: PLGA microparticles containing degarelix dihydroxynaphthyl salt, DL 43.3%, in an oily carrier, applied in IM) has a higher C than TF6 and the reference product. max Values. Within the first 84 days after administration, TF7 showed similar exposure to TF6, but with persistently lower plasma concentrations. These values ​​observed for TF7 indicate that the drug load in composition E may be too high.

[0340] d) PK Research 8 (PK8)

[0341] Compositions F to J were suspended in physiologically acceptable oily carriers, as shown in Table 7 below.

[0342] Table 7

[0343] On the day of treatment, the resulting suspension was administered intramuscularly to male Sprague Dawley rats (5 to 6 weeks old) weighing 200 to 250 g at a single dose of degarelc at a concentration of 50 mg / kg. Plasma samples were collected after a specified time period, and degarelc concentrations were analyzed. The results are shown in Tables 20 to 25. Figure 10 , Figure 11 and Figure 12 middle.

[0344] TF1 (Formulation F: PLGA IV 0.42, containing microparticles of degarelix dihydroxynaphthyl salt, DL 32.3%, in an oily carrier, administered via IM) showed a particularly favorable PK profile.

[0345] TF1, TF3, and TF4 (Formulations F, G, and H: all microparticles contain degarelic acid dihydroxynaphthyl salt, have similar DL values, and exhibit PLGA initial intrinsic viscosity (intrinsic iv) varying between 0.33 and 0.50 in an oily carrier, administered via IM) show similar C max Similar exposure (slightly higher TF1), similar plasma concentrations on day 84 (C 84 The concentration levels, along with similar sustained concentration levels, indicate that the intrinsic viscosity range of the tested PLGA is acceptable.

[0346] Considering variability, TF1 also showed similarly slightly higher plasma levels and exposures compared to TF6 (Formulation I: PLGA microparticles containing degarelic acid to dihydroxynaphthyl salt in a ratio of 2.06:1, in an oily carrier, administered IM) and TF7 (Formulation J: PLGA microparticles containing degarelic acid to dihydroxynaphthyl salt, DL 34.3%, in an oily carrier, administered IM), indicating that the tested degarelic acid to dihydroxynaphthyl salt ratio and drug load (DL) were acceptable.

[0347] Table 8: PK3 plasma concentrations in individuals (B1, B4: animals that died after day 84)

[0348] Table 9: Individual and average PK parameters of PK3 individuals

[0349] Table 10: Individual PK4 Concentration

[0350] Table 11: Individual and average PK parameters for PK4 individuals

[0351] Table 12: Individual plasma concentrations of PK4

[0352] Table 13: Individual and average PK parameters for PK4 individuals

[0353] Table 14: Individual plasma concentrations of PK3 and PK4 (--- Dead rats)

[0354] Table 15: Individual and mean PK parameters for PK4 and PK3

[0355] Table 16: Individual PK5 Concentration

[0356] Table 17: Individual and Mean PK Parameters for PK5

[0357] Table 18: Individual PK5 Concentrations (--- Not Sampled)

[0358] Table 19: Individual and Average PK Parameters for PK5

[0359] Table 20: PK8 Individual Plasma Concentration

[0360] Table 21: Individual and average PK parameters of PK8 individuals

[0361] Table 22: Individual PK8 Concentration

[0362] Table 23: Individual PK8 Parameters and Average PK Parameters

[0363] Table 24: Individual PK8 Concentration

[0364] Table 25: Individual and average PK parameters of PK8 individuals

[0365] Example 3: Clinical Trial

[0366] A Phase 2, randomized, open-label, dose-discovery study of degarelix 12-week extended-release formulation (composition K, 200 or 300 mg degarelix in dihydroxynaphthyl salt form, in MIGLYOL® 812 N) [the investigational formulation] will be conducted in participants with locally advanced / metastatic prostate cancer. This study will evaluate the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety, and tolerability of the investigational formulation.

[0367] This study can recruit up to three cohorts. Each cohort can be closed after recruiting approximately 20 participants. Before starting a cohort at a higher dose level, at least six participants must be recruited in cohort 1 and followed up for 28 days.

[0368] Cohort 1: Participants will receive a single intramuscular (IM) administration of 200 mg (calculated as degarelk free base) of the study formulation.

[0369] Initially, six participants will be recruited into Cohort 1 (200 mg), after which recruitment will be paused. Four weeks after the administration of the study formulation to the last recruited participant, all PK, PD, and safety data collected up to that point will be analyzed. If the safety and PK / PD data from the first six participants are deemed adequate, recruitment into Cohort 1 will resume and parallel recruitment into Cohort 2 (300 mg) will be initiated in parallel. Therefore, once Cohort 2 is initiated, participants can be randomized to both Cohort 1 and Cohort 2.

[0370] Cohort 2: Participants will receive a single IM administration of 300 mg (calculated as degarelix base) of the study formulation.

[0371] For cohorts 1 and 2, the study consisted of a screening period of up to 5 weeks, a treatment period of up to 12 weeks, and a follow-up period of up to 12 weeks, which included safety follow-up (SFU) and one or more additional pharmacokinetic (PK) assessments. After the 12-week treatment period, participants were to continue with standard of care (SoC, i.e., SoC without or containing degarelix) at the researchers' discretion.

[0372] - Participants who receive a SoC without degarelk after EOT will continue to participate in the study and undergo safety and PK assessments until day 169, which will mark the end of study for these participants (EOS).

[0373] Participants receiving a degarelic-containing SoC after EOT will have a 4-week SFU and an EOS on day 113. The SFU visit and additional PK assessment on day 113 will represent these participants' EOS. These participants should be converted to a degarelic-containing SoC after EOS. Participants may receive a degarelic-containing SoC after EOT if medically necessary.

[0374] If, based on preliminary data (PK, PD, efficacy, and safety) from Cohort 1 and Cohort 2, a higher or alternative dose is deemed necessary, Cohort 3 will be initiated. The maintenance status of participants in Cohort 1 and Cohort 2 will be periodically assessed based on testosterone levels and castration outcomes in each cohort.

[0375] Cohort 3: Dosage selection for this cohort will be guided by population PK / PD modeling and simulation derived from PK and PD data from Cohorts 1 and 2, as well as safety and efficacy data from those cohorts. Based on preliminary assumptions, the provisional dose levels for this cohort are: a loading dose (IM) of 400 mg (calculated as degarelk free base) of the study formulation at study initiation (day 1) (200 mg in two injections), followed by a maintenance dose (IM) of 200 mg (calculated as degarelk free base) 12 weeks after the loading dose (i.e., day 85). The doses selected for Cohort 3 will be documented in the proceedings of the Study Commissioner Data Review Committee (DRC).

[0376] For cohort 3, the study consists of a screening period of up to 5 weeks, a treatment period of 24 weeks, and a SFU period of 4 weeks. For participants who have completed the expected study duration, EOS will be performed after the 4-week SFU period. After the treatment period, participants should receive SoC treatment at the discretion of the researchers.

[0377] Treatment completed: Cohort 1 and Cohort 2: End of treatment (EOT) visits will occur 12 weeks (i.e., day 85) after administration of the study formulation, or earlier if early termination occurs before EOT.

[0378] Cohort 3: The EOT visit will occur 12 weeks (i.e., day 169) after the maintenance dose of the study formulation, or earlier if early termination occurs before the EOT.

[0379] For all cohorts, participants who do not reach castration testosterone levels (< 50 ng / dL) by day 29 will receive a SoC (i.e., a SoC without or containing degarelic acid) at the researcher's discretion. Testosterone levels will be assessed locally to facilitate timely decision-making. An EOT visit will occur before switching to a new therapy.

[0380] Goal, endpoint, and measurement

[0381] Table 26 below presents the primary, secondary, and exploratory objectives of the study, as well as the measures taken (endpoints, populations, treatments, summative measurements, and intercurrent events).

[0382] Table 26

[0383] Abbreviations: ADA: Anti-drug antibody; AESI: Adverse events of particular interest; AUC 84d Area under the concentration-time curve over 12 weeks; C 84d Concentration at 12 weeks; CI: confidence interval; C max Maximum concentration; CV: Coefficient of variation; ECG: Electrocardiogram; EOS: End of study; FSH: Follicle-stimulating hormone; IM: Intramuscular; LH: Luteinizing hormone; Max: Maximum value; Min: Minimum value; NCI-CTCAE: National Cancer Institute Common Terminology Standard for Adverse Events; PD: Pharmacodynamics; PK: Pharmacokinetics; PSA: Prostate-specific antigen; SD: Standard deviation; TEAE: Treatment-induced adverse events; VAS: Visual Analogue Scale.

[0384] Study population

[0385] Participants (approximately N=20 per cohort) were histologically diagnosed with locally advanced / metastatic prostate cancer and were candidates for androgen deprivation therapy (ADT).

[0386] Inclusion criteria

[0387] The following inclusion criteria must be met during the screening process: 1. The participants were histologically diagnosed with locally advanced / metastatic prostate cancer.

[0388] 2. Obtain a signed and dated written informed consent form before conducting any research-specific procedures.

[0389] 3. Participants were identified by researchers as candidates for continuous ADT.

[0390] 4. At the screening visit, the baseline morning serum testosterone level is >150 ng / dL.

[0391] 5. Age ≥ 18 years old.

[0392] 6. The Eastern Cooperative Oncology Group (ECOG) has a daily fitness level of 0 to 2.

[0393] 7. Life expectancy of at least 6 months.

[0394] 8. Possessing sufficient bone marrow, liver, and kidney function at the screening visit: a. Hemoglobin ≥10 g / dL, b. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (for patients with Gilbert's syndrome, total bilirubin ≤ 3 times ULN is permissible). c. AST ≤ 2.5 times ULN, and / or ALT ≤ 2.5 times ULN, d. Absolute neutrophil count ≥1500 cells / µL and platelet count ≥100,000 cells / µL, e. Glomerular filtration rate ≥50 mL / min, estimated based on the Chronic Kidney Disease Epidemiology Collaboration-Creative Creatinine (CKD-EPIcr) formula.

[0395] 9. Participants must agree to use an acceptable method of contraception: a. Sexually active men, including those who have undergone vasectomy, must agree to use condoms during intercourse or to refrain from having children and donating sperm during the treatment period and for six months after the last administration of the study agent.

[0396] b. Female partners of participants should use highly effective methods of contraception (achieving a failure rate of <1% per year when used consistently and correctly), including but not limited to hormonal contraception (combined hormonal contraceptives [containing estrogen and progestin] associated with ovulation suppression [oral, vaginal, transdermal], progestin-only hormonal contraceptives associated with ovulation suppression [oral, injectable, implantable]), intrauterine devices (IUDs), intrauterine hormone-releasing systems, bilateral tubal occlusion / ligation, and abstinence throughout the study period (only for those consistent with the participant's usual lifestyle). Regular abstinence (e.g., calendar method, symptomatic temperature method, post-ovulation method) and withdrawal are not considered highly effective methods and are unacceptable.

[0397] c. If the female partner has a history of IUD or intrauterine system (IUS) insertion, a barrier method (condoms with spermicidal foam / gel / film / cream / suppository) should also be used.

[0398] 10. Willing and able to comply with scheduled visits, treatment plans, laboratory tests and other research procedures.

[0399] Exclusion criteria

[0400] Participants with any of the following conditions are ineligible to participate in this study: 1. Prior to the start of screening, the duration of previous ADT (neoadjuvant therapy or adjuvant hormone therapy) was ≥6 months and the interval between treatments was <6 months.

[0401] 2. Indications for androgen deprivation combination therapy.

[0402] 3. History of bilateral orchiectomy, adrenalectomy, or pituitary resection.

[0403] 4. Received chemotherapy or cryotherapy within 8 weeks prior to screening for prostate cancer treatment.

[0404] 5. Cardiovascular function: a. During the screening period, the QTc interval is > 450 ms (using the Fridricia formula).

[0405] b. A known history of torsades de pointes ventricular tachycardia.

[0406] c. Currently taking medications with warnings / precautions regarding QT interval prolongation.

[0407] d. Significant cardiovascular risk conditions: heart attack or stroke within the past 6 months; arrhythmia; uncontrolled hypertension.

[0408] 6. Used exogenous testosterone within 6 months prior to the start of screening.

[0409] 7. Had major surgery (including prostate cancer surgery) within 4 weeks prior to the start of screening.

[0410] 8. Uncontrolled symptomatic congestive heart failure (New York Heart Association Class III and IV), unstable angina, arrhythmia, or uncontrolled atrial fibrillation.

[0411] 9. Uncontrolled type 1 diabetes or uncontrolled type 2 diabetes (controlled with hypoglycemic agents is permitted).

[0412] 10. Have been diagnosed with or treated for active cancer (excluding prostate cancer or non-melanoma skin cancer) within the past 2 years.

[0413] 11. Participation in a previous clinical study involving the investigational treatment or any other type of medical research within 4 weeks prior to the start of screening or within 5 half-lives of the investigational product (whichever is longer).

[0414] 12. Any serious medical or mental illness, social condition, persistent illness or ailment (including drug or alcohol abuse) that, in the researcher's judgment, may affect the ability to comply with protocol requirements or give informed consent.

[0415] 13. Any other situation that, in the researcher's judgment, prevents a patient from participating in the clinical study due to safety concerns or compliance with clinical study procedures.

[0416] 14. Known allergy to degarelix or any excipients in the investigational formulation.

[0417] Study formulation, dosage and administration method

[0418] The study formulation is a 12-week extended-release formulation consisting of PLGA microparticles containing degarelix dihydroxynaphthyl salt of composition K, for intramuscular (IM) injection. The intended dose strengths are 200 and 300 mg, in single-dose vials containing powder for injection suspension. Prior to injection, the powder in each vial is suspended in an oily carrier (medium-chain triglyceride, MIGLYOL® 812 N).

[0419] Queues 1 and 2: Participants will receive a single injection of the study formulation at the start of the study (day 1), at a dose of 200 mg (cohort 1) or 300 mg (cohort 2).

[0420] Queue 3: As stated above, the dose selection for this cohort will be guided by population PK / PD modeling and simulation derived from PK and PD data from cohorts 1 and 2, as well as safety and efficacy in these cohorts. Based on preliminary assumptions, the provisional dose levels for this cohort are: a loading dose of 400 mg (two 200 mg injections) of the study formulation at the start of the study (day 1), followed by a maintenance dose of 200 mg (IM) 12 weeks after the loading dose (i.e., day 85).

[0421] Treatment duration

[0422] Cohort 1 and Cohort 2: The treatment period consisted of 84 days.

[0423] Cohort 3: The treatment period consisted of 168 days.

[0424] Overall research concluded: The overall EOS is defined as the date of the last visit of the last research participant.

Claims

1. A pharmaceutical composition comprising degarelic acid in the form of a dihydroxynaphthyl salt, wherein the degarelic acid dihydroxynaphthyl salt is contained in microparticles of a biodegradable copolymer (PLGA) of lactide and glycolide units, and wherein said microparticles comprise at least 50 wt% PLGA and about 20 wt% to about 34 wt% of free base equivalent of degarelic acid.

2. The pharmaceutical composition of claim 1, wherein the PLGA has a molar ratio of lactide units to glycolide units of about 75:25 to about 85:

15.

3. The pharmaceutical composition of claim 1 or 2, wherein the microparticles comprise about 55 to about 75 wt% PLGA, about 60 to about 70 wt% PLGA, or about 60 to about 65 wt% PLGA.

4. The pharmaceutical composition of any of the preceding claims, wherein the initial intrinsic viscosity (iv) of the PLGA is about 0.3 dL / g to about 0.5 dL / g, or about 0.35 dL / g to about 0.45 dL / g.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the particles have a particle size distribution as defined below: D(v,0.1) is approximately 5 to approximately 22 µm D(v,0.5) is approximately 25 to approximately 45 µm D(v,0.9) is approximately 55 to approximately 90 µm.

6. The pharmaceutical composition according to any one of the preceding claims further comprises a carrier, said carrier being an aqueous carrier or an oil-based carrier.

7. The pharmaceutical composition as claimed in any of the preceding claims, wherein the microparticles are microparticles.

8. The pharmaceutical composition of any one of the preceding claims, wherein the microparticles comprise about 28 wt% to about 33 wt% of degarelix free base equivalent.

9. A pharmaceutical composition according to any one of claims 1 to 8, used for the treatment of prostate cancer.

10. The pharmaceutical composition of claim 9, wherein the composition is to be administered once every 12 weeks.

11. The pharmaceutical composition for use as described in claim 9 or 10, wherein degarelix is ​​administered in an amount of about 200 mg to about 360 mg free base equivalent per dose, particularly about 200 mg to about 300 mg free base equivalent per dose.

12. The pharmaceutical composition for any one of claims 9 to 11, wherein degarelix is ​​continuously released from the microparticles, thereby reducing and maintaining serum testosterone levels to castration levels for at least 12 weeks.

13. The pharmaceutical composition for use according to any one of claims 9 to 12, wherein the average degarelix plasma concentration on day 1 to day 7 after administration is less than 100 ng / mL, less than 80 ng / mL, less than 60 ng / mL, less than 50 ng / mL, less than 40 ng / mL, or less than 30 ng / mL.

14. A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, comprising: (a) Degarelk in pharmaceutically acceptable form of dihydroxynaphthyl salt, particularly in powder form, is mixed with a biodegradable copolymer (PLGA) of lactide and glycolide units, particularly the biodegradable copolymer in powder form; (b) The mixture is gradually heated and extruded; (c) Granulate the obtained extrudate; (d) Granules obtained by grinding at low temperature.

15. A kit comprising a device, such as a pre-filled syringe, containing the pharmaceutical composition of any one of claims 1 to 8, and instructions for use.

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