Crystalline nanoparticles containing enzalutamide

Abstract

The present invention relates to compositions comprising or consisting essentially of (i) nanoparticles comprising or consisting essentially of enzalutamide in crystalline form, and (ii) one or more physiologically acceptable polymers and / or copolymers. The present invention also relates to processes for the preparation of such compositions, pharmaceutical dosage forms comprising or made from such compositions, and the use of such pharmaceutical dosage forms for medical purposes.

Description

[Technical Field]

[0001] Priority is claimed to European Patent Application No. 23152127.9, filed January 18, 2023.

[0002] The present invention relates to compositions comprising or consisting essentially of (i) nanoparticles comprising or consisting essentially of enzalutamide in crystalline form, and (ii) one or more physiologically acceptable polymers and / or copolymers. The present invention also relates to processes for the preparation of such compositions, pharmaceutical dosage forms comprising or made from such compositions, and the use of such pharmaceutical dosage forms for medical purposes.

[0003] Enzalutamide is an androgen receptor signaling inhibitor used as a drug for treating castration-resistant prostate cancer (US Pat. No. 7,709,517). Enzalutamide is a BCS Class II drug, i.e., it exhibits high permeability but low solubility. Enzalutamide is commercially available as soft gel capsules and tablets (brand name "XANDI®"). Soft gel capsules are filled with a liquid containing 40 mg of enzalutamide and pharmaceutical excipients per capsule. Tablets contain 40 or 80 mg of enzalutamide and pharmaceutical excipients per tablet. The daily dosage is typically 160 mg, so patients need to take four capsules, four 40 mg tablets, or two 80 mg tablets per day. A suitable single tablet of reasonable size containing a prescribed amount of enzalutamide and with suitable and advantageous solubility and / or dissolution stability and absorption would be advantageous as a suitable alternative to commercially available soft gel capsules and tablets. Such a tablet should result in improved patient compliance and a reduced incidence of medication errors.

[0004] WO2014 / 043208A1 provides formulations of enzalutamide and their use for treating hyperproliferative disorders.

[0005] US2015 / 0239848A1 relates to enzalutamide polymorphic forms and their preparation.

[0006] V. Wilson et al., Journal of Controlled Release, 292 (2018) 172-182, reported on amorphous solid dispersions of enzalutamide prepared using the hydrophilic polymers hydroxypropyl methylcellulose acetate succinate and copovidone (PVP / VA). The formulations were tested in vivo in rats using oral administration of the amorphous solid dispersions. Amorphous solid dispersions that underwent crystallization exhibited lower plasma exposure. Differences were also observed between amorphous solid dispersions that dissolved to form nanosized amorphous drug aggregates and those that dissolved to yield only a supersaturated solution, with the former exhibiting superior plasma exposure. The authors conclude that these observations highlight the importance of fully understanding the phase behavior of amorphous drug formulations after dissolution and the need to distinguish between different types of precipitation for the formation of nanosized amorphous aggregates, specifically crystallization and glass-liquid phase separation.

[0007] Methods for producing microparticles and nanoparticles are described in various patent applications and patents, for example US 5,833,891, US 5,534,270, US 6,862,890, US 6,177,103, DE10 2005 053 862, US 5,833,891, US 5,534,270, US 6,862,890, US 6,177,103, DE10 2005 017 777 and DE10 2005 053 862.

[0008] Ch. Thangavel et al., Mol. Pharm. 2018, 15(5), 1778-1790, relates to anti-PSMA conjugate hybrid antiandrogen nanoparticles and their therapeutic efficacy and cytotoxicity.

[0009] WO 02 / 60275 A1 describes a method for producing nanoparticles in which two immiscible liquids are charged to achieve encapsulation. This does not preclude the use of toxic substances, which can result in significant impairment of product quality. Furthermore, this method does not allow for particle size control.

[0010] US2009 / 0214655A1 also describes the use of two immiscible liquids. While a microreactor is used to generate nanoparticles, only emulsion production is described. Furthermore, the nanoparticles are produced in a liquid-filled space, again making it impossible to control either particle size or particle properties. Furthermore, due to the fact that the reaction takes place in a microchannel, the device may be prone to clogging.

[0011] The dissolution rate of a pharmaceutical active ingredient generally depends on the available surface area. Particle size reduction can be used to increase the surface area and dissolution rate; and can also increase solubility. Solubility can also be increased by providing the pharmaceutical active ingredient in amorphous form. Therefore, particle size reduction and amorphization are effective approaches to improve the bioavailability of pharmaceutical active ingredients with low solubility. Unfortunately, amorphous materials tend to crystallize during processing, storage, or administration. Crystallization can also adversely increase particle size.

[0012] WO2014 / 041487A2 relates to crystalline and amorphous forms of enzalutamide. The present application further relates to an amorphous solid dispersion of enzalutamide with a pharmaceutically acceptable carrier. The present application also relates to processes for preparing crystalline forms R1 and R2, amorphous forms, and amorphous solid dispersions of enzalutamide.

[0013] WO2019 / 030691A1 relates to an extruded pharmaceutical composition for oral administration of enzalutamide. The extruded composition includes one or more suitable polymers and is prepared using twin-screw extrusion or hot-melt extrusion. A method for preparing such a composition is also provided. The extruded composition can be used to treat prostate cancer.

[0014] WO2020 / 234448A1 relates to nanoparticles comprising enzalutamide, processes for the preparation of such nanoparticles, pharmaceutical compositions and pharmaceutical dosage forms comprising such nanoparticles, processes for the preparation of such pharmaceutical dosage forms, and the use of pharmaceutical dosage forms for medical purposes.

[0015] Controlled Expansion of Supercritical Solutions (CESS™) is a known process for producing nanoparticles of pharmacologically active ingredients. The CESS™ process was developed by Professor Jouko Yliruusi and Professor Edward Haggstrom of the University of Helsinki and Nanoformat Finland Oyj. The controlled process produces small, uniformly sized particles that are made directly from solution without the use of excipients. For more details, see, for example, J. Pessi et al., "Controlled Expansion of Supercritical Solution: A Robust Method to Produce Pure Drug Nanoparticles With Narrow Size-Distribution," J Pharm Sci 2016, 105(8), 2293-7; WO2016 / 055696; and WO2021 / 152204.

[0016] The properties of known formulations of enzalutamide are not satisfactory in all respects, and there is a need for pharmaceutical formulations and dosage forms containing enzalutamide that are advantageous over the prior art, e.g., with respect to drug loading (wt.%), dose strength (mg), loading dose, dosage form size, patient compliance, patient safety from medication errors, and / or ease of manufacture.

[0017] Therefore, it is an object of the present invention to provide pharmaceutical formulations and oral dosage forms containing enzalutamide that are advantageous over the prior art. In one aspect, the present invention aims to provide pharmaceutical formulations and dosage forms that provide immediate release of enzalutamide. In another aspect, the present invention aims to provide pharmaceutical formulations and oral dosage forms containing relatively high doses of enzalutamide, preferably 160 mg or more per dosage form. It is desirable to provide swallowable 160 mg tablets, i.e., tablets having a total weight of about 1000 mg or less and thus a drug load of at least about 16 wt.%. In yet another aspect, the present invention aims to provide pharmaceutical formulations and oral dosage forms containing enzalutamide, preferably exhibiting high bioavailability upon oral administration. In yet another aspect, the present invention aims to provide pharmaceutical formulations and oral dosage forms that are easy to manufacture and stable.

[0018] These objects have been achieved by the subject matter of the claims.

[0019] Enzalutamide nanoparticles can be obtained from a solution of enzalutamide in supercritical CO2 by CESS™ technology. These nanoparticles were found to contain enzalutamide in amorphous form (amorphous nanoparticles).

[0020] Furthermore, it has surprisingly been found that suspending nanoparticles containing enzalutamide in amorphous form (amorphous nanoparticles) in an aqueous solution of a suitable polymer and / or copolymer, such as copovidone (PVP / VA), induces the crystallization of enzalutamide; the nanoparticles thus obtained contain enzalutamide in crystalline form (crystalline nanoparticles). This is unusual, as traditional polymer excipients are expected to tend to stabilize the amorphous form but not induce or promote its crystallization. Aqueous solutions of other polymers, such as HPMC or HPMC-AS, do not induce the crystallization of enzalutamide.

[0021] Furthermore, it has been surprisingly found that by selecting appropriate conditions, crystallization can be controlled and undesired growth of crystalline nanoparticles can be prevented.When amorphous nanosized enzalutamide is crystallized by contacting it with an aqueous solution containing one or more polymers and / or copolymers to form a suspension or slurry, uncontrolled crystal growth can be avoided or at least mitigated.Therefore, the size of nanoparticles containing amorphous enzalutamide (amorphous nanoparticles) is not significantly increased by inducing crystallization under appropriate conditions.Crystallization and crystal growth are controlled by suitable polymers and / or copolymers in the solution, preferably an aqueous solution.

[0022] Furthermore, it has surprisingly been found that, depending on the size, concentration and excipients, it is possible to prepare nanoparticles (crystalline nanoparticles) containing enzalutamide in crystalline form that disperse completely or almost completely from suspension into gastric fluid, thereby indicating that such crystalline nanoparticles are likely to provide good bioavailability of enzalutamide upon in vivo administration.

[0023] The present invention achieves high bioavailability of enzalutamide by providing it in nanoparticle form, where the crystalline enzalutamide nanoparticles do not tend to increase in size during storage. The nanoparticles are contained in a composition further comprising one or more physiologically acceptable polymers and / or copolymers. The content of enzalutamide in the composition may be quite high. The content of one or more physiologically acceptable polymers and / or copolymers does not need to exceed the content of enzalutamide by an order of magnitude to achieve beneficial effects. As a result, the composition has a high drug load (wt.%), dose strength (mg), and / or loading dose, and a reasonable size, which makes it useful as an intermediate for the preparation of pharmaceutical dosage forms that facilitate manufacturing and improve patient compliance and safety.

[0024] A first aspect of the present invention is - nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; - one or more physiologically acceptable polymers and / or copolymers; and - optionally one or more physiologically acceptable surfactants; the nanoparticles have a z-average particle size of up to 800 nm; and The composition relates to a composition in which the relative weight ratio of the total amount of enzalutamide to the total amount of one or more physiologically acceptable polymers and / or copolymers is within the range of 5.0:1.0 to 1.0:5.0.

[0025] For the purposes of this specification, a distinction is made between nanoparticles that comprise or essentially consist of enzalutamide in crystalline form (also referred to as "crystalline nanoparticles") and nanoparticles that comprise or essentially consist of enzalutamide in amorphous form (also referred to as "amorphous nanoparticles").

[0026] All components of the composition do not need to be in crystalline form.In particular, one or more physiologically acceptable polymers and / or copolymers, and one or more physiologically acceptable surfactants that are optionally present, are typically not present in crystalline form.In a preferred embodiment, one or more physiologically acceptable polymers and / or copolymers, and one or more physiologically acceptable surfactants that are optionally present, are dissolved in the liquid phase of slurry or suspension, even if they are not present in solid form, and in addition, the liquid phase contains crystalline nanoparticles as a solid phase.

[0027] Amorphous nanoparticles are preferably used as starting material for the preparation of crystalline nanoparticles. The crystalline and amorphous nanoparticles preferably consist essentially of enzalutamide.

[0028] Unless otherwise specified, all percentages are by weight.

[0029] Unless otherwise specified, "consisting essentially of" means to the extent of at least 98%, preferably at least 99%, and more preferably about 100%. [Brief explanation of the drawings]

[0030] [Figure 1] A shows electron micrographs at a magnification of 25,000x of crystalline nanoparticles of enzalutamide obtained by stirring amorphous nanoparticles of enzalutamide in aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%, respectively. B shows electron micrographs at a magnification of 5,000x of crystalline nanoparticles of enzalutamide obtained by stirring amorphous nanoparticles of enzalutamide in aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%, respectively. [Figure 2]A shows electron micrographs at a magnification of 25,000x of crystalline nanoparticles of enzalutamide obtained by stirring amorphous nanoparticles of enzalutamide in aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%, respectively. B shows electron micrographs at a magnification of 5,000x of crystalline nanoparticles of enzalutamide obtained by stirring amorphous nanoparticles of enzalutamide in aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%, respectively. [Figure 3] A shows electron micrographs at a magnification of 25,000x of crystalline nanoparticles of enzalutamide obtained by stirring amorphous nanoparticles of enzalutamide in aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%, respectively. B shows electron micrographs at a magnification of 5,000x of crystalline nanoparticles of enzalutamide obtained by stirring amorphous nanoparticles of enzalutamide in aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%, respectively. [Figure 4] A shows electron micrographs at a magnification of 25,000x of crystalline nanoparticles of enzalutamide obtained by stirring amorphous nanoparticles of enzalutamide in aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%, respectively. B shows electron micrographs at a magnification of 5,000x of crystalline nanoparticles of enzalutamide obtained by stirring amorphous nanoparticles of enzalutamide in aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%, respectively. [Figure 5] 1 shows XRPD spectra of crystalline nanoparticles of enzalutamide obtained from aqueous solutions of PVP-VA at concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.%. [Figure 6] Figure 1 shows the z-average particle size of crystalline nanoparticles obtained after mixing with an aqueous solution of PVP-VA under various conditions. [Figure 7] Figure 1 shows the z-average particle size of crystalline nanoparticles obtained after mixing with an aqueous solution of PVP-VA under various conditions. [Figure 8] 1 shows the XRPD intensity counts of crystalline nanoparticles of enzalutamide obtained from a suspension (slurry) of an aqueous PVA-VA solution containing 30 wt.% enzalutamide and 30 wt.% PVP-VA at different mixing times. [Figure 9] 1 shows the Z-average particle size in nm for wet and dry crystalline nanoparticles in the absence and presence of SLS. [Figure 10] 1 shows the corresponding XRPD intensity coefficients for wet and dry crystalline nanoparticles in the absence and presence of SLS. [Figure 11] Plasma concentration time curves are shown. DETAILED DESCRIPTION OF THE INVENTION

[0031] The composition according to the present invention comprises nanoparticles comprising or consisting essentially of enzalutamide. The nanoparticles according to the present invention comprise or consist essentially of enzalutamide in crystalline form (crystalline nanoparticles).

[0032] Enzalutamide is a nonsteroidal antiandrogen (NSAA) drug used to treat prostate cancer. Enzalutamide is indicated for use in combination with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic castration-resistant prostate cancer. Enzalutamide is an antiandrogen drug that acts as an androgen receptor antagonist. Enzalutamide prevents the effects of androgens on the prostate.

[0033] Enzalutamide (CAS 915087-33-1) has the following chemical structure: [ka]

[0034] Enzalutamide is a water-insoluble white to off-white solid. One crystalline form and four solvates have been observed. For purposes of this specification, unless otherwise specified, the term "enzalutamide" refers to enzalutamide, its non-salt form, physiologically acceptable salt, cocrystal, polymorph, and / or solvate.

[0035] Preferably, the crystalline nanoparticles according to the present invention contain enzalutamide in its non-salt form.

[0036] Unless otherwise specified, all dosage amounts and weight percentages used herein are based on equivalent weights for the unsalted, unsolvated, and non-co-crystalline forms of enzalutamide, i.e., the additional weight of the salt portion or solvent portion or co-crystalline portion is not taken into account in the quantification.

[0037] It is primarily contemplated that the compositions according to the present invention may contain other pharmacologically active ingredients in addition to enzalutamide, but preferably, enzalutamide is the only pharmacologically active ingredient contained in the composition. In this context, a pharmacologically active ingredient is another substance useful in treating the same or related disorders, diseases, and conditions as enzalutamide. Therefore, compounds that have physiological effects but no pharmacological effects, such as sodium chloride and vitamins, should not be considered pharmacologically active ingredients in the above sense.

[0038] Preferably, the crystalline nanoparticles in the compositions according to the present invention are solid.

[0039] Preferably, the crystalline nanoparticles according to the present invention and the enzalutamide contained therein are not conjugated with an antigen, for example, for the purpose of drug targeting. In particular, the crystalline nanoparticles according to the present invention are not encapsulated in prostate-specific membrane antigen (PSMA), i.e., are not coated with PSMA.

[0040] Preferably, the content of enzalutamide relative to the total weight of the nanoparticles is at least 90.0 wt.%, preferably at least 92.5 wt.%, more preferably at least 95 wt.%, even more preferably at least 96 wt.%, even more preferably at least 97 wt.%, even more preferably at least 98 wt.%, most preferably at least 99.0 wt.%, and in particular at least 99.5 wt.%.

[0041] Preferably, the content of enzalutamide relative to the total dry solids content of the composition is at least 10 wt.%, preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 25 wt.%, even more preferably at least 30 wt.%, even more preferably at least 35 wt.%, most preferably at least 40 wt.%, and in particular at least 45 wt.%.

[0042] Preferably, the content of enzalutamide relative to the total dry solids content of the composition is at most 90 wt.%, preferably at most 85 wt.%, more preferably at most 80 wt.%, even more preferably at most 75 wt.%, even more preferably at most 70 wt.%, even more preferably at most 65 wt.%, most preferably at most 60 wt.%, and in particular at most 55 wt.%.

[0043] Preferably, the content of enzalutamide relative to the total weight of the composition is at least 7.5 wt.%, preferably at least 10 wt.%, more preferably at least 12.5 wt.%, even more preferably at least 15 wt.%, even more preferably at least 17.5 wt.%, even more preferably at least 20 wt.%, most preferably at least 22.5 wt.%, and in particular at least 25 wt.%.

[0044] Preferably, the content of enzalutamide relative to the total weight of the nanoparticles is at most 60 wt.%, preferably at most 55 wt.%, more preferably at most 50 wt.%, even more preferably at most 45 wt.%, even more preferably at most 40 wt.%, even more preferably at most 35 wt.%, most preferably at most 30 wt.%, and in particular at most 25 wt.%.

[0045] In the crystalline nanoparticles according to the present invention, enzalutamide is present in a crystalline form. Thus, it is contemplated that the crystalline nanoparticles include crystalline enzalutamide and, optionally, non-crystalline (i.e., amorphous) enzalutamide.

[0046] In a preferred embodiment, the crystalline nanoparticles according to the present invention are nanoflakes, i.e., non-uniform particles having at least one nanometer dimension, one dimension being substantially smaller than the other two, and characterized by a plate-like morphology or structure.

[0047] The crystalline nanoparticles according to the invention have a z-average particle size of up to 800 nm.

[0048] In a preferred embodiment, the size and size distribution of the crystalline nanoparticles according to the present invention are expressed in units of the Z-average size Dz.

[0049] Preferably, the crystalline nanoparticles according to the invention have a Z-average particle size of at most 750 nm, preferably at most 700 nm, more preferably at most 650 nm, even more preferably at most 600 nm, even more preferably at most 550 nm, and even more preferably at most 500 nm, most preferably at most 450 nm, and especially at most 400 nm.

[0050] Preferably, the crystalline nanoparticles according to the invention have a Z-average particle size Dz of at least 10 nm, preferably at least 20 nm, more preferably at least 30 nm, even more preferably at least 40 nm, even more preferably at least 50 nm, even more preferably at least 60 nm, most preferably at least 70 nm, and especially at least 80 nm.

[0051] Preferably, unless otherwise specified, the Z-average particle size (Dz) and particle size distribution of the crystalline nanoparticles according to the present invention are determined according to ISO 22412:2008 Particle size analysis - Dynamic light scattering. The Z-average particle size Dz is an intensity-based harmonic mean (also known as the "cumulant mean").

[0052] Dynamic light scattering (DLS) measurements are preferably performed using a Malvern Zetasizer Nano device, such as the Zetasizer Nano ZS. The composition (dry powder slurry / suspension) according to the present invention is redispersed in water or 0.1% HPMC (aqueous solution), and the sample is stirred and measured after complete dispersion. A backscattering measurement device is preferably used, and the CUMULANTS algorithm is preferably used to obtain the Z-average particle size (diameter) and polydispersity index (PI). For details, see, for example, the User Manual for the Zetasizer Nano Series, NANO485 Issue 1.1 April 2013.

[0053] In another preferred embodiment, the particle size and particle size distribution of the crystalline nanoparticles according to the present invention are V 50 and / or D V It is expressed in units of 90.

[0054] Preferably, the crystalline nanoparticles according to the invention have a D VThe crystalline nanoparticles have a particle size distribution characterized by a 90 value of 900 nm or less, i.e., 90% of the volume fraction is composed of a large number of particles with a diameter of 900 nm or less. The particle size may be between 10 nm and 900 nm, for example, between 10 nm and 200 nm, between 200 nm and 500 nm, or between 500 nm and 900 nm. The size distribution can be adjusted as needed.

[0055] Preferably, the crystalline nanoparticles according to the invention have a D V The particle size distribution is characterized by a 90 value of at most 600 nm, preferably at most 550 nm, more preferably at most 500 nm, even more preferably at most 450 nm, even more preferably at most 400 nm, still more preferably at most 350 nm, most preferably at most 300 nm, and especially preferably at most 250 nm.

[0056] Preferably, the crystalline nanoparticles according to the invention have a D V The particle size distribution is characterized by a 50 value of at most 600 nm, preferably at most 550 nm, more preferably at most 500 nm, even more preferably at most 450 nm, even more preferably at most 400 nm, still more preferably at most 350 nm, most preferably at most 300 nm, and especially preferably at most 250 nm.

[0057] Preferably, unless otherwise specified, D V 50 and D V 90 is preferably determined by volume (D V ) is determined by laser light diffraction, which provides a distribution according to the particle size distribution. Samples of known particle size distribution are commercially available and can be used for calibration.

[0058] In a preferred embodiment, particle size is analyzed by the Polarized Intensity Differential Scattering (PIDS) technique, which is based on the Mie theory of light scattering and uses different wavelengths to measure the difference between vertically and horizontally polarized signals. A suitable instrument is, for example, the LS 13 320 XR Particle Size Analyzer from Beckman Coulter Inc.

[0059] The width of the particle size distribution in a suspension characterizes the "polydispersity" or "PDI" of the crystalline nanoparticles, which, as known to those skilled in the art, is defined as the relative dispersion in the correlation decay rate distribution. The polydispersity index (PDI) can also be calculated from cumulant analysis of DLS-measured intensity autocorrelation functions, as defined in ISO 22412:2008. Preferably, the polydispersity of the crystalline nanoparticles according to the present invention is less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1.

[0060] The compositions according to the invention comprise one or more physiologically acceptable polymers and / or copolymers. For the purposes of this specification, a copolymer is derived from at least two different monomers (comonomers). Preferably, the physiologically acceptable copolymer is a bipolymer, i.e., derived from two different monomers (comonomers).

[0061] Surprisingly, it has been found that in order to induce and control the crystallization of enzalutamide, one or more physiologically acceptable polymers and / or copolymers are preferably soluble in a poor solvent for enzalutamide, preferably water.

[0062] Preferably, the one or more physiologically acceptable polymers and / or copolymers can be biopolymers, such as synthetic polymers or proteins. Exemplary polymers are polyvinylpyrrolidone / vinyl acetate (PVPVA), polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), polyacrylic acid (PAA), polyethylene glycol (PEG), poloxamer, polyvinylcaprolactam (PVCL), poly(N-vinylcaprolactam)-poly(vinyl acetate)-poly(ethylene glycol) (Soluplus®), and copolymers or mixtures of any of the foregoing. Proteins, such as wheat protein, can also be used. A preferred copolymer is PPVVA.

[0063] Preferably, the one or more physiologically acceptable polymers and / or copolymers have a solubility in water (15-25°C) according to Ph.Eur. of at least "slightly soluble" (30-100 mL of water per gram), preferably at least "soluble" (10-30 mL of water per gram), more preferably at least "freely soluble" (1-10 mL of water per gram).

[0064] Furthermore, it has surprisingly been found that in order to induce and control the crystallization of enzalutamide, one or more physiologically acceptable polymers and / or copolymers should be composed of repeating units each having different hydrophilic and hydrophobic properties.

[0065] Preferably, the one or more physiologically acceptable polymers and / or copolymers are sufficiently hydrophilic to be water soluble and sufficiently lipophilic to interact with enzalutamide.

[0066] Preferably, the one or more physiologically acceptable polymers and / or copolymers comprise or consist essentially of a copolymer derived from a first monomer and a second monomer, the first monomer being more hydrophilic than the second monomer. Preferably, the first monomer has a dipole moment in its neat state that is at least 0.1 Debye, preferably at least 0.2 Debye, more preferably at least 0.3 Debye, and even more preferably at least 0.4 Debye greater relative to the dipole moment of the second monomer in its neat state.

[0067] In a preferred embodiment, the one or more physiologically acceptable polymers and / or copolymers comprise or consist essentially of vinylpyrrolidone vinyl acetate copolymer (copovidone), such as commercially available as Kollidon® VA64, or Copovidon K25-31.

[0068] Preferably, the vinylpyrrolidone vinyl acetate copolymer is a copolymer of 1-vinyl-2-pyrrolidone (1-ethenylpyrrolidin-2-one) and vinyl acetate (ethenyl acetate) in a weight ratio of about 3:2.

[0069] Preferably, the vinylpyrrolidone vinyl acetate copolymer contains 35.0 wt.% to 42.0 wt.% vinyl acetate (ethenyl acetate), calculated on a dry basis.

[0070] Preferably, the total content of one or more physiologically acceptable polymers and / or copolymers relative to the total dry solids content of the composition is at least 10 wt.%, preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 25 wt.%, even more preferably at least 30 wt.%, even more preferably at least 35 wt.%, most preferably at least 40 wt.%, and in particular at least 45 wt.%.

[0071] Preferably, the total content of one or more physiologically acceptable polymers and / or copolymers relative to the total dry solids content of the composition is at most 90 wt.%, preferably at most 85 wt.%, more preferably at most 80 wt.%, even more preferably at most 75 wt.%, even more preferably at most 70 wt.%, still more preferably at most 65 wt.%, most preferably at most 60 wt.%, and in particular at most 55 wt.%.

[0072] Preferably, the total content of one or more physiologically acceptable polymers and / or copolymers relative to the weight of the composition is at least 7.5 wt.%, preferably at least 10 wt.%, more preferably at least 12.5 wt.%, even more preferably at least 15 wt.%, even more preferably at least 17.5 wt.%, even more preferably at least 20 wt.%, most preferably at least 22.5 wt.%, and in particular at least 25 wt.%.

[0073] Preferably, the total content of one or more physiologically acceptable polymers and / or copolymers relative to the total weight of the composition is at most 60 wt.%, preferably at most 55 wt.%, more preferably at most 50 wt.%, even more preferably at most 45 wt.%, even more preferably at most 40 wt.%, and even more preferably at most 35 wt.%, most preferably at most 30 wt.%, and in particular at most 25 wt.%.

[0074] The relative weight ratio of the total amount of enzalutamide to the total amount of one or more physiologically acceptable polymers and / or copolymers is within the range of 5.0:1.0 to 1.0:5.0.

[0075] In a preferred embodiment, the relative weight ratio of the total amount of enzalutamide to the total amount of one or more physiologically acceptable polymers and / or copolymers is within the range of 4.5:1.0 to 1.0:4.5, preferably 4.0:1.0 to 1.0:4.0, more preferably 3.5:1.0 to 1.0:3.5, even more preferably 3.0:1.0 to 1.0:3.0, even more preferably 2.5:1.0 to 1.0:2.5, and even more preferably 2.0:1.0 to 1.0:2.0, most preferably 1.5:1.0 to 1.0:1.5, and especially 1.3:1.0 to 1.0:1.3.

[0076] In a preferred embodiment, the composition according to the present invention is a suspension or slurry comprising or essentially consisting of: (i) a solid phase comprising or essentially consisting of nanoparticles comprising or essentially consisting of enzalutamide in crystalline form; and (ii) a liquid phase, preferably comprising or essentially consisting of a liquid (e.g., a solvent, preferably water); one or more physiologically acceptable polymers and / or copolymers; and optionally one or more physiologically acceptable surfactants; wherein the relative weight ratio of the total amount of enzalutamide to the total amount of one or more physiologically acceptable polymers and / or copolymers is in the range of 2.0:1.0 to 2.0:3.0, wherein the amount of enzalutamide is calculated as mg / mL of the slurry or suspension and the amount of polymers and / or copolymers is calculated as wt.% of the slurry or suspension.

[0077] The compositions according to the invention optionally comprise one or more physiologically acceptable surfactants.

[0078] In a preferred embodiment, the composition according to the invention does not contain a surfactant. Preferably, the composition does not contain sodium lauryl sulfate; more preferably, it does not contain any anionic surfactant; and even more preferably, it does not contain any physiologically acceptable surfactant.

[0079] In another preferred embodiment, the composition according to the invention comprises one or more physiologically acceptable surfactants, which improve wetting efficiency.

[0080] The properties of surfactants can be described by their hydrophilic-lipophilic balance (HLB). Preferably, the one or more physiologically acceptable surfactants comprise or consist essentially of surfactants having an HLB value of at least 10, preferably at least 15, more preferably at least 20, even more preferably at least 25, even more preferably at least 30, even more preferably at least 32, most preferably at least 34, and especially at least 36.

[0081] The properties of surfactants can also be described by their charge.

[0082] In a preferred embodiment, the one or more physiologically acceptable surfactants comprise or consist essentially of a non-ionic surfactant.

[0083] In a preferred embodiment, the one or more physiologically acceptable surfactants comprise or consist essentially of an anionic surfactant.

[0084] In a preferred embodiment, the one or more physiologically acceptable surfactants comprise or consist essentially of a cationic surfactant.

[0085] In a preferred embodiment, the one or more physiologically acceptable surfactants comprise or consist essentially of an amphoteric surfactant.

[0086] Preferably, the one or more physiologically acceptable surfactants are selected from the group consisting of: (i) alkyl sulfates; preferably selected from sodium lauryl sulfate (sodium dodecyl sulfate), sodium cetyl sulfate, sodium cetylstearyl sulfate, sodium stearyl sulfate, sodium dioctyl sulfosuccinate (docusate sodium); and their corresponding potassium or calcium salts; (ii) fatty acid salts; preferably selected from stearates and oleates; (iii) comprising or consisting essentially of a surfactant selected from the group consisting of salts of cholic acid; preferably selected from sodium deoxycholate, sodium glycocholate, sodium taurocholate, and the corresponding potassium or ammonium salts.

[0087] Preferably, the one or more physiologically acceptable surfactants comprise or consist essentially of alkyl sulfates; preferably, alkyl sulfates of the general formula C n H 2n+1 O-SO3 - M + In the formula, n is an integer of 8 to 30, preferably 10 to 24, more preferably 12 to 18; M is Li + , Na + , K. + , NH4 + , 1 / 2Mg 2+ and 1 / 2Ca 2+ is selected from.

[0088] In particularly preferred embodiments, the one or more physiologically acceptable surfactants comprise or consist essentially of sodium lauryl sulfate.

[0089] Preferably, the one or more physiologically acceptable surfactants are selected from the group consisting of: (a) a straight-chain or branched-chain fatty alcohol; preferably selected from cetyl alcohol, cetostearyl alcohol, stearyl alcohol, oleyl alcohol, octyldodecanol, or 2-hexyldecan-1-ol; (b) a sterol; preferably cholesterol; (c) lanolin alcohol; (d) partial fatty acid esters of polyhydric alcohols, such as glycerol fatty acid monoesters or glycerol fatty acid diesters; preferably, glycerol behenate, glycerol dibehenate, glycerol distearate, glycerol monocaprylate, glycerol monolinoleate, glycerol monooleate, glycerol monostearate, ethylene glycol monopalmitostearate, ethylene glycol stearate, diethylene glycol palmitostearate, diethylene glycol stearate, propylene glycol dicaprylocaprate, propylene glycol dilaurate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monopalmitostearate, propylene glycol monostearate, pentaerythritol monostearate, and superglycerinated fully hydrogenated rapeseed oil; (e) partial fatty acid esters of sorbitan; preferably selected from sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate; (f) partial fatty acid esters of polyoxyethylene sorbitan (polyoxyethylene-sorbitan-fatty acid esters), such as fatty acid monoesters of polyoxyethylene sorbitan, fatty acid diesters of polyoxyethylene sorbitan, or fatty acid triesters of polyoxyethylene sorbitan; examples include monolauryl and trilauryl esters, palmityl, stearyl, and oleyl esters; preferably selected from polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (5) sorbitan monooleate, and polyoxyethylene (20) sorbitan trioleate; (g) polyoxyethylene glycerol fatty acid esters, such as mixtures of glycerol monoesters, diesters, and triesters with macrogol diesters and monoesters having a molecular weight in the range of 200 to 4000 g / mol; preferably selected from macrogolglycerol caprylocaprate, macrogolglycerol laurate, macrogolglycerol cocoate, macrogolglycerol linoleate, macrogol-20-glycerol monostearate, macrogol-6-glycerol caprylocaprate, macrogolglycerol oleate, macrogolglycerol stearate, macrogolglycerol hydroxystearate, and macrogolglycerol lysinolate; (h) polyoxyethylene fatty acid esters, preferably selected from macrogol oleate, macrogol stearate, macrogol-15-hydroxystearate, and polyoxyethylene esters of 12-hydroxystearic acid; (i) Polyoxyethylene fatty alcohol ethers; preferably selected from polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene cetostearyl ether, lauromacrogol 400, macrogol oleyl ether, and macrogol stearyl ether; (j) reaction products of natural or hydrogenated castor oil with ethylene oxide, such as that commercialized under the trademark Cremophor®; (k) polyoxypropylene-polyoxyethylene block copolymers (poloxamers); preferably according to the general formula: [ka] (wherein, a is independently an integer ranging from 2 to 130, preferably from 90 to 110, and b is an integer ranging from 15 to 67, preferably from 46 to 66); (l) polyglycololytic glycerides; preferably selected from those commercialized as Gelucire®, Labrasol®; (m) fatty acid esters of sucrose; preferably selected from sucrose distearate, sucrose dioleate, sucrose dipalmitate, sucrose monostearate, sucrose monopalmitate, sucrose monooleate, sucrose monomyristate, and sucrose mono(molo)laurate; (n) fatty acid esters of polyglycerol; preferably selected from polyglycerol oleate, polyglycerol dioleate, polyglycerol poly-12-hydroxystearate, triglycerol diisostearate; and (o) comprising or consisting essentially of a surfactant selected from the group consisting of polyoxyethylene esters of D-α-tocopheryl succinate; preferably D-α-tocopherol polyethylene glycol 1000 succinate.

[0090] Preferably, the one or more physiologically acceptable surfactants comprise or consist essentially of a surfactant selected from the group consisting of sodium lauryl sulfate (SLS), Tween 80, Tween 20, dioctyl sulfosuccinate sodium salt (DOSS), and tocophersolan (TPGS).

[0091] Preferably, the total content of one or more physiologically acceptable surfactants relative to the total weight of the composition is at most 7.0 wt.%, preferably at most 6.0 wt.%, even more preferably at most 5.0 wt.%, even more preferably at most 4.0 wt.%, even more preferably at most 3.0 wt.%, most preferably at most 2.0 wt.%, and in particular at most 1.0 wt.%.

[0092] Preferably, the composition is a suspension or slurry comprising or consisting essentially of (i) a solid phase comprising or consisting essentially of nanoparticles, and (ii) a liquid phase, wherein the total content of the one or more surfactants in the liquid phase is in the range of 0.0025 to 1.5 wt.%.

[0093] In a particularly preferred embodiment, the composition according to the invention comprises: - nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; - vinylpyrrolidone vinyl acetate copolymer; and optionally comprising or consisting essentially of sodium lauryl sulfate; The Z-average particle size of the nanoparticles is at most 700 nm; preferably at most 600 nm; more preferably at most 500 nm; The relative weight ratio of the total amount of enzalutamide to the vinylpyrrolidone vinyl acetate copolymer is within the range of 4.0:1.0 to 1.0:4.0, preferably 2.5:1.0 to 1.0:2.5.

[0094] In a preferred embodiment, the composition according to the invention is a solid.

[0095] Under these circumstances, the composition according to the invention preferably comprises: - nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; - one or more physiologically acceptable polymers and / or copolymers; and - optionally consisting essentially of one or more physiologically acceptable surfactants.

[0096] In another preferred embodiment, the composition according to the invention comprises: (i) a solid phase, preferably comprising or consisting essentially of nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; and (ii) a liquid phase, preferably comprising: - a liquid (e.g. a solvent, preferably water); - one or more physiologically acceptable polymers and / or copolymers; and - optionally a liquid phase comprising or consisting essentially of one or more physiologically acceptable surfactants.

[0097] Preferably, the liquid phase is aqueous. Preferably, water is the only liquid component of the composition, although it is contemplated that physiologically acceptable surfactants may be liquid in their neat state, and thus the liquid component of the liquid phase may consist essentially of water and such liquid physiologically acceptable surfactant(s).

[0098] Preferably, at least a portion, and more preferably essentially all, of the one or more physiologically acceptable polymers and / or copolymers is dissolved in the liquid phase.

[0099] Preferably, at least a portion, and more preferably essentially all, of the one or more physiologically acceptable surfactants optionally present is dissolved in the liquid phase.

[0100] In a preferred embodiment, the composition according to the invention has a liquid content, preferably a water content, of at least 5.0 wt.%, preferably at least 10 wt.%, more preferably at least 15 wt.%, even more preferably at least 20 wt.%, even more preferably at least 25 wt.%, still more preferably at least 30 wt.%, most preferably at least 25 wt.%, and in particular at least 40 wt.%, in each case relative to the total weight of the composition (i.e. suspension or slurry).

[0101] In a particularly preferred embodiment of the composition according to the invention, - the content of enzalutamide is in the range of 25±20 wt.%, preferably 25±15 wt.%, more preferably 25±10 wt.%, even more preferably 25±5.0 wt.%; - the total content of one or more physiologically acceptable polymers and / or copolymers is in the range of 25±20 wt.%, preferably 25±15 wt.%, more preferably 25±10 wt.%, even more preferably 25±5.0 wt.%; The water content is in the range of 50±40 wt.%, preferably 50±30 wt.%, more preferably 50±20 wt.%, even more preferably 50±10 wt.%.

[0102] Preferably, the composition according to the invention has a viscosity of at least 5,000 mPa·s, preferably at least 7,500 mPa·s, more preferably at least 10,000 mPa·s, at a temperature in the range of 15°C to 40°C.

[0103] Preferably, the composition according to the invention has a viscosity of at most 40,000 mPa·s, preferably at most 35,000 mPa·s, more preferably at most 30,000 mPa·s at a temperature in the range of 15°C to 40°C.

[0104] Preferably, the composition according to the invention contains nanoparticles at a total concentration relative to the total weight of the composition (slurry or suspension) of at least 7.5 mg / mL, preferably at least 10 mg / mL, more preferably at least 12.5 mg / mL, even more preferably at least 15 mg / mL, even more preferably at least 17.5 mg / mL, and even more preferably at least 20 mg / mL, most preferably at least 22.5 mg / mL, and especially at least 25 mg / mL.

[0105] Preferably, the composition according to the invention contains nanoparticles at a total concentration relative to the total weight of the composition (slurry or suspension) of at least 75 mg / mL, preferably at least 100 mg / mL, more preferably at least 125 mg / mL, even more preferably at least 150 mg / mL, even more preferably at least 175 mg / mL, and even more preferably at least 200 mg / mL, most preferably at least 225 mg / mL, and especially at least 250 mg / mL.

[0106] Preferably, the composition according to the invention contains nanoparticles at a total concentration relative to the total weight of the composition (slurry or suspension) of at most 475 mg / mL, preferably at most 450 mg / mL, more preferably at most 425 mg / mL, even more preferably at most 400 mg / mL, even more preferably at most 375 mg / mL, and even more preferably at most 350 mg / mL, most preferably at most 325 mg / mL, and especially at most 300 mg / mL.

[0107] Preferably, the composition according to the invention contains nanoparticles at a total concentration relative to the total weight of the composition (slurry or suspension) of at most 47.5 mg / mL, preferably at most 45 mg / mL, more preferably at most 42.5 mg / mL, even more preferably at most 40 mg / mL, even more preferably at most 37.5 mg / mL, still more preferably at most 35 mg / mL, most preferably at most 32.5 mg / mL, and especially at most 30 mg / mL.

[0108] The synthesis strategy according to the present invention, which involves treating amorphous nanoparticles of enzalutamide with a solution of one or more physiologically acceptable polymers and / or copolymers in a poor solvent for enzalutamide, preferably in water, is unique and has unexpected advantages because: (i) Enzalutamide in the nanoparticles is converted from its initial amorphous state (amorphous nanoparticles) to a crystalline state (crystalline nanoparticles); (ii) the initial size of amorphous nanoparticles consisting essentially of enzalutamide molecules (starting material) is small and therefore does not increase significantly upon conversion from the initial amorphous state to the crystalline state; (iii) The small size of the crystalline nanoparticles thus obtained is stabilized by the presence of one or more physiologically acceptable polymers and / or copolymers in the composition, thus providing good storage stability to the composition.

[0109] Another aspect of the present invention relates to a process for converting nanoparticles comprising or consisting essentially of enzalutamide in amorphous form (amorphous nanoparticles) into nanoparticles comprising enzalutamide in crystalline form (crystalline nanoparticles).

[0110] Another aspect of the present invention relates to a process for the preparation of a composition comprising or consisting essentially of nanoparticles (crystalline nanoparticles) comprising enzalutamide in crystalline form, one or more physiologically acceptable polymers and / or copolymers, and optionally one or more physiologically acceptable surfactants, in accordance with the invention described above.

[0111] In either case, the process involves the following steps: (a) providing nanoparticles comprising or consisting essentially of enzalutamide in amorphous form; (b) contacting the nanoparticles provided in step (a) with one or more physiologically acceptable polymers and / or copolymers in a liquid to obtain a suspension or slurry; (c) optionally mixing the suspension or slurry; (d) optionally drying the suspension or slurry to obtain a residual composition; and (e) optionally, grinding the residual composition; This results in nanoparticles that contain or consist essentially of enzalutamide in crystalline form (crystalline nanoparticles).

[0112] In step (a) of the process according to the present invention, nanoparticles comprising or essentially consisting of enzalutamide in amorphous form (amorphous nanoparticles, starting material) are provided. This can be achieved by conventional methods known in the prior art, such as a milling process (top-down method) such as wet nano-milling using a stirred media mill or high-pressure homogenization; or by nanoprecipitation (bottom-up method). Preferably, step (a) comprises dissolving enzalutamide in supercritical CO2 and using CESS™ technology to provide nanoparticles comprising or essentially consisting of enzalutamide in amorphous form (amorphous nanoparticles).

[0113] Preferably, the amorphous nanoparticles provided in step (a) have a Z-average particle size of at most 600 nm, preferably at most 550 nm, more preferably at most 500 nm, even more preferably at most 450 nm, even more preferably at most 400 nm, even more preferably at most 350 nm, most preferably at most 300 nm, and especially preferably at most 250 nm.

[0114] Preferably, the amorphous nanoparticles provided in step (a) have a Z-average particle size of at least 60 nm, preferably at least 80 nm, more preferably at least 100 nm, even more preferably at least 120 nm, even more preferably at least 140 nm, even more preferably at least 160 nm, most preferably at least 180 nm, and especially at least 200 nm.

[0115] Preferably, the amorphous nanoparticles provided in step (a) are D V The particle size distribution is characterized by a 90 value of at most 1000 nm, preferably at most 900 nm, more preferably at most 800 nm, even more preferably at most 700 nm, even more preferably at most 650 nm, still more preferably at most 600 nm, most preferably at most 550 nm, and especially at most 500 nm.

[0116] Preferably, the amorphous nanoparticles provided in step (a) are DV The particle size distribution is characterized by a 50 value of at least 50 nm, preferably at least 100 nm, more preferably at least 150 nm, even more preferably at least 200 nm, even more preferably at least 250 nm, and even more preferably at least 300 nm, most preferably at least 350 nm, and especially at least 400 nm.

[0117] In step (b) of the process according to the invention, the amorphous nanoparticles provided in step (a) are suspended in a liquid comprising one or more physiologically acceptable polymers and / or copolymers and, optionally, one or more physiologically acceptable surfactants, thereby obtaining a suspension or slurry.

[0118] Typically, the liquid on the one hand and the nanoparticles on the other hand are separate phases of a slurry or suspension, ie, the liquid and solid phases, respectively.

[0119] Preferably, in step (b), the liquid is a solution of one or more physiologically acceptable polymers and / or copolymers, and optionally one or more physiologically acceptable surfactants.

[0120] Preferably, in step (b), the liquid is aqueous; preferably, water is the only liquid component.

[0121] Preferably, the amorphous nanoparticles (amorphous nanosized enzalutamide) provided in step (a) are contacted with a liquid, preferably an aqueous solution, containing one or more polymers and / or copolymers to form a slurry or suspension, wherein the content of the amorphous nanoparticles (amorphous nanosized enzalutamide) provided in step (a) in the slurry or suspension is higher than the solubility of the amorphous nanoparticles (amorphous nanosized enzalutamide) provided in step (a) in the liquid, preferably an aqueous solution, from which the suspension or slurry is formed.

[0122] Preferably, the content of amorphous nanosized enzalutamide in the slurry or suspension is at least 10 times higher, more preferably at least 50 times higher, even more preferably at least 100 times higher, and even more preferably at least 500 times higher than its solubility in a liquid, preferably an aqueous solution, containing one or more polymers and / or copolymers to form the suspension or slurry. Therefore, the required amount of enzalutamide amorphous nanoparticles provided in step (a) depends on their solubility. Solubility can be measured by any method known in the art. The kinetic solubility of enzalutamide in fasting simulated intestinal fluid (FaSSIF) at 37°C is about 74 mg / mL, and in simulated gastric fluid (SGF) it is about 50 mg / mL. Therefore, a sufficient slurry can be produced if the slurry or suspension contains, for example, 5 mg of the amorphous nanoparticles provided in step (a) per mL of slurry or suspension.

[0123] Preferably, in step (b), the liquid, preferably the aqueous solution, contains one or more physiologically acceptable polymers and / or copolymers at a concentration in the range of 0.2 to 40% by weight, preferably 1 to 10% by weight, more preferably 1 to 5.0% by weight, based on the total weight of the liquid. Too high a polymer content may slow down crystal formation.

[0124] Preferably, in step (b), the liquid contains one or more physiologically acceptable polymers and / or copolymers in a total concentration of at least 7.5 wt.%, preferably at least 10 wt.%, more preferably at least 12.5 wt.%, even more preferably at least 15 wt.%, even more preferably at least 17.5 wt.%, even more preferably at least 20 wt.%, most preferably at least 22.5 wt.%, and in particular at least 25 wt.%, relative to the total weight of the liquid.

[0125] Preferably, in step (b), the liquid contains one or more physiologically acceptable polymers and / or copolymers in a total concentration of at most 47.5 wt.%, preferably at most 45 wt.%, more preferably at most 42.5 wt.%, even more preferably at most 40 wt.%, even more preferably at most 37.5 wt.%, still more preferably at most 35 wt.%, most preferably at most 32.5 wt.%, and in particular at most 30 wt.%, based on the total weight of the liquid.

[0126] Preferably, in step (b), the liquid contains one or more physiologically acceptable surfactants in a total concentration of at least 0.06 wt.%, preferably at least 0.08 wt.%, more preferably at least 0.10 wt.%, even more preferably at least 0.12 wt.%, even more preferably at least 0.14 wt.%, even more preferably at least 0.16 wt.%, most preferably at least 0.18 wt.%, and in particular at least 0.20 wt.%, relative to the total weight of the liquid.

[0127] Preferably, in step (b), the liquid contains one or more physiologically acceptable surfactants in a total concentration of at most 0.75 wt.%, preferably at most 1.0 wt.%, more preferably at most 1.25 wt.%, even more preferably at most 1.5 wt.%, even more preferably at most 1.75 wt.%, even more preferably at most 2.0 wt.%, most preferably at most 2.25 wt.%, and especially at most 2.5 wt.%, relative to the total weight of the liquid.

[0128] Preferably, in step (b), the liquid contains one or more physiologically acceptable surfactants at a concentration in the range of 0.0025 to 1.5% by weight, which surfactants improve wetting efficiency.

[0129] Preferably, in step (b), the resulting suspension or slurry contains nanoparticles at a total concentration of at least 7.5 mg / mL, preferably at least 10 mg / mL, more preferably at least 12.5 mg / mL, even more preferably at least 15 mg / mL, even more preferably at least 17.5 mg / mL, even more preferably at least 20 mg / mL, most preferably at least 22.5 mg / mL, and especially at least 25 mg / mL, based on the total weight of the liquid.

[0130] Preferably, in step (b), the resulting suspension or slurry contains nanoparticles at a total concentration of at least 75 mg / mL, preferably at least 100 mg / mL, more preferably at least 125 mg / mL, even more preferably at least 150 mg / mL, even more preferably at least 175 mg / mL, and even more preferably at least 200 mg / mL, most preferably at least 225 mg / mL, and especially at least 250 mg / mL, based on the total weight of the liquid.

[0131] Preferably, in step (b), the resulting suspension or slurry contains nanoparticles at a total concentration of at most 475 mg / mL, preferably at most 450 mg / mL, more preferably at most 425 mg / mL, even more preferably at most 400 mg / mL, even more preferably at most 375 mg / mL, even more preferably at most 350 mg / mL, most preferably at most 325 mg / mL, and especially at most 300 mg / mL, based on the total weight of the liquid.

[0132] Preferably, in step (b), the resulting suspension or slurry contains nanoparticles at a total concentration of at most 47.5 mg / mL, preferably at most 45 mg / mL, more preferably at most 42.5 mg / mL, even more preferably at most 40 mg / mL, even more preferably at most 37.5 mg / mL, even more preferably at most 35 mg / mL, most preferably at most 32.5 mg / mL, and especially at most 30 mg / mL, based on the total weight of the liquid.

[0133] The nanosized enzalutamide (amorphous nanoparticles) contained in the suspension or slurry are then crystallized to obtain crystalline nanosized enzalutamide (crystalline nanoparticles) contained in the suspension or slurry. Typically, the desired crystalline nanosized enzalutamide is produced within 24 hours using 150 to 350 mg / mL of amorphous nanosized enzalutamide, with a weight ratio of enzalutamide to the total weight of one or more physiologically acceptable polymers and / or copolymers of approximately 1.0:1.0.

[0134] The conversion of amorphous enzalutamide to crystalline enzalutamide typically requires some time and is preferably facilitated by mixing the slurry or suspension (optional step (c)) and / or sonication. It is contemplated that the suspension or slurry obtained in step (b) is allowed to stand for a sufficient period of time under suitable conditions. However, preferably, the suspension or slurry obtained in step (b) is actively mixed in the subsequent optional step (c).

[0135] Preferably, the conversion of amorphous enzalutamide to crystalline enzalutamide is carried out for at least 6 hours, more preferably at least 12 hours, even more preferably at least 16 hours, and even more preferably at least 24 hours, with longer times being preferred to achieve complete wetting and good dispersion.

[0136] Preferably, the conversion of amorphous enzalutamide to crystalline enzalutamide is carried out at a temperature in the range of 15°C to 40°C, preferably 25°C to 35°C.

[0137] In optional step (c) of the process according to the invention, the suspension or slurry obtained in step (b) is mixed, preferably with mechanical energy.

[0138] Preferably, in step (c), the mixing is carried out at a temperature in the range of 15°C to 40°C, preferably 25°C to 35°C.

[0139] Preferably, in step (c), the mixing is carried out by stirring the suspension or slurry.

[0140] Preferably, in step (c), the mixing is carried out for a duration of 2 hours to 48 hours, preferably at least 6 hours, more preferably at least 12 hours, even more preferably at least 16 hours, and even more preferably at least 24 hours. Typically, in step (c), the mixing is carried out until enzalutamide is present in crystalline form.

[0141] Typically, at the end of step (b), or if the process includes step (c), at the end of step (c), the nanoparticles can be considered crystalline nanoparticles within the meaning of the present invention, because the enzalutamide has been converted from an amorphous state (amorphous nanoparticles, starting material) to a crystalline state (crystalline nanoparticles, product). Optional subsequent process steps rather serve the purpose of workup, but typically do not further alter the amorphous / crystalline state of the enzalutamide contained in the nanoparticles.

[0142] However, optional subsequent steps may change the absolute and relative contents of components in the composition, for example as a result of evaporation of the liquid (optional step (d)) and / or as a result of solid / liquid separation techniques.

[0143] It is contemplated that the crystalline nanoparticles may be completely isolated from the suspension or slurry. It is further contemplated that the crystalline nanoparticles so isolated may be purified, for example, by washing with water.

[0144] However, since the product prepared by the process according to the invention is a composition comprising or consisting essentially of crystalline nanoparticles and one or more physiologically acceptable polymers and / or copolymers, work-up of the slurry or suspension obtained at the end of step (b) or (c) preferably involves modifying the absolute and / or relative amounts of the components without completely separating the crystalline nanoparticles from the one or more physiologically acceptable polymers and / or copolymers.

[0145] Evaporation of volatile components (e.g., partial or complete removal of water in optional step (d)) increases the absolute concentration of crystalline nanoparticles and one or more physiologically acceptable polymers and / or copolymers relative to the total weight of the composition, but does not significantly change the relative weight ratio of the total amount of enzalutamide to the total amount of one or more physiologically acceptable polymers and / or copolymers.

[0146] Other techniques, particularly solid / liquid separation techniques, typically further alter the relative weight ratio of the total amount of enzalutamide to the total amount of one or more physiologically acceptable polymers and / or copolymers.

[0147] Solid / liquid separation can be achieved, for example, by centrifugation, ultrafiltration, nanofiltration, etc. The substantial total amount of enzalutamide contained in the slurry or suspension is typically contained in the solid phase (crystalline nanoparticles), while the majority of the total amount of one or more physiologically acceptable polymers and / or copolymers is typically contained in the liquid phase (e.g., aqueous solution). Thus, any technique for separating a portion of the liquid phase from the solid phase will relatively reduce the amount of one or more physiologically acceptable polymers and / or copolymers in the composition, but will not significantly affect the amount of enzalutamide in the composition.

[0148] Depending on the solubility and given concentration of the one or more physiologically acceptable polymers and / or copolymers in the liquid, the one or more physiologically acceptable polymers and / or copolymers may partially precipitate, such that a first portion of the one or more physiologically acceptable polymers and / or copolymers remains in the liquid phase in dissolved form, while a second portion of the one or more physiologically acceptable polymers and / or copolymers is present in the solid phase, i.e., together with the crystalline nanoparticles. For example, the second portion of the one or more physiologically acceptable polymers and / or copolymers may form a solid matrix in which the crystalline nanoparticles can be embedded.

[0149] The excess amount of one or more physiologically acceptable polymers and / or copolymers and the excess amount of one or more physiologically acceptable surfactants can be removed from the suspension or slurry, for example, by filtration through a hydrophilic filter or by centrifugation followed by discarding the supernatant, i.e., the solution of one or more physiologically acceptable polymers and / or copolymers and, optionally, one or more physiologically acceptable surfactants. The residual material thus obtained can be washed with a solvent, for example, water. The filtration or centrifugation step can be repeated as many times as necessary.

[0150] For example, the suspension or slurry may be centrifuged and a portion of the upper solution (supernatant) may be decanted or otherwise removed. The remaining material is either a wet solid or is still a suspension or slurry, which now contains a higher concentration of crystalline nanoparticles.

[0151] Alternatively or additionally, ultrafiltration techniques known to those skilled in the art can be performed. Centrifugal ultrafiltration devices can be used to purify, wash, and concentrate crystalline nanoparticles based on size. Centrifugal ultrafiltration units are commercially available, such as Amicon® Ultra (Merck KGaA) and Centricon® Plus (Merck Millipore). Purification systems are also commercially available, such as Amicon® Pro (Merck KGaA). The separation and concentration of molecules during ultrafiltration is based on size exclusion. The majority of biomolecules have molecular weights less than 500,000 Da, and crystalline nanoparticles fit well into this category. Suitable filter systems are provided with membrane nominal molecular weight cutoffs (NMWL) of 3,000, 10,000, 30,000, 50,000, and 100,000 Da. To retain crystalline nanoparticles, the molecular weight cutoff of the filtration membrane needs to be smaller than that of crystalline nanoparticles, but large enough to filter smaller components.

[0152] In optional step (d) of the process according to the invention, the suspension or slurry obtained in step (b), the mixed suspension or slurry obtained in step (c), or the subsequently concentrated suspension or slurry is dried, thereby obtaining a residue composition, e.g., a solid dry material, or a solid but still moist material. Drying typically involves evaporation of volatile liquid components.

[0153] Drying may be complete or partial. Thus, for purposes of this specification, drying may encompass evaporation of essentially all (complete) or only a portion (partial) of the volatile liquid component.

[0154] Partial drying is preferred because the residual composition thus obtained still contains a residual amount of liquid (e.g., water), which can subsequently be used as a granulation liquid for preparing a pharmaceutical formulation or dosage form from the composition.

[0155] According to another preferred embodiment, the suspension or slurry is dried to obtain a solid residual composition comprising crystallized nanosized enzalutamide (crystalline nanoparticles), one or more physiologically acceptable polymers and / or copolymers, and optionally one or more physiologically acceptable surfactants.

[0156] In the solid state, i.e., after removal of essentially all of the volatile liquid components, the crystalline nanoparticles according to the invention, the precipitated one or more physiologically acceptable polymers and / or copolymers, and optionally the precipitated one or more physiologically acceptable surfactants, may be associated with one another. Alternatively, the one or more physiologically acceptable polymers and / or copolymers, and optionally the precipitated one or more physiologically acceptable surfactants, may be separated independently of one another into a first fraction and a second fraction, the first fraction being associated with the crystalline nanoparticles according to the invention, and the second fraction not being associated with the crystalline nanoparticles according to the invention.

[0157] The same applies to association in a semi-liquid state, in which a residual amount of liquid is still present, but which is not sufficient to dissolve the total amount of the one or more physiologically acceptable polymers and / or copolymers and / or the total amount of the one or more physiologically acceptable surfactants optionally present, thereby inducing their (partial) precipitation.

[0158] The association may be of any type. For example, as described above, the crystalline nanoparticles may be embedded in a matrix comprising one or more physiologically acceptable polymers and / or copolymers, and optionally one or more physiologically acceptable surfactants. The surface of the crystalline nanoparticles may be completely or partially coated with one or more physiologically acceptable polymers and / or copolymers, and optionally one or more physiologically acceptable surfactants.

[0159] If the process according to the invention does not involve solid / liquid separation techniques, then the suspension or slurry obtained in step (b) may comprise: - Enzalutamide; - one or more physiologically acceptable polymers and / or copolymers; and - optionally one or more physiologically acceptable surfactants; The total content of remains essentially constant and is therefore included in the dry residue composition as well.

[0160] Drying is preferably carried out in an oven, preferably at a temperature in the range 20-40°C, more preferably at about 30°C, for example for 24 hours or until the residual moisture content is ≦5 wt.%.

[0161] Drying can be carried out using methods known in the art. Exemplary drying methods include heating, evaporation, vacuum drying, use of a fluidized bed dryer, spray drying, and freeze drying.

[0162] In optional step (e) of the process according to the invention, the crystalline nanoparticles are crushed or ground, for example in a suitable mill. The dried residual composition is crushed or ground to obtain a powder ready for tableting.

[0163] The crystalline nanoparticles are preferably obtained by drying in step (d) followed by crushing / grinding in step (e).

[0164] Another aspect of the present invention relates to a composition obtainable or obtained by the process according to the invention as described above.

[0165] Another aspect of the present invention relates to a pharmaceutical formulation comprising the composition according to the present invention as described above and one or more pharmaceutical excipients, which are typically different from the one or more physiologically acceptable polymers and / or copolymers and any one or more physiologically acceptable surfactants already contained in the composition according to the present invention as described above.

[0166] An additional amount of one or more pharmaceutical excipients (e.g., polymers or copolymers) already contained in the composition according to the invention can be added as pharmaceutical excipients to the pharmaceutical formulation according to the invention, in which case a first portion is already contained in the composition and the remainder is added when preparing the pharmaceutical formulation from the composition. However, in a preferred embodiment, the pharmaceutical excipient included in the composition is different from the pharmaceutical excipient added when preparing the pharmaceutical formulation from the composition.

[0167] Preferably, the pharmaceutical excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a lubricant, a glidant, a retarding polymer, and any combination thereof.

[0168] Examples of fillers (diluents) include, but are not limited to, starch, lactose, xylitol, sorbitol, refined powdered sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, dicalcium phosphate dehydrate, calcium sulfate, etc. Fillers typically represent 20% to 80% by weight of the pharmaceutical formulation.

[0169] Examples of binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch, etc.; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), ethyl cellulose, sodium carboxymethylcellulose, etc.; natural gums such as acacia, alginic acid, guar gum, etc.; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinylamide, polyethylene glycol, gelatin, polypropylene glycol, tragacanth, etc. Binders typically represent up to 10 wt.% of the pharmaceutical formulation.

[0170] Examples of disintegrants include, but are not limited to, alginic acid, DVB methacrylate, cross-linked PVP, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, corn or maize starch, starch, including pregelatinized starch, etc. The disintegrant(s) typically represent up to 20 wt.% of the pharmaceutical formulation.

[0171] Examples of surfactants have already been described above in relation to the pharmaceutical excipients preferably contained in the crystalline nanoparticles. The same surfactants are also primarily useful. The surfactant(s) typically represent up to 5.0 wt.% of the pharmaceutical formulation.

[0172] Examples of lubricants include, but are not limited to, magnesium stearate, aluminum stearate, calcium stearate, zinc stearate, stearic acid, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, talc, hydrogenated vegetable oils, etc. Surfactants typically represent 0.2 wt.% to 5.0 wt.% of the pharmaceutical formulation.

[0173] Examples of glidants include, but are not limited to, silicon dioxide, anhydrous colloidal silica, magnesium trisilicate, tricalcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, powdered cellulose, starch, talc, etc. Glidants typically represent 0.01 wt.% to 0.3 wt.% of the pharmaceutical formulation.

[0174] Examples of retardation polymers include, but are not limited to, cellulose derivatives such as cellulose ethers or cellulose esters; guar and guar derivatives; pectin; carrageenan; xanthan gum; locust bean gum; agar; algin and its derivatives, gellan gum, acacia, starch and modified starches; and synthetic polymers, including, but not limited to, homopolymers and copolymers of carboxyvinyl monomers, homopolymers and copolymers of acrylate or methacrylate monomers, homopolymers and copolymers of oxyethylene or oxypropylene monomers; or any combination of the foregoing.

[0175] The weight content of enzalutamide in the pharmaceutical formulation is not particularly limited. Preferably, the weight content of enzalutamide is at least 1.0 wt.%, preferably at least 2.5 wt.%, more preferably at least 5.0 wt.% in each case relative to the total weight of the pharmaceutical formulation. Preferably, the weight content of enzalutamide is at least 10 wt.%, preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 25 wt.%, even more preferably at least 30 wt.%, even more preferably at least 35 wt.%, even more preferably at least 40 wt.%, most preferably at least 45 wt.%, and in particular at least 50 wt.% in each case relative to the total weight of the pharmaceutical formulation.

[0176] In particularly preferred embodiments, the pharmaceutical dosage form according to the invention comprises one or more excipients selected from fillers, disintegrants, glidants, and lubricants.

[0177] Preferably present in the pharmaceutical dosage form: - nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; - one or more physiologically acceptable polymers and / or copolymers; and the total content of optional one or more physiologically acceptable surfactants, In each case, it amounts to at least 20 wt.%, preferably at least 22.5 wt.%, more preferably at least 25 wt.%, even more preferably at least 27.5 wt.%, even more preferably at least 30 wt.%, even more preferably at least 32.5 wt.%, most preferably at least 35 wt.%, and especially at least 37.5 wt.%, relative to the total weight of the pharmaceutical dosage form.

[0178] Preferably, the pharmaceutical dosage form according to the invention contains one or more fillers; preferably microcrystalline cellulose, a cellulose ether, or a mixture thereof.

[0179] Preferably, the total content of the one or more fillers amounts to at least 30 wt.%, preferably at least 32.5 wt.%, more preferably at least 30 wt.%, even more preferably at least 32.5 wt.%, even more preferably at least 35 wt.%, and even more preferably at least 37.5 wt.%, most preferably at least 40 wt.%, and in particular at least 42.5 wt.%, in each case relative to the total weight of the pharmaceutical formulation.

[0180] In a preferred embodiment, the pharmaceutical dosage form according to the invention contains one or more disintegrants; preferably croscarmellose sodium.

[0181] Preferably, the total content of the one or more disintegrants amounts to at least 0.5 wt.%, preferably at least 1.0 wt.%, more preferably at least 1.5 wt.%, even more preferably at least 2.5 wt.%, in each case relative to the total weight of the pharmaceutical formulation.

[0182] Preferably, the pharmaceutical dosage form according to the invention contains one or more lubricants, preferably magnesium stearate, silica, or mixtures thereof.

[0183] Preferably, the pharmaceutical dosage form according to the invention does not contain any binders other than one or more physiologically acceptable polymers and / or copolymers.

[0184] Preferably, the pharmaceutical dosage form according to the invention comprises or consists essentially of an intragranular phase and an extragranular phase.

[0185] Preferably, essentially present in the pharmaceutical dosage form, - nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; - one or more physiologically acceptable polymers and / or copolymers; and the total content of optional one or more physiologically acceptable surfactants, It is contained in the intragranular phase.

[0186] In a preferred embodiment, the pharmaceutical dosage form according to the invention contains a first portion of the disintegrant in the intragranular phase and a second portion of the disintegrant in the extragranular phase.

[0187] Preferably, the weight content of the intragranular phase amounts to at least 60 wt.%, preferably at least 65 wt.%, more preferably at least 70 wt.%, even more preferably at least 75 wt.%, even more preferably at least 80 wt.%, even more preferably at least 85 wt.%, most preferably at least 90 wt.%, and in particular at least 95 wt.%, in each case relative to the total weight of the pharmaceutical formulation.

[0188] Another aspect of the present invention relates to a pharmaceutical dosage form comprising a composition according to the present invention as described above or a pharmaceutical formulation according to the present invention as described above.

[0189] Preferably, the pharmaceutical dosage form is selected from tablets, microtablets, capsules, powders, granules, suspensions, emulsions.

[0190] In a preferred embodiment, the pharmaceutical dosage form according to the invention is a film-coated tablet.

[0191] The total weight of the pharmaceutical dosage form according to the present invention is not particularly limited. However, as far as oral dosage forms are concerned, the size should preferably not exceed a certain limit for ease of swallowing and patient compliance.

[0192] Preferably, the pharmaceutical dosage form has a total weight of 1000 mg or less, preferably 950 mg or less, more preferably 900 mg or less, even more preferably 850 mg or less, even more preferably 800 mg or less, still more preferably 750 mg or less, most preferably 700 mg or less, and especially 650 mg or less.

[0193] In a preferred embodiment, the pharmaceutical dosage form according to the present invention contains enzalutamide in a dose within the range of 30±15 mg, or 40±20 mg, or 60±30 mg, or 80±40 mg, or 120±60 mg, or 150±75 mg, or 160±80 mg, or 200±80 mg, or 240±120 mg, or 300±150 mg, or 360±180 mg, in each case expressed as the weight equivalent of the non-salt form of enzalutamide. Preferably, the dose of enzalutamide is 120 mg or 160 mg.

[0194] Another aspect of the present invention is a method for preparing a pharmaceutical formulation according to the invention as described above, comprising the following steps: (i) providing a composition according to the present invention as described above; (ii) granulating, preferably wet granulating, the composition with one or more pharmaceutical excipients; and (iii) compressing the granules.

[0195] Preferably, the process for the preparation of the pharmaceutical dosage form comprises the process for the preparation of the composition according to the invention described above.

[0196] Another aspect of the present invention relates to a pharmaceutical dosage form according to the present invention as described above for use in the treatment of a hyperproliferative disease. Another aspect of the present invention relates to a method for treating a hyperproliferative disease, comprising administering to a subject in need thereof a pharmaceutical dosage form according to the present invention as described above. Another aspect of the present invention relates to the use of enzalutamide for the manufacture of a pharmaceutical dosage form according to the present invention as described above for the treatment of a hyperproliferative disease.

[0197] Preferably, the hyperproliferative disorder is selected from the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer. Preferably, the hyperproliferative disorder is prostate cancer selected from hormone-refractory prostate cancer and hormone-sensitive prostate cancer.

[0198] Preferably, the pharmaceutical dosage form according to the invention is administered orally.

[0199] Preferably, the pharmaceutical dosage form according to the present invention is administered once a day or twice a day; preferably once a day, and in either case, optionally includes simultaneous administration of multiple pharmaceutical dosage forms. In this regard, "simultaneous administration" means that a subject takes two or more pharmaceutical preparations within a relatively short period of time, for example, within 10 minutes, preferably within 5 minutes.

[0200] In a preferred embodiment, the pharmaceutical dosage form according to the invention is orally administered after a meal. In another preferred embodiment, the pharmaceutical dosage form according to the invention is orally administered before a meal. [Example]

[0201] The following examples further illustrate the present invention but should not be construed as limiting its scope.

[0202] Materials and Methods Amorphous nano-sized enzalutamide was prepared from bulk enzalutamide using the process disclosed in US 10,098,842.

[0203] ZEM images were acquired using a Zeiss Sigma300 VP SEM instrument. Samples were dispersed in water and filtered through a 0.1 μm filter. The filter was dried, transferred to an SEM sample holder, and coated with a 5 nm thick platinum layer.

[0204] XRPD measurements were performed using a Malvern PANalytical Empyrean X-ray diffractometer equipped with a Cu Kα (1.54 Å) source, MultiCore optics, and a solid-state PIXcel3D detector. Samples were attached to aluminum or polycrystalline silicon sample holders using Kapton tape. Dry slurries were measured without further sample preparation under Kapton tape; the suspension was filtered, dried, and the filter attached with double-sided tape. Samples were measured in reflection geometry on a spinning measurement stage. The measurement range was 5–40° (2θ). The step size and time per step values ​​were varied depending on the number of counts per second obtained.

[0205] Dynamic light scattering (DLS) measurements were performed using a Malvern Zetasizer. The slurry or dry powder was redispersed in water or 0.1% HPMC (aqueous solution) and stirred until the sample was completely dispersed. DLS measurements were performed using a backscattering analyzer and the CUMULANTS algorithm to obtain the mean particle size (Z-average) and polydispersity index (PI).

[0206] Example 1 - Preparation of amorphous nanoparticles of Enzalutamide: Amorphous nanoparticles of enzalutamide were prepared from a solution of enzalutamide in supercritical CO2 by controlled expansion of supercritical fluids (CESS™) (similar to US 10,098,842, Example 1 thereof).

[0207] The CESS™ process was carried out by using an apparatus including a pressure vessel, tubing, and a vacuum vessel connected together in a series arrangement. Comparative Example - Crystallization of Nanosized Amorphous Enzalutamide from Water

[0208] Amorphous enzalutamide nanoparticles obtained according to Example 1 were weighed and placed in a small glass vial. Deionized (DI) water was added to an amount sufficient to achieve an enzalutamide content of 5 mg / ml. The mixture was mixed with a magnetic stirrer and sonicated until all enzalutamide was completely surrounded (wetted) by water, and stirring was continued for at least 1 hour. SEM and XRD samples were prepared as described above. SEM images showed the formation of large (>2 μm) enzalutamide crystals.

[0209] Example 2 - Suspension of amorphous particles of Enzalutamide in polymer solution: Amorphous nanoparticles of enzalutamide obtained according to Example 1 were weighed and placed in a small glass vial. An aqueous polymer solution was added to the nanoparticles to achieve an enzalutamide content of 25 mg / ml. The mixture was mixed with a magnetic stirrer and sonicated until all the enzalutamide was completely surrounded (wet) by water. Stirring was continued for 16-24 hours. SEM and XRPD samples were prepared as described above. The results are summarized in the following table:

[0210] [Table 1]

[0211] As demonstrated by the experimental data above, the best nanocrystals of enzalutamide were obtained when crystallization was performed using an aqueous solution containing PVP-VA. Surprisingly, it was found that only under the conditions of Examples 2 and 3 did enzalutamide crystallize, i.e., convert from its original amorphous state to a crystalline state, while maintaining its nanoscale particle size. PVP-VA promotes the formation of nanoflakes that are at least partially crystalline. Crystallization from an aqueous suspension / slurry containing PVP-VA in an aqueous solution significantly reduces particle size.

[0212] Substitution of PVP-VA with other polymers significantly reduced the formation of the desired crystalline enzalutamide nanoparticles. The corresponding Example 2-2, in which HPMC was used instead of poly(vinylpyrrolidone vinyl acetate) copolymer, did not induce crystallization of enzalutamide.

[0213] In additional experiments, the concentration of amorphous enzalutamide nanoparticles and the concentration of PVP-VA were varied to investigate their effect on crystal size. A suspension / slurry of 25 mg / mL enzalutamide and 5 wt.% PVP-VA (high water content) yielded flakes and large crystals, whereas a slurry of 250 mg / mL enzalutamide and 25 wt.% PVP-VA (low water content) yielded flakes.

[0214] Electron micrographs revealed that increasing the PVP-VA content in the solution led to a decrease in particle size. Figures 1–4 show electron micrographs of PVP-VA solutions with concentrations of 1 wt.%, 2.5 wt.%, 5 wt.%, and 10 wt.% (A: 25,000x magnification, B: 5,000x magnification).

[0215] Furthermore, XRPD analysis revealed that decreasing the content of PVP-VA in the solution promoted crystallinity (see Figure 5).

[0216] Example 3 - Various mixing conditions: According to Example 2, amorphous nanoparticles of enzalutamide were suspended in an aqueous solution of poly(vinylpyrrolidone-vinyl acetate) copolymer (PVP-VA, Copovidone). The solution further contained 0.2 wt.% sodium lauryl sulfate (SLS). The resulting suspension / slurry was mixed under various conditions, and the properties of the resulting crystalline nanoparticles were investigated.

[0217] It was observed that increasing the mixing time resulted in the breakup of agglomerates, while increasing the concentration of PVP-VA accelerated the process (see Figure 6 , Z-average particle size in nm).

[0218] Similar results were achieved by ultrasonic bath treatment (see Figure 7, Z-average particle size in nm).

[0219] Additional suspension / slurry experiments were performed at the following ratios / weight percentages of enzalutamide:PVP-VA: (a) 15:15%, (b) 20:20%, (c) 20:10%, (d) 20:30%, (e) 25:25%, (f) 30:30%, and (g) 35:35%.

[0220] The properties of the crystalline nanoparticles thus obtained were investigated by electron microscopy. For a 30:30% ratio (f), the degree of crystallinity was observed by XRPD as a function of mixing time. Figure 8 shows the XRPD intensity coefficients of crystalline enzalutamide nanoparticles obtained from a suspension / slurry of 30 wt.% enzalutamide and 30 wt.% PVP-VA in an aqueous PVA-VA solution at different mixing times.

[0221] Based on electron micrographs, it was revealed that optimal results could be achieved when the relative weight ratio of enzalutamide:PVP-VA was approximately 1:1, the concentration of PVP-VA in the aqueous solution was approximately 20-30 wt.%, and the mixing time was approximately 6-24 hours.

[0222] Example 4 - Preparation of crystalline nanoparticles of Enzalutamide with or without surfactant: Amorphous nanoparticles of enzalutamide according to Example 1 were suspended in aqueous PVP-VA solutions at a concentration of 20 wt.% according to Examples 2 and 3 in the absence and presence of 0.2 wt.% SLS.

[0223] FIG. 9 shows the Z-average particle size in nm of the wet and dry particles in the absence and presence of SLS, and FIG. 10 shows the corresponding XRPD intensity coefficients of the wet and dry particles thus obtained in the absence and presence of SLS.

[0224] Example 5 - Comparison of nanosuspensions in vivo: Preparation of the suspension: Each vial was filled with 180 mg of dried nanocrystals produced by a controlled crystallization process, and 18 mL (4 × 4.5 mL) of the various suspension vehicles was added 45 minutes to 1.5 hours before dosing. To ensure adequate dispersion, the suspension was mixed using a magnetic stirrer until administration. The enzalutamide concentration was 5 mg / mL. Xtandi® suspensions were prepared in 1% MC.

[0225] [Table 2]

[0226] result: Enzalutamide nanocrystal suspension demonstrated similar plasma concentration versus time profiles compared to 1% MC Xtandi® suspension; AUC 0-last , C max , or T max The pharmacokinetic parameters of the nanocrystals in different suspension vehicles compared to the Xtandi® ASD formulation in 1% MC suspension are now summarized in the table below:

[0227] [Table 3]

[0228] FIG. 11 shows the plasma concentration time curves.

[0229] Conclusions from in vivo studies: The nanocrystal formulation achieved exposure levels comparable to the reference product, Xtandi®, in an in vivo pharmacokinetic study in rats. Various suspension formulations of enzalutamide performed similarly.

[0230] Example 6 - Tablets: Three formulations were manufactured using wet granulation techniques. A drug loading of 20% w / w was used, and tablet compression parameters (e.g., die cavity height, compression force, ejection force, strokes / min) were kept constant to investigate the effect of excipients on tablet properties.

[0231] Compressed tablets were manufactured by a process involving the following steps: 1. Controlled Crystallization: A slurry of Enzalutamide and Copovidone was first prepared and considered as the preliminary raw material / starting material for further wet granulation process. 2. Wet Blend: Dry powder excipients (fillers, binders, disintegrants, etc.) were added to the intermediate wet mass during continuous mixing using an overhead stirrer. 3. Wet Granulation: Mixing was continued with an agitator to allow for proper wetting and adhesion and to obtain a homogenous mixture of active agents and excipients. The wet mass was passed through a larger screen sieve and collected in a suitable container for drying process. Prior to the drying process, the granules were properly layered / spread in the container to allow for a uniform drying process. 4. Drying: The granules were dried in a tray dryer / hot air oven at an inlet temperature of 32±5° C. (to an LOD of less than 5%) and 10% relative humidity. 5. Grinding and sieving: The dried granules were crushed in a mortar and pestle. The crushed granules were passed through different sieves to create different size fractions. The required amount of different granule fractions was weighed separately. 6. Lubrication: The granules were blended in a separate container with the extragranular excipients magnesium stearate and Aerosil®. 7. Compression: The final blend was manually filled into the die cavity. Tablets were compressed using predefined process parameters. 8. De-dusting and storage: The compressed tablets were collected, manually de-dusted and stored in sealed glass vials until further investigation.

[0232] To study the effect of excipient concentration on tablet quality, three different formulations were evaluated. The composition of the formulations is now summarized in the table below:

[0233] [Table 4]

[0234] No change in tablet properties was observed when tablets were prepared with or without the additional binder - HPMC. It was concluded that the concentration and type of excipients had only a small effect on tablet hardness and disintegration time.

Claims

1. - nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; one or more physiologically acceptable polymers and / or copolymers; and - optionally one or more physiologically acceptable surfactants; the nanoparticles have a z-average particle size of at most 800 nm; and The composition, wherein the relative weight ratio of the total amount of enzalutamide to the total amount of the one or more physiologically acceptable polymers and / or copolymers is within the range of 5.0:1.0 to 1.0:5.

0.

2. 2. The composition of claim 1, wherein the one or more physiologically acceptable polymers and / or copolymers have a solubility in water according to Ph. Eur. of at least "slightly soluble", preferably at least "soluble", more preferably at least "freely soluble".

3. 3. The composition of claim 1 or 2, wherein the one or more physiologically acceptable polymers and / or copolymers comprise or consist essentially of a copolymer derived from a first monomer and a second monomer, the first monomer being more hydrophilic than the second monomer.

4. 4. The composition of claim 3, wherein the first monomer has a dipole moment that is relatively at least 0.1 Debye, preferably at least 0.2 Debye, more preferably at least 0.3 Debye, and even more preferably at least 0.4 Debye greater than the dipole moment of the second monomer.

5. 10. A composition according to any preceding claim, wherein the one or more physiologically acceptable polymers and / or copolymers comprise or consist essentially of vinylpyrrolidone vinyl acetate copolymer.

6. 6. The composition of claim 5, wherein the vinylpyrrolidone vinyl acetate copolymer is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a weight ratio of about 3:

2.

7. 7. The composition of claim 5 or 6, wherein the vinylpyrrolidone vinyl acetate copolymer contains at least 35.0 wt. % and at most 42.0 wt. % vinyl acetate, calculated on a dry basis.

8. 10. A composition according to any preceding claim, wherein the total content of the one or more physiologically acceptable polymers and / or copolymers, relative to the total dry solids content of the composition, is at least 10 wt.%, preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 25 wt.%, even more preferably at least 30 wt.%, still more preferably at least 35 wt.%, most preferably at least 40 wt.%, and especially at least 45 wt.%.

9. 10. A composition according to any preceding claim, wherein the total content of the one or more physiologically acceptable polymers and / or copolymers, relative to the total dry solids content of the composition, is at most 90 wt.%, preferably at most 85 wt.%, more preferably at most 80 wt.%, even more preferably at most 75 wt.%, even more preferably at most 70 wt.%, still more preferably at most 65 wt.%, most preferably at most 60 wt.%, and in particular at most 55 wt.%.

10. 10. A composition according to any preceding claim, wherein the total content of the one or more physiologically acceptable polymers and / or copolymers relative to the weight of the composition is at least 7.5 wt.%, preferably at least 10 wt.%, more preferably at least 12.5 wt.%, even more preferably at least 15 wt.%, even more preferably at least 17.5 wt.%, still more preferably at least 20 wt.%, most preferably at least 22.5 wt.%, and especially at least 25 wt.%.

11. 10. A composition according to any of the preceding claims, wherein the total content of the one or more physiologically acceptable polymers and / or copolymers relative to the total weight of the composition is at most 60 wt.%, preferably at most 55 wt.%, more preferably at most 50 wt.%, even more preferably at most 45 wt.%, even more preferably at most 40 wt.%, even more preferably at most 35 wt.%, most preferably at most 30 wt.%, and in particular at most 25 wt.%.

12. 10. A composition according to any of the preceding claims, wherein the content of enzalutamide relative to the total weight of the nanoparticles is at least 90.0 wt.%, preferably at least 92.5 wt.%, more preferably at least 95 wt.%, even more preferably at least 96 wt.%, even more preferably at least 97 wt.%, still more preferably at least 98 wt.%, most preferably at least 99.0 wt.%, and in particular at least 99.5 wt.%.

13. 10. A composition according to any one of the preceding claims, wherein the content of enzalutamide relative to the total dry solids content of the composition is at least 10 wt.%, preferably at least 15 wt.%, more preferably at least 20 wt.%, even more preferably at least 25 wt.%, even more preferably at least 30 wt.%, even more preferably at least 35 wt.%, most preferably at least 40 wt.%, and especially at least 45 wt.%.

14. 10. A composition according to any preceding claim, wherein the content of enzalutamide relative to the total dry solids content of the composition is at most 90 wt.%, preferably at most 85 wt.%, more preferably at most 80 wt.%, even more preferably at most 75 wt.%, even more preferably at most 70 wt.%, still more preferably at most 65 wt.%, most preferably at most 60 wt.%, and in particular at most 55 wt.%.

15. 10. A composition according to any preceding claim, wherein the content of enzalutamide relative to the total weight of the composition is at least 7.5 wt.%, preferably at least 10 wt.%, more preferably at least 12.5 wt.%, even more preferably at least 15 wt.%, even more preferably at least 17.5 wt.%, even more preferably at least 20 wt.%, most preferably at least 22.5 wt.%, and in particular at least 25 wt.%.

16. 10. The composition according to any one of the preceding claims, wherein the content of enzalutamide relative to the total weight of the composition is at most 60 wt.%, preferably at most 55 wt.%, more preferably at most 50 wt.%, even more preferably at most 45 wt.%, even more preferably at most 40 wt.%, even more preferably at most 35 wt.%, most preferably at most 30 wt.%, and in particular at most 25 wt.%.

17. 10. A composition according to any preceding claim, wherein the relative weight ratio of the total amount of enzalutamide to the total amount of the one or more physiologically acceptable polymers and / or copolymers is in the range of 4.5:1.0 to 1.0:4.5, preferably 4.0:1.0 to 1.0:4.0, more preferably 3.5:1.0 to 1.0:3.5, even more preferably 3.0:1.0 to 1.0:3.0, even more preferably 2.5:1.0 to 1.0:2.5, still more preferably 2.0:1.0 to 1.0:2.0, most preferably 1.5:1.0 to 1.0:1.5, and especially 1.3:1.0 to 1.0:1.

3.

18. 10. A composition according to any preceding claim, wherein the one or more physiologically acceptable surfactants comprise or consist essentially of a surfactant selected from the group consisting of: (i) alkyl sulfates, preferably selected from sodium lauryl sulfate (sodium dodecyl sulfate), sodium cetyl sulfate, sodium cetylstearyl sulfate, sodium stearyl sulfate, sodium dioctyl sulfosuccinate, and their corresponding potassium or calcium salts; (ii) fatty acid salts, preferably selected from stearates and oleates; and (iii) salts of cholic acid, preferably selected from sodium deoxycholate, sodium glycocholate, sodium taurocholate, and the corresponding potassium or ammonium salts.

19. 10. A composition according to any preceding claim, wherein the one or more physiologically acceptable surfactants comprise or consist essentially of a surfactant selected from the group consisting of sodium lauryl sulfate (SLS), Tween 80, Tween 20, dioctyl sulfosuccinate sodium salt (DOSS), and tocophersolan (TPGS).

20. 10. A composition according to any preceding claim, wherein the one or more physiologically acceptable surfactants comprise or consist essentially of sodium lauryl sulfate.

21. 10. A composition according to any preceding claim, wherein the total content of the one or more physiologically acceptable surfactants relative to the total weight of the composition is at most 7.0 wt.%, preferably at most 6.0 wt.%, even more preferably at most 5.0 wt.%, even more preferably at most 4.0 wt.%, still more preferably at most 3.0 wt.%, most preferably at most 2.0 wt.%, and in particular at most 1.0 wt.%.

22. 10. A composition according to any preceding claim, which is completely free of surfactants.

23. 10. A composition according to any preceding claim, which is a suspension or slurry comprising, or consisting essentially of, (i) a solid phase comprising, or consisting essentially of, said nanoparticles, and (ii) a liquid phase, wherein the total content of said one or more surfactants in said liquid phase is in the range of 0.0025 to 1.5 wt. %.

24. 10. The composition of any preceding claim, wherein the nanoparticles are nanoflakes.

25. 10. A composition according to any preceding claim, wherein the nanoparticles have a Z-average particle size of at most 750 nm, preferably at most 700 nm, more preferably at most 650 nm, even more preferably at most 600 nm, even more preferably at most 550 nm, and even more preferably at most 500 nm, most preferably at most 450 nm, in particular at most 400 nm.

26. 10. A composition according to any preceding claim, wherein the nanoparticles have a Z-average particle size of at least 10 nm, preferably at least 20 nm, more preferably at least 30 nm, even more preferably at least 40 nm, even more preferably at least 50 nm, and even more preferably at least 60 nm, most preferably at least 70 nm, in particular at least 80 nm.

27. The nanoparticles are D Ｖ 9. The composition according to any of the preceding claims, having a particle size distribution characterized by a 90 value of at most 600 nm, preferably at most 550 nm, more preferably at most 500 nm, even more preferably at most 450 nm, even more preferably at most 400 nm, still more preferably at most 350 nm, most preferably at most 300 nm and especially preferably at most 250 nm.

28. The nanoparticles are D Ｖ 5. The composition according to any of the preceding claims, having a particle size distribution characterized in that the .SQ value is at most 600 nm, preferably at most 550 nm, more preferably at most 500 nm, even more preferably at most 450 nm, even more preferably at most 400 nm, still more preferably at most 350 nm, most preferably at most 300 nm and especially preferably at most 250 nm.

29. A composition according to any of the preceding claims, comprising: - nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; vinylpyrrolidone vinyl acetate copolymer; and optionally comprising or consisting essentially of sodium lauryl sulfate; The Z-average particle size of said nanoparticles is at most 700 nm; preferably at most 600 nm; more preferably at most 500 nm; The composition, wherein the relative weight ratio of the total amount of enzalutamide to the vinylpyrrolidone vinyl acetate copolymer is within the range of 4.0:1.0 to 1.0:4.0, preferably 2.5:1.0 to 1.0:2.

5.

30. 10. A composition according to any preceding claim, which is free of sodium lauryl sulfate; preferably free of any anionic surfactant; more preferably free of any physiologically acceptable surfactant.

31. 10. A composition according to any preceding claim which is a solid.

32. 10. A composition according to any preceding claim which is a suspension or a slurry.

33. 33. The composition of claim 32, comprising or consisting essentially of: (i) a solid phase, preferably comprising or consisting essentially of said nanoparticles; and (ii) a liquid phase, preferably in which at least a portion of said one or more physiologically acceptable polymers and / or copolymers are dissolved.

34. 34. A composition according to claim 32 or 33, wherein the liquid phase is aqueous; preferably water is the only liquid component of the composition.

35. 35. The composition according to claim 34, having a water content of at least 5.0 wt.%, preferably at least 10 wt.%, more preferably at least 15 wt.%, even more preferably at least 20 wt.%, even more preferably at least 25 wt.%, still more preferably at least 30 wt.%, most preferably at least 25 wt.%, and especially at least 40 wt.%, in each case based on the total weight of the composition (suspension or slurry).

36. The composition according to any one of claims 32 to 35, comprising, relative to the total weight of the composition: - the content of enzalutamide is within the range of 25±20 wt.%, preferably 25±15 wt.%, more preferably 25±10 wt.%, and even more preferably 25±5.0 wt.%; the total content of said one or more physiologically acceptable polymers and / or copolymers is in the range of 25±20 wt.%, preferably 25±15 wt.%, more preferably 25±10 wt.%, even more preferably 25±5.0 wt.%; The composition, wherein the water content is within the range of 50±40 wt.%, preferably 50±30 wt.%, more preferably 50±20 wt.%, and even more preferably 50±10 wt.%.

37. 37. The composition of any of claims 32 to 36, having a viscosity of at least 5,000 mPa·s, preferably at least 7,500 mPa·s, more preferably at least 10,000 mPa·s.

38. 38. The composition according to any one of claims 32 to 37, having a viscosity of at most 40,000 mPa·s, preferably at most 35,000 mPa·s, more preferably at most 30,000 mPa·s.

39. 39. The composition according to any one of claims 32 to 38, comprising nanoparticles at a total concentration relative to the total weight of the composition (slurry or suspension) of at least 7.5 mg / mL, preferably at least 10 mg / mL, more preferably at least 12.5 mg / mL, even more preferably at least 15 mg / mL, even more preferably at least 17.5 mg / mL, even more preferably at least 20 mg / mL, most preferably at least 22.5 mg / mL, and especially at least 25 mg / mL.

40. 40. The composition according to any one of claims 32 to 39, comprising nanoparticles at a total concentration relative to the total weight of the composition (slurry or suspension) of at least 75 mg / mL, preferably at least 100 mg / mL, more preferably at least 125 mg / mL, even more preferably at least 150 mg / mL, even more preferably at least 175 mg / mL, even more preferably at least 200 mg / mL, most preferably at least 225 mg / mL, and especially at least 250 mg / mL.

41. 41. The composition according to any one of claims 32 to 40, containing said nanoparticles at a total concentration of at most 475 mg / mL, preferably at most 450 mg / mL, more preferably at most 425 mg / mL, even more preferably at most 400 mg / mL, even more preferably at most 375 mg / mL, still more preferably at most 350 mg / mL, most preferably at most 325 mg / mL, and especially at most 300 mg / mL, relative to the total weight of the composition (slurry or suspension).

42. 42. The composition according to any one of claims 32 to 41, containing said nanoparticles at a total concentration of at most 47.5 mg / mL, preferably at most 45 mg / mL, more preferably at most 42.5 mg / mL, even more preferably at most 40 mg / mL, even more preferably at most 37.5 mg / mL, still more preferably at most 35 mg / mL, most preferably at most 32.5 mg / mL, and especially at most 30 mg / mL relative to the total weight of the composition (slurry or suspension).

43. 1. A process for converting nanoparticles comprising or consisting essentially of enzalutamide in amorphous form (amorphous nanoparticles) into nanoparticles comprising enzalutamide in crystalline form (crystalline nanoparticles), the process comprising the steps of: (a) providing nanoparticles comprising or consisting essentially of enzalutamide in amorphous form; (b) contacting the nanoparticles provided in step (a) with the one or more physiologically acceptable polymers and / or copolymers in a liquid to obtain a suspension or slurry; (c) optionally mixing said suspension or said slurry; (d) optionally drying the suspension or the slurry to obtain a residual composition; and (e) optionally, crushing the residual composition.

44. A process for the preparation of nanoparticles according to any of the preceding claims, comprising the following steps: (a) providing nanoparticles comprising or consisting essentially of enzalutamide in amorphous form; (b) contacting the nanoparticles provided in step (a) with the one or more physiologically acceptable polymers and / or copolymers in a liquid to obtain a suspension or slurry; (c) optionally mixing said suspension or said slurry; (d) optionally drying the suspension or the slurry to obtain a residual composition; and (e) optionally, crushing the residual composition.

45. Step (a) is a process for preparing a supercritical CO ２ 45. The process of claim 43 or 44, comprising dissolving enzalutamide in

46. 46. ​​The process according to any of claims 43 to 45, wherein the amorphous nanoparticles provided in step (a) have a Z-average particle size of at most 600 nm, preferably at most 550 nm, more preferably at most 500 nm, even more preferably at most 450 nm, even more preferably at most 400 nm, even more preferably at most 350 nm, most preferably 300 nm, and especially preferably 250 nm.

47. 47. The process according to any of claims 43 to 46, wherein the amorphous nanoparticles provided in step (a) have a Z-average particle size of at least 60 nm, preferably at least 80 nm, more preferably at least 100 nm, even more preferably at least 120 nm, even more preferably at least 140 nm, still more preferably at least 160 nm, most preferably at least 180 nm, and especially at least 200 nm.

48. The amorphous nanoparticles provided in step (a) are D Ｖ 48. A process according to any of claims 43 to 47, wherein the particle size distribution is characterized by a 90 value of at most 1000 nm, preferably at most 900 nm, more preferably at most 800 nm, even more preferably at most 700 nm, even more preferably at most 650 nm, still more preferably at most 600 nm, most preferably at most 550 nm, and especially at most 500 nm.

49. The amorphous nanoparticles provided in step (a) are D Ｖ 49. A process according to any of claims 43 to 48, wherein the particle size distribution is characterized by a 50 value of at least 50 nm, preferably at least 100 nm, more preferably at least 150 nm, even more preferably at least 200 nm, even more preferably at least 250 nm, still more preferably at least 300 nm, most preferably at least 350 nm, and especially at least 400 nm.

50. 50. The process according to any of claims 43 to 49, wherein in step (b), the liquid, preferably an aqueous solution, contains the one or more physiologically acceptable polymers and / or copolymers in a concentration in the range of 0.2 to 40% by weight, preferably 1 to 10% by weight, more preferably 1 to 5.0% by weight, relative to the total weight of the liquid.

51. 51. The process according to any of claims 43 to 50, wherein in step (b) the liquid contains the one or more physiologically acceptable polymers and / or copolymers in a total concentration of at least 7.5 wt.%, preferably at least 10 wt.%, more preferably at least 12.5 wt.%, even more preferably at least 15 wt.%, even more preferably at least 17.5 wt.%, still more preferably at least 20 wt.%, most preferably at least 22.5 wt.%, and especially at least 25 wt.%, relative to the total weight of the liquid.

52. 52. The process according to any of claims 43 to 51, wherein in step (b) the liquid contains the one or more physiologically acceptable polymers and / or copolymers in a total concentration of at most 47.5 wt.%, preferably at most 45 wt.%, more preferably at most 42.5 wt.%, even more preferably at most 40 wt.%, even more preferably at most 37.5 wt.%, still more preferably at most 35 wt.%, most preferably at most 32.5 wt.%, and especially at most 30 wt.%, relative to the total weight of the liquid.

53. 53. The process according to any of claims 43 to 52, wherein in step (b) the liquid contains the one or more physiologically acceptable surfactants in a total concentration of at least 0.06 wt.%, preferably at least 0.08 wt.%, more preferably at least 0.10 wt.%, even more preferably at least 0.12 wt.%, even more preferably at least 0.14 wt.%, still more preferably at least 0.16 wt.%, most preferably at least 0.18 wt.%, and especially at least 0.20 wt.%, relative to the total weight of the liquid.

54. 54. The process according to any of claims 43 to 53, wherein in step (b) the liquid contains the one or more physiologically acceptable surfactants in a total concentration of at most 0.75 wt.%, preferably at most 1.0 wt.%, more preferably at most 1.25 wt.%, even more preferably at most 1.5 wt.%, even more preferably at most 1.75 wt.%, still more preferably at most 2.0 wt.%, most preferably at most 2.25 wt.%, and especially at most 2.5 wt.%, based on the total weight of the liquid.

55. 55. The process of any of claims 43 to 54, wherein in step (b), the liquid contains the one or more physiologically acceptable surfactants at a concentration in the range of 0.0025 to 1.5% by weight. The surfactant improves wetting efficiency.

56. 56. The process according to any of claims 43 to 55, wherein in step (b) the obtained suspension or slurry contains said nanoparticles at a total concentration relative to the total weight of the liquid of at least 7.5 mg / mL, preferably at least 10 mg / mL, more preferably at least 12.5 mg / mL, even more preferably at least 15 mg / mL, even more preferably at least 17.5 mg / mL, still more preferably at least 20 mg / mL, most preferably at least 22.5 mg / mL, and especially at least 25 mg / mL.

57. 57. The process according to any of claims 43 to 56, wherein in step (b) the obtained suspension or slurry contains said nanoparticles at a total concentration relative to the total weight of the liquid of at least 75 mg / mL, preferably at least 100 mg / mL, more preferably at least 125 mg / mL, even more preferably at least 150 mg / mL, even more preferably at least 175 mg / mL, still more preferably at least 200 mg / mL, most preferably at least 225 mg / mL, and especially at least 250 mg / mL.

58. 58. The process according to any of claims 43 to 57, wherein in step (b) the obtained suspension or slurry contains said nanoparticles at a total concentration relative to the total weight of the liquid of at most 475 mg / mL, preferably at most 450 mg / mL, more preferably at most 425 mg / mL, even more preferably at most 400 mg / mL, even more preferably at most 375 mg / mL, still more preferably at most 350 mg / mL, most preferably at most 325 mg / mL, and especially at most 300 mg / mL.

59. 59. The process according to any of claims 43 to 58, wherein in step (b) the obtained suspension or slurry contains said nanoparticles at a total concentration relative to the total weight of the liquid of at most 47.5 mg / mL, preferably at most 45 mg / mL, more preferably at most 42.5 mg / mL, even more preferably at most 40 mg / mL, even more preferably at most 37.5 mg / mL, still more preferably at most 35 mg / mL, most preferably at most 32.5 mg / mL, and especially at most 30 mg / mL.

60. 60. The process of any of claims 43 to 59, wherein in step (c), the mixing is carried out at a temperature in the range of from 15°C to 40°C, preferably from 25°C to 35°C.

61. 61. The process of any of claims 43 to 60, wherein in step (c), mixing is carried out by stirring the suspension or slurry.

62. 62. The process according to any of claims 43 to 61, wherein in step (c), the mixing is carried out for a duration of from 2 hours to 48 hours, preferably from 6 hours to 24 hours.

63. A composition obtainable or obtained by a process according to any of claims 43 to 62.

64. 64. A pharmaceutical dosage form for oral administration comprising the composition of any of claims 1-42 or 63.

65. 65. The pharmaceutical dosage form of claim 64 prepared by a process involving wet granulation.

66. 66. The pharmaceutical dosage form of claim 64 or 65, selected from tablets, microtablets, capsules, powders, granules, suspensions, and emulsions.

67. A pharmaceutical dosage form according to any one of claims 64 to 66, which is a tablet; preferably a film-coated tablet.

68. 68. A pharmaceutical dosage form according to any of claims 64 to 67, having a total weight of not more than 1000 mg, preferably not more than 950 mg, more preferably not more than 900 mg, even more preferably not more than 850 mg, even more preferably not more than 800 mg, still more preferably not more than 750 mg, most preferably not more than 700 mg, and especially not more than 650 mg.

69. 69. The pharmaceutical dosage form of any of claims 64 to 68, containing the enzalutamide in a dose within the range of 30±15 mg, or 40±20 mg, or 60±30 mg, or 80±40 mg, or 120±60 mg, or 150±75 mg, or 160±80 mg, or 200±80 mg, or 240±120 mg, or 300±150 mg, or 360±180 mg, in each case expressed as the weight equivalent of the non-salt form of enzalutamide.

70. 70. A pharmaceutical dosage form according to any one of claims 64 to 69, comprising one or more excipients selected from fillers, disintegrants, glidants, and lubricants.

71. 71. A pharmaceutical dosage form according to any one of claims 64 to 70, wherein present in the pharmaceutical dosage form: - said nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; - said one or more physiologically acceptable polymers and / or copolymers; and the total content of said optional one or more physiologically acceptable surfactants is In each case, said pharmaceutical dosage form represents at least 20 wt.%, preferably at least 22.5 wt.%, more preferably at least 25 wt.%, even more preferably at least 27.5 wt.%, even more preferably at least 30 wt.%, still more preferably at least 32.5 wt.%, most preferably at least 35 wt.%, and especially at least 37.5 wt.%, relative to the total weight of said pharmaceutical dosage form.

72. 72. A pharmaceutical dosage form according to any of claims 64 to 71, containing one or more fillers; preferably microcrystalline cellulose, a cellulose ether, or mixtures thereof.

73. 73. A pharmaceutical dosage form according to claim 72, wherein the total content of the one or more fillers is at least 30 wt.%, preferably at least 32.5 wt.%, more preferably at least 30 wt.%, even more preferably at least 32.5 wt.%, even more preferably at least 35 wt.%, and even more preferably at least 37.5 wt.%, most preferably at least 40 wt.%, and in particular at least 42.5 wt.%, in each case relative to the total weight of the pharmaceutical formulation.

74. 74. A pharmaceutical dosage form according to any one of claims 64 to 73, containing one or more disintegrants; preferably croscarmellose sodium.

75. 75. A pharmaceutical dosage form according to claim 74, wherein the total content of the one or more disintegrants is at least 0.5 wt.%, preferably at least 1.0 wt.%, more preferably at least 1.5 wt.%, and even more preferably at least 2.5 wt.%, in each case relative to the total weight of the pharmaceutical formulation.

76. 76. A pharmaceutical dosage form according to any of claims 64 to 75, containing one or more lubricants and / or glidants; preferably magnesium stearate, silica, or mixtures thereof.

77. 77. A pharmaceutical dosage form according to any one of claims 64 to 76, which does not contain any binder other than said one or more physiologically acceptable polymers and / or copolymers.

78. 78. A pharmaceutical dosage form according to any one of claims 64 to 77, comprising or consisting essentially of an intragranular phase and an extragranular phase.

79. 79. The pharmaceutical dosage form of claim 78, wherein the pharmaceutical dosage form is essentially - said nanoparticles comprising or consisting essentially of enzalutamide in crystalline form; - said one or more physiologically acceptable polymers and / or copolymers; and the total content of said optional one or more physiologically acceptable surfactants is The pharmaceutical dosage form, contained in the intragranular phase.

80. 80. A pharmaceutical dosage form according to claim 78 or 79, wherein the intragranular phase contains a first portion of a disintegrant and the extragranular phase contains a second portion of a disintegrant.

81. 81. A pharmaceutical dosage form according to claims 78 to 80, wherein the weight content of the intragranular phase is in each case at least 60 wt.%, preferably at least 65 wt.%, more preferably at least 70 wt.%, even more preferably at least 75 wt.%, even more preferably at least 80 wt.%, still more preferably at least 85 wt.%, most preferably at least 90 wt.%, and in particular at least 95 wt.%, relative to the total weight of the pharmaceutical formulation.

82. A pharmaceutical dosage form according to any one of claims 64 to 81 for use in the treatment of a hyperproliferative disorder.

83. 83. The pharmaceutical preparation of claim 82, wherein the hyperproliferative disorder is selected from the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer.

84. 84. The pharmaceutical preparation of claim 82 or 83, wherein the hyperproliferative disorder is prostate cancer selected from hormone refractory prostate cancer and hormone sensitive prostate cancer.

85. 85. The pharmaceutical preparation according to any one of claims 82 to 84, which is administered orally.

86. 86. The pharmaceutical formulation of any one of claims 82 to 85, which is administered once daily, optionally comprising the simultaneous administration of multiple pharmaceutical dosage forms.

87. 87. The pharmaceutical preparation according to any one of claims 82 to 86, which is orally administered after a meal.

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