Nanoparticles comprising enzalutamide

Abstract

To provide pharmaceutical compositions and dosage forms comprising Enzalutamide, which are advantageous over the prior art, for example, with respect to release profile and / or drug content.SOLUTION: The present invention provides 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 uses of the pharmaceutical dosage forms for medical purposes.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to European Patent Application No. 19176304.4 filed May 23, 2019 and European Patent Application No. 19209182.5 filed November 14, 2019.

[0002] The present invention relates to nanoparticles comprising enzalutamide, methods for preparing such nanoparticles, pharmaceutical compositions and pharmaceutical dosage forms comprising such nanoparticles, methods for preparing such pharmaceutical dosage forms, and uses of the pharmaceutical dosage forms for medical purposes. [Background technology]

[0003] Enzalutamide is an androgen receptor signaling inhibitor used to treat castration-resistant prostate cancer (US Pat. No. 7,709,517). Enzalutamide is commercially available as softgel capsules and tablets (trade name "XTANDI®"). Softgel capsules are filled with a liquid containing 40 mg of enzalutamide and pharmaceutical excipients per capsule. Tablets contain 40 mg or 80 mg of enzalutamide and pharmaceutical excipients per tablet. The daily dose is 160 mg, so patients need to take four capsules, four 40 mg tablets, or two 80 mg tablets per day. A reasonably sized, suitable single tablet containing a prescribed amount of enzalutamide and with suitable and favorable solubility and / or dissolution stability and absorption would be an advantageous alternative to softgel capsules.

[0004] US2002 / 031547 relates to a pharmaceutical composition useful for rapid disintegration, which contains a poorly soluble drug held as a solid dispersion on a gel-forming water-soluble polymer. This includes an alkali and a weak or strong acid, and a salt substance with an endothermic standard enthalpy of solution or heat of solution. The rapid disintegration of the pharmaceutical composition of the present invention and the rapid dissolution of the drug contained in the formulation can occur in the gastrointestinal tract regardless of pH, thereby achieving excellent bioavailability.

[0005] US2002 / 009494 proposes a spray-dried solid dispersion containing a poorly soluble drug and hydroxypropyl methylcellulose acetate succinate (HPMCAS) to provide increased aqueous solubility and / or bioavailability in the environment of use.

[0006] WO2014 / 043208 provides formulations of enzalutamide and their use for treating hyperproliferative diseases.

[0007] Methods for producing microparticles and nanoparticles are described in various patent applications and patents, for example in US 5,833,891, US 5,534,270, US 6,862,890, US 6,177,103, DE102005053862, US 5,833,891, US 5,534,270, US 6,862,890, US 6,177,103, US102005017777, and DE102005053862.

[0008] V. Wilson et al., Journal of Controlled Release, 292 (2018) 172-182, reported on amorphous solid dispersions of enzalutamide prepared with the hydrophilic polymers hydroxypropyl methylcellulose acetate succinate and copovidone (PVP / VA). The formulations were tested in vivo in rats using oral administration of amorphous solid dispersion suspensions. The crystallized amorphous solid dispersions exhibited lower plasma exposure. Differences were also observed between amorphous solid dispersions dissolved to form nanosized amorphous drug aggregates and those dissolved to obtain only a supersaturated solution, with the former being superior to the latter in terms of plasma exposure. The inventors conclude that these observations highlight the importance of fully understanding the phase behavior of amorphous formulations after dissolution and the need to distinguish between various types of precipitation, particularly crystallization, and glass-liquid phase separation to form nanosized amorphous aggregates.

[0009] Ch. Thangavel et al., Mol. Pharm. 2018, 15(5), 1778-1790, relates to anti-PSMA conjugated hybrid antiandrogen nanoparticles and their therapeutic efficacy and cytotoxicity.

[0010] WO 02 / 60275 A1 describes a method for producing nanoparticles in which two immiscible liquids are charged for encapsulation. This does not exclude the use of toxic substances, which can result in a significant loss of product quality. Furthermore, particle size cannot be controlled using this method.

[0011] US2009 / 0214655A1 also describes the use of two immiscible liquids. While a microreactor is used there to produce nanoparticles, only the production of an emulsion is described. Additionally, the nanoparticles are produced in a liquid-filled space, again making it impossible to control either particle size or particle properties. Furthermore, because the reaction takes place in a microchannel, the device may be prone to clogging.

[0012] The properties of known formulations of enzalutamide are not satisfactory in all respects and there is a need for pharmaceutical compositions and dosage forms that contain enzalutamide and that are advantageous over the prior art, for example in terms of release profile and / or drug content. Summary of the Invention

[0013]

[0009] Accordingly, it is an object of the present invention to provide pharmaceutical compositions and dosage forms containing enzalutamide that are advantageous over the prior art. In one aspect, the present invention aims to provide pharmaceutical compositions and dosage forms that provide immediate release of enzalutamide. In another aspect, the present invention aims to provide pharmaceutical compositions and oral dosage forms having a relatively high drug content, preferably up to about 160 mg of enzalutamide per dosage form. In yet another aspect, the present invention aims to provide pharmaceutical compositions and oral dosage forms that contain enzalutamide and preferably exhibit high bioavailability upon oral administration. In yet another aspect, the present invention aims to provide pharmaceutical compositions and oral dosage forms that are easy to manufacture and can be stabilized.

[0014] This object has been achieved by the subject matter of the claims.

[0015] Surprisingly, it has been found that nanoparticles containing enzalutamide can be prepared by precipitation from a solvent (e.g., acetone, THF) when mixed with a suitable non-solvent (e.g., water). Furthermore, it has been surprisingly found that the size of the nanoparticles thus obtained can be influenced by the selection of an appropriate excipient that also stabilizes the nanoparticles. Additionally, it has been surprisingly found that, depending on the size, concentration, and excipient, enzalutamide-containing nanoparticles can be prepared that completely or nearly completely disperse from suspension in fasted-state simulated fluid (FaSSIF), thereby suggesting that such nanoparticles are likely to provide excellent bioavailability of enzalutamide when administered in vivo. [Brief explanation of the drawings]

[0016] [Figure 1] 1 shows the z-average particle size of nanoparticles prepared from the Pluronic® F127 / Soluplus® / THF system by precipitation in beaker and microjet reactor techniques, respectively, depending on the concentration of enzalutamide (API) in the suspension. [Figure 2]Figure 1 shows the percentage of dispersion in FaSSIF of nanoparticles prepared from the Pluronic® F127 / Soluplus® / THF system by precipitation in a beaker and microjet reactor technique, respectively, depending on the concentration of enzalutamide (API) in the suspension. [Figure 3] 1 shows the percentage of dispersion in FaSSIF depending on the z-average particle size of nanoparticles prepared from the Pluronic® F127 / Soluplus® / THF system by precipitation in beaker and microjet reactor techniques, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0017] A first aspect of the present invention relates to nanoparticles containing enzalutamide.

[0018] The nanoparticles of the present invention contain enzalutamide. Enzalutamide is a nonsteroidal antiandrogen (NSAA) drug used to treat prostate cancer. It is indicated for use in combination with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castration-resistant prostate cancer. Enzalutamide is an antiandrogen agent and acts as an androgen receptor antagonist, blocking the effects of androgens on the prostate.

[0019] Enzalutamide (CAS 915087-33-1) has the following chemical structure: [ka] It has.

[0020] Enzalutamide is a water-insoluble white to off-white solid. To date, 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 solvates thereof.

[0021] Preferably, the nanoparticles according to the present invention comprise enzalutamide in a non-salt form.

[0022] Unless expressly stated otherwise, all doses and weight percentages used herein are based on weight equivalents for the unsalted, unsolvated, and non-co-crystal form of enzalutamide, i.e., the additional weight of the salt or solvent or co-crystal portion is not taken into account for quantification.

[0023] Preferably, the nanoparticles according to the invention are solid.

[0024] Preferably, the enzalutamide in the nanoparticles has a crystallinity of at least 10%, preferably at least 20%, more preferably at least 30%. Preferably, the enzalutamide in the nanoparticles has a crystallinity of at least 40%, preferably at least 50%, more preferably at least 60%. Preferably, the enzalutamide in the nanoparticles has a crystallinity of at least 70%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 99%, and particularly about 100%.

[0025] Methods for determining crystallinity are known to those skilled in the art and include, for example, X-ray powder diffraction analysis or differential scanning calorimetry (DSC).

[0026] In another preferred embodiment, the enzalutamide in the nanoparticles is substantially non-crystalline, i.e., amorphous. According to this embodiment, the enzalutamide in the nanoparticles preferably has a crystallinity of at most 20%, preferably at most 15%, more preferably at most 10%. Preferably, the enzalutamide in the nanoparticles has a crystallinity of at most 5.0%, preferably at most 2.5%, more preferably at most 1.0%.

[0027] Although it is generally contemplated that the nanoparticles according to the present invention may contain other pharmacologically active ingredients in addition to enzalutamide, preferably, enzalutamide is the only pharmacologically active ingredient contained in the nanoparticles. In this context, a pharmacologically active ingredient is another substance useful for treating the same or related disorders, diseases, and conditions as enzalutamide. Therefore, compounds that have physiological but no pharmacological activity, such as sodium chloride or vitamins, are not considered pharmacologically active ingredients in the above sense.

[0028] Preferably, the nanoparticles according to the present invention and the enzalutamide contained therein are not conjugated to an antigen, such as an antigen for drug targeting purposes. In particular, the nanoparticles according to the present invention are not encapsulated in, i.e., coated with, prostate-specific membrane antigen (PSMA).

[0029] The particle size of the nanoparticles according to the present invention is not particularly limited. However, the term "nanoparticle" already refers to a certain particle size on the nanometer scale. When the nanoparticles have a core-shell structure, the particle size is determined by combining the core and the shell. The term "nanoparticle" typically refers to particles having a diameter ranging from 1 to 1000 nm. The diameter can be determined according to methods known to those skilled in the art, for example, using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Advantageously, the nanoparticles according to the present invention have a diameter ranging from 20 to 1000 nm, more advantageously from 30 to 500 nm, even more advantageously from 40 to 350 nm, and preferably from 60 to 250 nm.

[0030] Preferably, the nanoparticles according to the present invention have a z-average particle size Dz of 1000 nm or less, preferably 900 nm or less, more preferably 800 nm or less, as determined according to ISO 22412:2008 Particle size analysis - dynamic light scattering. Preferably, the nanoparticles according to the present invention have a z-average particle size Dz of 700 nm or less, preferably 600 nm or less, more preferably 500 nm or less. Preferably, the nanoparticles according to the present invention have a z-average particle size Dz of 400 nm or less, preferably 300 nm or less, more preferably 200 nm or less. Preferably, the nanoparticles according to the present invention have a z-average particle size Dz of 150 nm or less, preferably 125 nm or less, more preferably 100 nm or less.

[0031] In a preferred embodiment, the nanoparticles according to the invention have a z-average particle size Dz within the range of 60±50 nm, or 70±50 nm, or 80±50 nm, or 90±50 nm, or 100±50 nm, or 110±50 nm, or 120±50 nm, or 130±50 nm, or 140±50 nm. In a preferred embodiment, the nanoparticles according to the invention have a z-average particle size Dz within the range of 60±30 nm, or 70±30 nm, or 80±30 nm, or 90±30 nm, or 100±30 nm, or 110±30 nm, or 120±30 nm, or 130±30 nm, or 140±30 nm. In preferred embodiments, the nanoparticles according to the invention have a z-average particle size Dz in the range of 60±10 nm, or 70±10 nm, or 80±10 nm, or 90±10 nm, or 100±10 nm, or 110±10 nm, or 120±10 nm, or 130±10 nm, or 140±10 nm.

[0032] In another preferred embodiment, the nanoparticles according to the invention have a diameter of 200±150 nm, or 200±100 nm, or 200±50 nm; or 300±150 nm, or 300±100 nm, or 300±50 nm; or 400±150 nm, or 400±100 nm, or 400±50 nm; or 500±150 nm, or 500±100 nm, or 500±50 nm; or 600±150 nm, or 600±100 nm, or 600±50 nm; or 700±150 nm, or 700±100 nm, or 700±50 nm; or 800±150 nm, or 800±100 nm, or 800±50 nm; or 900±150 nm, or 900±100 nm, or 900±50 nm.

[0033] In particularly preferred embodiments, the nanoparticles according to the invention have a z-average particle size Dz in the range of 850±150 nm, or 850±100 nm, or 850±50 nm.

[0034] The z-average particle diameter Dz is the intensity-based harmonic mean (2,3), and methods for determining Dz are known to those skilled in the art, such as laser scattering. According to the present invention, Dz is preferably determined according to ISO 22412:2008 Particle Size Analysis—Dynamic Light Scattering.

[0035] The width of the particle size distribution in a suspension is characterized by the "polydispersity" or "PDI" of the nanoparticles, which, as known to those skilled in the art, is defined as the relative dispersion of the correlation decay rate distribution. The polydispersity index (PDI) can also be calculated from cumulant analysis of the DLS measured intensity autocorrelation function as specified in ISO 22412:2008. Preferably, the polydispersity of the 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.

[0036] Nanoparticles consisting essentially of enzalutamide are typically not stable, therefore, the nanoparticles according to the present invention preferably further contain one or more pharmaceutical excipients selected from the group consisting of surfactants and polymers.

[0037] It is believed that nanoparticles according to the present invention can exist in a number of different configurations.

[0038] In one embodiment, the nanoparticles according to the present invention comprise a core, wherein the core comprises enzalutamide or a pharmaceutically acceptable salt thereof. As used herein, the term "core" refers to the interior portion of the nanoparticle. The nanoparticles according to this embodiment also have a "surface" or "exterior" portion. Thus, the nanoparticles can have a core (i.e., interior) and a surface or exterior portion that substantially surrounds the core. In one embodiment of the present invention, the core comprises essentially the entire amount of enzalutamide or a pharmaceutically acceptable salt thereof, together with optional one or more excipients, and the exterior portion is substantially composed of one or more excipients but essentially does not contain enzalutamide or a pharmaceutically acceptable salt thereof.

[0039] In another embodiment, the concentration of enzalutamide or a pharmaceutically acceptable salt thereof may vary throughout the nanoparticle, with the concentration of enzalutamide or a pharmaceutically acceptable salt thereof being highest, for example, in the core. For example, the nanoparticles of the present invention may comprise a matrix of one or more excipients and enzalutamide or a pharmaceutically acceptable salt thereof, such that a certain amount of enzalutamide or a pharmaceutically acceptable salt thereof may be dispersed in the outer portion of the nanoparticle, a certain amount of the excipient or a combination of excipients may be dispersed within the core of the nanoparticle, or a combination thereof. Thus, in some embodiments, the enzalutamide or a pharmaceutically acceptable salt thereof may be attached to at least a portion of the outer portion of the excipient. Thus, a certain amount of the enzalutamide or a pharmaceutically acceptable salt thereof may be attached to the surface of, encapsulated within, surrounded by, and / or dispersed or diffused throughout the outer portion of the excipient of the nanoparticle.

[0040] In some embodiments, substances can be adsorbed to the surface portion of a nanoparticle. Such substances are considered part of the nanoparticle but are distinguishable from the core of the nanoparticle. Methods for distinguishing between substances present in the core and those adsorbed to the surface portion of a nanoparticle include: (1) thermal methods such as differential scanning calorimetry (DSC); (2) spectroscopic methods such as X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM) using energy dispersive X-ray (EDX) analysis, Fourier transform infrared (FTIR) analysis, and Raman spectroscopy; (3) chromatographic techniques such as high-performance liquid chromatography (HPLC) and gel permeation chromatography (GPC); and (4) other techniques known in the art.

[0041] In a preferred embodiment, the nanoparticles according to the invention are (i) at least one surfactant and at least one polymer; (ii) at least two different surfactants; and / or (iii) at least two different polymers; Contains:

[0042] The weight content of all pharmaceutical excipients contained in the nanoparticles according to the present invention is not particularly limited.

[0043] Preferably, the total content of all pharmaceutical excipients contained in the nanoparticles is in each case 90% by weight or less, preferably 85% by weight or less, more preferably 80% by weight or less, relative to the total weight of the nanoparticles. Preferably, the total content of all pharmaceutical excipients contained in the nanoparticles is in each case 75% by weight or less, preferably 70% by weight or less, more preferably 65% by weight or less, relative to the total weight of the nanoparticles. Preferably, the total content of all pharmaceutical excipients contained in the nanoparticles is in each case 60% by weight or less, preferably 55% by weight or less, more preferably 50% by weight or less, relative to the total weight of the nanoparticles. Preferably, the total content of all pharmaceutical excipients contained in the nanoparticles is in each case 45% by weight or less, preferably 40% by weight or less, more preferably 35% by weight or less, relative to the total weight of the nanoparticles. Preferably, the total content of all pharmaceutical excipients contained in the nanoparticles is in each case 30% by weight or less, preferably 25% by weight or less, more preferably 20% by weight or less, relative to the total weight of the nanoparticles.

[0044] Preferably, the total content of all pharmaceutical excipients contained in the nanoparticles is in each case at least 0.5 wt.%, preferably at least 1.0 wt.%, more preferably at least 1.5 wt.%, relative to the total weight of the nanoparticles. Preferably, the total content of all pharmaceutical excipients contained in the nanoparticles is in each case at least 2.5 wt.%, preferably at least 5.0 wt.%, more preferably at least 7.5 wt.%, relative to the total weight of the nanoparticles. Preferably, the total content of all pharmaceutical excipients contained in the nanoparticles is in each case at least 10 wt.%, preferably at least 20 wt.%, more preferably at least 30 wt.%, relative to the total weight of the nanoparticles.

[0045] In a preferred embodiment, the total weight content of all pharmaceutical excipients contained in the nanoparticles is in the range of 25±20%, 30±20%, 35±20%, 40±20%, 45±20%, 50±20%, 55±20%, 60±20%, 65±20%, or 70±20% by weight, in each case relative to the total weight of the nanoparticles. In a preferred embodiment, the total weight content of all pharmaceutical excipients contained in the nanoparticles is in the range of 25±10%, 30±10%, 35±10%, 40±10%, 45±10%, 50±10%, 55±10%, 60±10%, 65±10%, or 70±10% by weight, in each case relative to the total weight of the nanoparticles. In a preferred embodiment, the total weight content of all pharmaceutical excipients contained in the nanoparticles is in each case within the range of 25±5 wt%, or 30±5 wt%, or 35±5 wt%, or 40±5 wt%, or 45±5 wt%, or 50±5 wt%, or 55±5 wt%, or 60±5 wt%, or 65±5 wt%, or 70±5 wt%, relative to the total weight of the nanoparticles.

[0046] In some embodiments, the nanoparticles are stabilized using one or more water-soluble (e.g., hydrophilic) excipients, one or more water-insoluble (e.g., lipophilic) excipients, or a combination of one or more water-soluble and one or more water-insoluble excipients. Examples of water-soluble excipients include, but are not limited to, vitamin E TPGS, polysorbate 80, polysorbate 20, Triton X-100, lauryl glucoside, NP-40, oleyl alcohol, sorbitan (monostearate tristearate), stearyl alcohol, nonoxynol, Cremophore (RH60 or EL), Solutol HS15, plutonic acid, sodium dodecyl sulfate (SDS), bile salts, polyethylene glycol, and polypropylene glycol, and combinations thereof. The bile salt is preferably selected from the group consisting of salts of cholic acid, chenodeoxycholic acid, deoxycholic acid, and urodeoxycholic acid. Examples of water-insoluble excipients include, but are not limited to, vitamin E and its derivatives, bile acids and its derivatives and phospholipid derivatives, lecithin, lysolecithin, phosphotidylserine, glycerophosphocholine, oleic acid, glycerol, inositol, diethylenetriaminepentaacetic acid, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil base, polyoxyethylene sorbitan monolaurate, and combinations thereof.

[0047] Preferably, the nanoparticles according to the invention comprise one or more surfactants.

[0048] In a preferred embodiment, the nanoparticles according to the invention comprise a single surfactant. In another preferred embodiment, the nanoparticles according to the invention comprise two, three, or four different surfactants.

[0049] The weight content of all surfactants contained in the nanoparticles according to the present invention is not particularly limited.

[0050] Preferably, the total content of one or more surfactants contained in the nanoparticles is in each case 20% by weight or less, preferably 15% by weight or less, more preferably 10% by weight or less, relative to the total weight of the nanoparticles. Preferably, the total content of one or more surfactants contained in the nanoparticles is in each case 7.5% by weight or less, preferably 5.0% by weight or less, more preferably 2.5% by weight or less, relative to the total weight of the nanoparticles. Preferably, the total content of one or more surfactants contained in the nanoparticles is in each case 1.5% by weight or less, preferably 1.0% by weight or less, more preferably 0.5% by weight or less, relative to the total weight of the nanoparticles.

[0051] Preferably, the total content of one or more surfactants contained in the nanoparticles is in each case at least 0.01 wt.%, preferably at least 0.05 wt.%, more preferably at least 0.1 wt.%, relative to the total weight of the nanoparticles. Preferably, the total content of one or more surfactants contained in the nanoparticles is in each case at least 0.2 wt.%, preferably at least 0.3 wt.%, more preferably at least 0.4 wt.%, relative to the total weight of the nanoparticles. Preferably, the total content of one or more surfactants contained in the nanoparticles is in each case at least 0.5 wt.%, preferably at least 0.6 wt.%, more preferably at least 0.7 wt.%, relative to the total weight of the nanoparticles.

[0052] In a preferred embodiment, the total weight content of all surfactants contained in the nanoparticles is in each case 0.10±0.05% by weight, or 0.15±0.05% by weight, or 0.20±0.05% by weight, or 0.25±0.05% by weight, or 0.30±0.05% by weight, or 0.35±0.05% by weight, or 0.40±0.05% by weight, or 0.4 5±0.05% by weight, or 0.50±0.05% by weight, or 0.55±0.05% by weight, or 0.60±0.05% by weight, or 0.65±0.05% by weight, or 0.70±0.05% by weight, or 0.75±0.05% by weight, or 0.80±0.05% by weight, or 0.85±0.05% by weight, or 0.90±0.05% by weight, or 0.95±0.05% by weight.

[0053] The properties of surfactants can be expressed by their hydrophilic-lipophilic balance (HLB).

[0054] Preferably, the one or more surfactants comprise or consist essentially of surfactants having an HLB value of at least 10, preferably at least 15, more preferably at least 20. Preferably, the one or more surfactants comprise or consist essentially of surfactants having an HLB value of at least 25, preferably at least 30, more preferably at least 32. Preferably, the one or more surfactants comprise or consist essentially of surfactants having an HLB value of at least 34, preferably at least 36, more preferably at least 38.

[0055] Preferably, the one or more surfactants comprise or consist essentially of surfactants having an HLB value of 40 or less, preferably 38 or less, more preferably 35 or less. Preferably, the one or more surfactants comprise or consist essentially of surfactants having an HLB value of 33 or less, preferably 30 or less, more preferably 28 or less. Preferably, the one or more surfactants comprise or consist essentially of surfactants having an HLB value of 25 or less, preferably 23 or less, more preferably 20 or less.

[0056] In preferred embodiments, the one or more surfactants comprise, or consist essentially of, a surfactant having an HLB value within the range of 12±10, or 14±10, or 16±10, or 18±10, or 20±10, or 22±10, or 24±10, or 26±10, or 28±10, or 30±10. In preferred embodiments, the one or more surfactants comprise, or consist essentially of, a surfactant having an HLB value within the range of 12±5, or 14±5, or 16±5, or 18±5, or 20±5, or 22±5, or 24±5, or 26±5, or 28±5, or 30±5, or 32±5, or 34±5.

[0057] The properties of surfactants can also be expressed by their charge. In a preferred embodiment, one or more surfactants comprise or essentially consist of nonionic surfactants. In a preferred embodiment, one or more surfactants comprise or essentially consist of anionic surfactants. In a preferred embodiment, one or more surfactants comprise or essentially consist of cationic surfactants. In a preferred embodiment, one or more surfactants comprise or essentially consist of amphoteric surfactants.

[0058] In a particularly preferred embodiment, the one or more surfactants comprise or consist essentially of a non-ionic surfactant. Preferably, the non-ionic surfactant is linear or branched fatty alcohols; preferably those chosen from cetyl alcohol, cetostearyl alcohol, stearyl alcohol, oleyl alcohol, octyldodecanol, or 2-hexyldecan-1-ol; - sterols; preferably cholesterol; - Lanolin alcohol; 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, superglycerinated fully hydrogenated rapeseed oil; partial fatty acid esters of sorbitan; preferably selected from sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate; 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; such as monolauryl, trilauryl, 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; - 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, macrogolglycerol lysinolate; - polyoxyethylene fatty acid esters, preferably selected from macrogol oleate, macrogol stearate, macrogol-15-hydroxystearate, polyoxyethylene esters of 12-hydroxystearic acid; - 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, macrogol stearyl ether; - reaction products of natural or hydrogenated castor oil with ethylene oxide, such as those commercialized under the trademark Cremophor®; - 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); - polyglycolized glycerides; preferably selected from those commercialized under the trademarks Gelucire®, Labrasol®; - fatty acid esters of sucrose; preferably selected from sucrose distearate, sucrose dioleate, sucrose dipalmitate, sucrose monostearate, sucrose monopalmitate, sucrose monooleate, sucrose monomyristate, sucrose monolaurate; - fatty acid esters of polyglycerol; preferably selected from polyglycerol oleate, polyglycerol dioleate, polyglycerol poly-12-hydroxystearate, triglycerol diisostearate; and - polyoxyethylene ester of D-α-tocopheryl succinate; preferably D-α-tocopherol polyethylene glycol 1000 succinate; is selected from the group consisting of:

[0059] In a particularly preferred embodiment, the nonionic surfactant is a polyoxyethylene ester of D-α-tocopheryl succinate; preferably D-α-tocopherol polyethylene glycol 1000 succinate. Such surfactants are commercially available, for example, under the trade name Vitamin E TPGS.

[0060] In another particularly preferred embodiment, the non-ionic surfactant is a polyoxypropylene-polyoxyethylene block copolymer (poloxamer); preferably according to the following general formula: [ka] (wherein a is independently an integer in the range of 2 to 130, preferably 90 to 110, more preferably about 101; and b is an integer in the range of 15 to 67, preferably 46 to 66, more preferably about 56); preferably poloxamer 407. Poloxamers are commercially available under the trade names Pluronic®, Kollifor®, and Lutrol®.

[0061] In another particularly preferred embodiment, the one or more surfactants comprise or consist essentially of an anionic surfactant. Preferably, the anionic surfactant is: alkyl sulfates, preferably selected from sodium lauryl sulfate (sodium dodecyl sulfate), sodium cetyl sulfate, sodium cetylstearyl sulfate, sodium stearyl sulfate, sodium dioctyl sulfosuccinate (sodium docusate); and the corresponding potassium or calcium salts thereof; - fatty acid salts, preferably selected from stearates and oleates; and - salts of cholic acid, preferably selected from sodium deoxycholate, sodium glycocholate, sodium taurocholate and the corresponding potassium or ammonium salts; particularly preferably sodium deoxycholate; is selected from the group consisting of:

[0062] In a particularly preferred embodiment, the anionic surfactant is an alkyl sulfate; preferably, n H 2n+1 O-SO3 - M + wherein 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+ Preferably, the anionic surfactant is sodium dodecyl sulfate.

[0063] In another particularly preferred embodiment, the anionic surfactant is a salt of cholic acid; preferably selected from sodium deoxycholate, sodium glycocholate, sodium taurocholate, and the corresponding potassium or ammonium salts; particularly preferred is sodium deoxycholate.

[0064] Preferably, the nanoparticles according to the invention comprise one or more polymers, which typically have a dispersed molecular weight distribution.

[0065] In a preferred embodiment, the nanoparticles according to the invention comprise a single polymer. In another preferred embodiment, the nanoparticles according to the invention comprise two, three, or four different polymers.

[0066] The weight content of all polymers contained in the nanoparticles according to the present invention is not particularly limited.

[0067] Preferably, the total content of one or more polymers contained in the nanoparticles is in each case 45% by weight or less, preferably 40% by weight or less, more preferably 35% by weight or less, relative to the total weight of the nanoparticles. Preferably, the total content of one or more polymers contained in the nanoparticles is in each case 30% by weight or less, preferably 25% by weight or less, more preferably 20% by weight or less, relative to the total weight of the nanoparticles. Preferably, the total content of one or more polymers contained in the nanoparticles is in each case 15% by weight or less, preferably 10% by weight or less, more preferably 5.0% by weight or less, relative to the total weight of the nanoparticles.

[0068] In a particularly preferred embodiment, the nanoparticles comprise a graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g. Soluplus®), the total content of said graft polymers in the nanoparticles being in each case at most 6.0% by weight, preferably at most 5.5% by weight, more preferably at most 5.0% by weight, even more preferably at most 4.5% by weight, even more preferably at most 4.0% by weight, even more preferably at most 3.5% by weight, most preferably at most 3.0% by weight and in particular at most 2.5% by weight, relative to the total weight of the nanoparticles.

[0069] Preferably, the total content of one or more polymers contained in the nanoparticles is in each case at least 1.0 wt.%, preferably at least 1.5 wt.%, or at least 2.0 wt.%, or at least 2.5 wt.%, more preferably at least 5.0 wt.%, relative to the total weight of the nanoparticles. Preferably, the total content of one or more polymers contained in the nanoparticles is in each case at least 7.5 wt.%, preferably at least 10 wt.%, more preferably at least 12.5 wt.%, relative to the total weight of the nanoparticles. Preferably, the total content of one or more polymers contained in the nanoparticles is in each case at least 15 wt.%, preferably at least 17.5 wt.%, more preferably at least 20 wt.%, relative to the total weight of the nanoparticles.

[0070] In preferred embodiments, the total content of one or more polymers contained in the nanoparticles is within the range of 2.5±2.0% by weight, or 3.0±2.0% by weight, or 3.5±2.0% by weight, or 4.0±2.0% by weight, or 4.5±2.0% by weight, or 5.0±2.0% by weight, or 5.5±2.0% by weight, or 6.0±2.0% by weight, or 6.5±2.0% by weight, or 70±20% by weight, in each case relative to the total weight of the nanoparticles. In preferred embodiments, the total content of one or more polymers contained in the nanoparticles is within the range of 25±20% by weight, or 30±20% by weight, or 35±20% by weight, or 40±20% by weight, or 45±20% by weight, or 50±20% by weight, or 55±20% by weight, or 60±20% by weight, or 65±20% by weight, or 70±20% by weight, in each case relative to the total weight of the nanoparticles. In preferred embodiments, the total content of one or more polymers contained in the nanoparticles is in the range of 15±10% by weight, or 20±10% by weight, 25±10% by weight, or 30±10% by weight, or 35±10% by weight, or 40±10% by weight, or 45±10% by weight, or 50±10% by weight, or 55±10% by weight, or 60±10% by weight, or 65±10% by weight, or 70±10% by weight, in each case relative to the total weight of the nanoparticles. In preferred embodiments, the total content of one or more polymers contained in the nanoparticles is within the range of 10±5 wt%, or 15±5 wt%, or 20±5 wt%, or 25±5 wt%, or 30±5 wt%, or 35±5 wt%, or 40±5 wt%, or 45±5 wt%, or 50±5 wt%, or 55±5 wt%, or 60±5 wt%, or 65±5 wt%, or 70±5 wt%, in each case relative to the total weight of the nanoparticles.

[0071] In a preferred embodiment, the one or more polymers comprise or consist essentially of a polymer selected from the group consisting of: - neutral non-cellulosic polymers, preferably selected from vinyl polymers and copolymers having hydroxyl, alkylacyloxy, and cyclic amide polyvinyl alcohol substituents, with at least a portion of the repeating units in non-hydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinylpyrrolidone; polyvinylpyrrolidone vinyl acetate; and polyethylene polyvinyl alcohol copolymers; - ionizable non-cellulosic polymers; preferably carboxylic acid-functionalized vinyl polymers; preferably those selected from carboxylic acid-functionalized polymethacrylates and carboxylic acid-functionalized polyacrylates; amine-functionalized polyacrylates and polymethacrylates; proteins; and carboxylic acid-functionalized starches; - amphiphilic non-cellulosic polymers; preferably selected from acrylate and methacrylate copolymers and graft copolymers of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate; - neutral cellulosic polymers having at least one ester- and / or ether-linked substituent; preferably selected from hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose; - an ionizable cellulosic polymer having at least one ester- and / or ether-bonded substituent; preferably hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate succinate phthalate, hydroxypropyl selected from pyrmethylcellulose succinate phthalate, cellulose propionate phthalate, hydroxypropylcellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose acetate salicylate, hydroxypropylsalicylate cellulose acetate, ethylbenzoate cellulose acetate, hydroxypropylethylbenzoate cellulose acetate, ethylphthalate cellulose acetate, ethylnicotinate cellulose acetate, and ethylpicolinate cellulose acetate; and - amphiphilic cellulosic polymers obtained by substituting cellulose with at least one hydrophobic substituent at any or all of the three hydroxyl substituents present in each saccharide repeat unit, said hydrophobic substituent being preferably selected from ether- and ester-linked alkyl groups, ether- and / or ester-linked aryl groups, and phenylates; in addition to the hydrophobic substituents, at least one hydrophilic substituent may also be present; said hydrophilic substituent being preferably selected from ether- or ester-linked non-ionizable groups, preferably hydroxyalkyl substituents, alkyl ether groups, carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates, or sulfonates.

[0072] In particularly preferred embodiments, the one or more polymers comprise or consist essentially of polyvinylpyrrolidone (PVP).

[0073] In another preferred embodiment, the one or more polymers comprise or consist essentially of polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA).

[0074] In another particularly preferred embodiment, the one or more polymers comprise or consist essentially of hydroxypropyl methylcellulose (HPMC).

[0075] In yet another particularly preferred embodiment, the one or more polymers comprise or consist essentially of hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0076] In yet another particularly preferred embodiment, the one or more polymers comprise or consist essentially of a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG).

[0077] In a preferred embodiment, the nanoparticles according to the invention comprise a polyoxypropylene-polyoxyethylene block copolymer, preferably Poloxamer 407 as detailed above, in combination with a polyoxyethylene ester of D-α-tocopheryl succinate, preferably D-α-tocopherol polyethylene glycol 1000 succinate.

[0078] In a preferred embodiment, the nanoparticles according to the invention comprise a polyoxypropylene-polyoxyethylene block copolymer, preferably Poloxamer 407 as detailed above, in combination with a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG).

[0079] In a preferred embodiment, the nanoparticles according to the invention comprise a polyoxypropylene-polyoxyethylene block copolymer, preferably Poloxamer 407 as detailed above, in combination with polyvinylpyrrolidone (PVP).

[0080] In a preferred embodiment, the nanoparticles according to the invention comprise a polyoxypropylene-polyoxyethylene block copolymer, preferably Poloxamer 407 as detailed in 24 above, in combination with hydroxypropylmethylcellulose (HPMC).

[0081] In a preferred embodiment, the nanoparticles according to the invention comprise a polyoxypropylene-polyoxyethylene block copolymer, preferably Poloxamer 407 as detailed above, in combination with hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0082] In a preferred embodiment, the nanoparticles according to the invention comprise an alkyl sulfate, preferably sodium dodecyl sulfate as detailed above, in combination with a polyoxyethylene ester of D-α-tocopheryl succinate, preferably D-α-tocopherol polyethylene glycol 1000 succinate.

[0083] In a preferred embodiment, the nanoparticles according to the invention comprise an alkyl sulfate, preferably sodium dodecyl sulfate as detailed above, in combination with a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG).

[0084] In a preferred embodiment, the nanoparticles according to the invention comprise an alkyl sulfate, preferably sodium dodecyl sulfate as detailed above, in combination with polyvinylpyrrolidone (PVP).

[0085] In a preferred embodiment, the nanoparticles according to the invention comprise an alkyl sulfate, preferably sodium dodecyl sulfate as detailed above, in combination with hydroxypropylmethylcellulose (HPMC).

[0086] In a preferred embodiment, the nanoparticles according to the present invention comprise an alkyl sulfate, preferably sodium dodecyl sulfate as detailed above, in combination with hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0087] In a preferred embodiment, the nanoparticles according to the invention comprise D-α-tocophenylsuccinate, preferably D-α-tocophenylsuccinate as detailed above, in combination with polyvinylpyrrolidone (PVP).

[0088] In a preferred embodiment, the nanoparticles according to the invention comprise D-α-tocophenylsuccinate, preferably D-α-tocophenylsuccinate as detailed above, in combination with hydroxypropylmethylcellulose (HPMC).

[0089] In a preferred embodiment, the nanoparticles according to the invention comprise D-α-tocophenylsuccinate, preferably D-α-tocophenylsuccinate as detailed above, in combination with hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0090] In a preferred embodiment, the nanoparticles according to the invention comprise one or more phospholipids, preferably selected from phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and lecithin.

[0091] The term "phospholipid" refers to a class of lipids typically composed of glycerol, a phosphate group, and a neutral or zwitterionic moiety (such as choline, serine, or inositol) as a characteristic moiety. The glycerol moiety may be esterified with long-chain fatty acids (C10-C22), which may be saturated (e.g., myristic, palmitic, and stearic acids), monounsaturated (e.g., oleic acid), or polyunsaturated (e.g., linoleic and arachidonic acids). For example, depending on the source, phosphatidylcholines include, but are not limited to, dilauryl-phosphatidylcholine, dimyristoyl-phosphatidylcholine, dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylcholine, palmitoyl-linoleoyl-phosphatidylcholine, stearoyl-oleoyl-phosphatidylcholine, stearoyl-linoleoyl-phosphatidylcholine, and the like.

[0092] At least one of the phospholipids is preferably adsorbed onto the surface of enzalutamide. For purposes of this specification, the term "adsorbed onto the surface" typically refers to the attachment of phospholipids to the surface of enzalutamide. This process results in the formation of a phospholipid film on the surface. The adsorption of phospholipids can be determined, for example, by differential scanning calorimetry (DSC) according to procedures known to those skilled in the art. For DSC analysis, the heat trace of dried nanoparticles should preferably not show an endothermic melting peak of enzalutamide.

[0093] In another preferred embodiment, the nanoparticles according to the invention are free of phospholipids.

[0094] In a preferred embodiment, the nanoparticles according to the present invention contain a cryoprotectant. Examples of cryoprotectants include, but are not limited to, mannitol, glycerol, propylene glycol, glycine, sucrose, lactose, trehalose, and mixtures thereof in any weight ratio, preferably mannitol, trehalose, and glycine, more preferably mannitol or trehalose, or mixtures thereof in any weight ratio. Preferably, the cryoprotectant is a mixture of mannitol and trehalose in a weight ratio comprised between 6:4 and 4:6, more preferably 1:1.

[0095] In another preferred embodiment, the nanoparticles according to the invention are free of cryoprotectants.

[0096] Particularly preferred embodiment X of the nanoparticles according to the invention 1 ~X 15 are summarized in the table below: [Table 1]

[0097] Another aspect of the present invention relates to a method for preparing the nanoparticles according to the invention described above, which comprises precipitating the nanoparticles from a liquid.

[0098] In a preferred embodiment, the method comprises: (a) providing a solution of enzalutamide in a first liquid, optionally with one or more pharmaceutical excipients; (b) providing a second liquid containing one or more pharmaceutical excipients, optionally in dissolved form; and (c) contacting the first liquid with the second liquid, thereby obtaining a third liquid containing a mixture of the first liquid and the second liquid and the precipitated nanoparticles; Includes:

[0099] The first liquid acts as a solvent for enzalutamide, while the second liquid typically acts as a poor solvent. The term "poor solvent" typically refers to a liquid that has little or no solvation ability for enzalutamide. When the solvent and the poor solvent are brought into contact with each other, for example, by collision in the form of a jet, enzalutamide instantly precipitates, thereby forming nanoparticles that are suspended in the combined first and second liquids.

[0100] Preferably, the solution provided in step (a) comprises one or more surfactants as described above and / or one or more polymers as described above.

[0101] Preferably, the second liquid provided in step (b) comprises one or more surfactants as described above and / or one or more polymers as described above.

[0102] Preferably, the amount of enzalutamide contained in the precipitated nanoparticles obtained in step (c) is, in each case, at least 82% by weight, preferably at least 84% by weight, and more preferably at least 86% by weight, of the amount of enzalutamide contained in the solution prepared in step (a). Preferably, the amount of enzalutamide contained in the precipitated nanoparticles obtained in step (c) is, in each case, at least 88% by weight, preferably at least 90% by weight, and more preferably at least 92% by weight, of the amount of enzalutamide contained in the solution prepared in step (a). Preferably, the amount of enzalutamide contained in the precipitated nanoparticles obtained in step (c) is, in each case, at least 94% by weight, preferably at least 96% by weight, and more preferably at least 98% by weight, of the amount of enzalutamide contained in the solution prepared in step (a).

[0103] Preferably, the first and second liquids are mixed as jets impinging on each other at a defined pressure and flow rate, causing instantaneous precipitation or co-precipitation during which nanoparticles are formed.

[0104] In a preferred embodiment of the method according to the invention, the particle size of the nanoparticles is - the temperature at which the first liquid comes into contact with the second liquid; - the flow rates of the first and second liquids; and / or - the pressure of the gas supplied to the reactor space of the microjet reactor where the first liquid and the second liquid are in contact; and / or - Concentration of individual compounds in each solvent and antisolvent; Therefore, it is controlled.

[0105] Particle size can be adjusted by the jet flow rate and mixing ratio. At low temperatures, the solubility decreases and the metastable zone is very narrow, making supersaturation more likely when a solvent is injected into an antisolvent. The nucleation process involves the loss of free energy and the release of heat. Therefore, low temperatures favor a high nucleation rate. Low temperatures can inhibit particle growth. Therefore, a high nucleation rate and a slow growth rate at low temperatures result in the formation of smaller particles. The finding that particle size and the degree of aggregation increase with increasing temperature can be explained by the fact that as the temperature increases, the substance or additive approaches its glass transition temperature. Particle size can also be controlled by the flow rates of the solvent and antisolvent. Small particles can be obtained by selecting a high flow rate, and large particles by selecting a low flow rate.

[0106] In a preferred embodiment of the method according to the invention, the first liquid comprises a solvent selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol, isopropanol, and acetonitrile, preferably tetrahydrofuran or acetone; and / or - the second liquid comprises water, preferably the second liquid consists essentially of water and optionally pharmaceutical excipients.

[0107] In another preferred embodiment of the method according to the invention, - the first liquid comprises glacial acetic acid; and / or the second liquid comprises or consists essentially of an aqueous base; preferably, the second liquid comprises or consists essentially of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous ammonia solution, together with pharmaceutical excipients which may optionally be present in each case.

[0108] It has been found that the use of glacial acetic acid as a solvent and an aqueous organic base as an antisolvent can be advantageous because the solubilizing ability of glacial acetic acid for enzalutamide can be rapidly reduced upon contact with an aqueous base, thereby suppressing the formation of amorphous enzalutamide, i.e., increasing the crystallinity of enzalutamide.

[0109] Preferably, the first liquid comprises a solvent for enzalutamide and the second liquid comprises an anti-solvent for enzalutamide, and contact of the first liquid with the second liquid in step (c) produces nanoparticles by controlled precipitation into the anti-solvent using microjet reactor technology.

[0110] In another preferred embodiment, the method comprises: (A) providing a solution of enzalutamide in a first liquid, preferably free of pharmaceutical excipients; (B) providing a second liquid that does not contain pharmaceutical excipients; (C) contacting the first liquid with the second liquid, thereby obtaining a third liquid containing a mixture of the first liquid and the second liquid and precipitated nanoparticles; (D) providing a fourth liquid comprising one or more pharmaceutical excipients in dissolved form; and (E) contacting the third liquid with the fourth liquid, thereby obtaining a fifth liquid containing a mixture of the third liquid and the fourth liquid and precipitated coated nanoparticles coated with one or more pharmaceutical excipients; Includes:

[0111] The first liquid acts as a solvent for enzalutamide, while the second and fourth liquids typically act as anti-solvents.

[0112] Preferably, the solution provided in step (D) comprises one or more surfactants as described above and / or one or more polymers as described above.

[0113] Preferably, the second liquid provided in step (B) consists essentially of an anti-solvent, and the fourth liquid provided in step (D) is a solution of one or more pharmaceutical excipients in the same anti-solvent, which is preferably water or an aqueous base.

[0114] Preferably, the precipitated nanoparticles obtained in step (C) consist essentially of enzalutamide.

[0115] Preferably, the amount of enzalutamide contained in the precipitated coated nanoparticles obtained in step (E) is, in each case, at least 82% by weight, preferably at least 84% by weight, and more preferably at least 86% by weight, of the amount of enzalutamide contained in the solution prepared in step (A). Preferably, the amount of enzalutamide contained in the precipitated coated nanoparticles obtained in step (E) is, in each case, at least 88% by weight, preferably at least 90% by weight, and more preferably at least 92% by weight, of the amount of enzalutamide contained in the solution prepared in step (A). Preferably, the amount of enzalutamide contained in the precipitated coated nanoparticles obtained in step (E) is, in each case, at least 94% by weight, preferably at least 96% by weight, and more preferably at least 98% by weight, of the amount of enzalutamide contained in the solution prepared in step (A).

[0116] Preferably, in step (C), the first and second liquids, and the third and fourth liquids, are mixed together as jets that collide with each other at a defined pressure and flow rate, causing instantaneous precipitation or co-precipitation during nanoparticle formation, and in step (E), the nanoparticles contained in the third liquid are coated with instantaneous precipitation or co-precipitation of one or more excipients contained in the fourth liquid. Preferably, the first and second liquids are mixed together as jets in a first microjet reactor, and the third liquid exiting the first microjet reactor is then mixed with the fourth liquid in a second microjet reactor located downstream from the first microjet reactor.

[0117] In a preferred embodiment of the method according to the invention, the particle size of the nanoparticles is - the temperature at which the first liquid contacts the second liquid, and optionally the temperature at which the third liquid contacts the fourth liquid; and / or - the flow rates of the first and second liquids, and optionally the flow rates of the third and fourth liquids; and / or - the pressure of the gas supplied to the reactor space of the microjet reactor where the first liquid and the second liquid come into contact, and optionally the pressure of the gas supplied to the reactor space of the microjet reactor where the third liquid and the fourth liquid come into contact; and / or - Concentration of individual compounds in each solvent and antisolvent; is controlled by

[0118] Particle size can be adjusted by the jet flow rate and mixing ratio. At low temperatures, the solubility decreases and the metastable zone is very narrow, making supersaturation more likely when a solvent is injected into an antisolvent. The nucleation process involves the loss of free energy and the release of heat. Therefore, low temperatures favor a high nucleation rate. Low temperatures can inhibit particle growth. Therefore, a high nucleation rate and a slow growth rate at low temperatures result in the formation of smaller particles. The finding that particle size and the degree of aggregation increase with increasing temperature can be explained by the fact that as the temperature increases, the substance or additive approaches its glass transition temperature. Particle size can also be controlled by the flow rates of the solvent and antisolvent. Small particles can be obtained by selecting a high flow rate, and large particles by selecting a low flow rate.

[0119] In a preferred embodiment of the method according to the invention, the first liquid comprises a solvent selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol, isopropanol, and acetonitrile, preferably tetrahydrofuran or acetone; and / or - the second liquid comprises water, preferably the second liquid consists essentially of water and optionally pharmaceutical excipients; and / or Optionally, the fourth liquid comprises water, preferably the fourth liquid consists essentially of water and optionally present pharmaceutical excipients.

[0120] In another preferred embodiment of the method according to the invention, - the first liquid comprises glacial acetic acid; and / or - the second liquid comprises or consists essentially of an aqueous base, preferably the second liquid comprises or consists essentially of aqueous sodium hydroxide, potassium hydroxide or ammonia, together with pharmaceutical excipients which may optionally be present in each case; and / or Optionally, the fourth liquid comprises or consists essentially of an aqueous base; preferably comprises or consists essentially of aqueous sodium hydroxide, potassium hydroxide, or ammonia, together with one or more pharmaceutical excipients in each case.

[0121] It has been found that the use of glacial acetic acid as a solvent and an aqueous organic base as an antisolvent can be advantageous because the solubilizing ability of glacial acetic acid for enzalutamide can be rapidly reduced upon contact with an aqueous base, thereby suppressing the formation of amorphous enzalutamide, i.e., increasing the crystallinity of enzalutamide.

[0122] Preferably, the first liquid comprises a solvent for enzalutamide and the second liquid comprises an anti-solvent for enzalutamide, and contact of the first liquid with the second liquid in step (c) produces nanoparticles by controlled precipitation into the anti-solvent using microjet reactor technology.

[0123] Preferably, in steps (a) and (A) of the method according to the present invention, enzalutamide is used in its non-salt form.

[0124] Preferably, the method according to the invention is carried out using one or more microjet reactors. Preferably, each of the microjet reactors has at least two nozzles, each with its own pump and supply line for injecting one liquid medium into a reactor chamber enclosed in a reactor housing and into a common impingement point, the reactor housing being provided with a first opening through which a gas can be introduced to facilitate the production of the nanoparticle suspension and its transport from the reactor cell, and an additional opening for removing the resulting product from the reactor housing. Reactors include all shapes described in EP1165224111 and DE102009008478A1, which are incorporated herein by reference in their entirety.

[0125] This method utilizes controlled solvent / antisolvent deposition, where streams of a solvent (first liquid) and a nonsolvent (second liquid), preferably at flow rates greater than 0.1 ml / min, collide as impinging jets, preferably at velocities greater than 1 m / s, more preferably greater than 50 m / s, and at Reynolds numbers greater than 100, preferably greater than 500. The solvent and antisolvent are formed in a nozzle into jets preferably less than 1,000 μm, more preferably less than 500 μm, and especially less than 300 μm, typically with pressures greater than 1 bar, preferably greater than 10 bar, and even more preferably greater than 50 bar, which pressure is controlled in this method by a pressure regulator. These two impinging jets collide in a microjet reactor, resulting in deposition at the point of jet impact, forming a double-disk-shaped structure containing fast-moving liquid jets, depending on the reactor geometry. In the edge regions of the disks, very rapid mixing occurs, typically with mixing speeds less than 1 ms, often less than 0.5 ms, and most often less than 0.1 ms.

[0126] According to the present invention, a microjet reactor can be used to produce nanoparticles by a controlled precipitation, co-precipitation, and / or self-assembly process. In a microjet reactor, a first liquid containing enzalutamide in dissolved form and a second liquid containing an antisolvent (non-solvent) are mixed in the microjet reactor as jets that collide with each other at a defined pressure and flow rate, causing very rapid precipitation or co-precipitation during the formation of nanoparticles. As already mentioned above, particle size can be controlled by the temperature at the time of liquid collision, the liquid flow rate, and / or the amount of gas. Typically, smaller particle sizes are obtained at lower temperatures, higher liquid flow rates, and / or in the complete absence of gas.

[0127] In a preferred embodiment, the method according to the present invention comprises: - dissolving enzalutamide in a water-miscible solvent, preferably under pressure, thereby obtaining a first liquid; - pumping the solution thus obtained (first liquid) through a heated capillary into a microjet reactor (e.g. sedimentation reactor, free jet reactor, etc.); - colliding a liquid jet of the solution (first liquid) with a liquid jet (second liquid) formed by another nozzle of the microjet reactor, the latter jet consisting of water or an aqueous solution of one or more excipients; - forming nanoparticle nuclei by diffusion-limited solvent / non-solvent precipitation at the point of impact and at the plate-like mixing zone of the liquid jet in a gaseous atmosphere; Includes:

[0128] The first and second liquids may be heated or cooled, i.e., by external heating means or directly within the pump, to dissolve the enzalutamide and / or pharmaceutical excipients, to enable the formation of nanoparticles with the desired particle size and surface properties, or to stabilize the resulting molecules.

[0129] Alternatively, another embodiment of the present invention may employ methods and apparatus that enable a self-assembly process in which one or more active target molecules are chemically reacted with one or more suitable adjuvants that are soluble in the antisolvent, resulting in a product that is insoluble in the solvent / antisolvent mixture, thereby enabling the formation of microparticles or nanoparticles with sizes that vary depending on parameters such as, but not limited to, the flow rate or concentration of the substances.

[0130] Methods for producing nanoparticles by colliding a solution of a drug in a solvent with a suitable antisolvent are known to those skilled in the art, and in this regard reference may be made, for example, to EP-A 2550092, EP-A 2978515, and EP-A 3408015, which are incorporated herein by reference in their entirety.

[0131] In a preferred embodiment, the nanoparticles prepared according to the present invention remain in suspension in a mixture of a first liquid and a second liquid, which suspension can then be advantageously used to produce a pharmaceutical dosage form, for example, by wet granulation, where the solvent contained in the first liquid and / or the solvent contained in the second liquid acts as the solvent in the wet granulation, optionally with additional solvent used during the wet granulation process.

[0132] Alternatively, nanoparticles prepared according to the invention in suspension in a mixture of a first liquid and a second liquid are spray dried and then further processed.

[0133] Another aspect of the present invention relates to nanoparticles obtainable by the method according to the invention described above.

[0134] Another aspect of the present invention relates to a pharmaceutical composition comprising the nanoparticles according to the present invention as described above and one or more pharmaceutical excipients, which are different from the one or more surfactants and one or more polymers preferably contained in the nanoparticles according to the present invention as described above. Thus, the one or more pharmaceutical excipients of the pharmaceutical composition are present outside the nanoparticles.

[0135] It is contemplated that one or more pharmaceutical excipients (e.g., surfactants and / or polymers) contained in the nanoparticles according to the invention are also included as pharmaceutical excipients in the pharmaceutical composition according to the invention, such that a first portion thereof is contained within the nanoparticles and the remainder thereof is contained outside the nanoparticles. However, in preferred embodiments, the pharmaceutical excipients contained within the nanoparticles are different from the pharmaceutical excipients of the pharmaceutical composition, i.e., those present outside the nanoparticles.

[0136] Preferably, the one or more pharmaceutical excipients form a matrix in which the nanoparticles are dispersed.

[0137] Preferably, the pharmaceutical excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a lubricant, a glidant, a retardant polymer, and any combination thereof.

[0138] Examples of fillers (diluents) include, but are not limited to, starch, lactose, xylitol, sorbitol, powdered sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, dicalcium phosphate dihydrate, calcium sulfate, etc. Fillers typically comprise 2% to 15% by weight of the pharmaceutical composition.

[0139] 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 comprise 0.2% to 14% by weight of the composition.

[0140] Examples of disintegrants include, but are not limited to, alginic acid, DVB methacrylate, cross-linked PVP, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, starches such as sodium starch glycolate, corn or maize starch, pregelatinized starch, etc. Disintegrants typically comprise 2% to 15% by weight of the pharmaceutical composition.

[0141] Examples of surfactants have already been mentioned above in connection with the pharmaceutical excipients preferably contained in the nanoparticles. Essentially the same surfactants are also useful in the pharmaceutical composition according to the invention.

[0142] 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. Lubricants typically comprise 0.2% to 5.0% by weight of the pharmaceutical composition.

[0143] 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 comprise 0.01% to 0.3% by weight of the pharmaceutical composition.

[0144] Examples of retardant 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 such as, 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.

[0145] The weight content of enzalutamide in the pharmaceutical composition 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 composition.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%, particularly at least 50 wt%, in each case relative to the total weight of the pharmaceutical composition.

[0146] Another aspect of the present invention relates to a pharmaceutical dosage form containing the nanoparticles according to the invention as described above or a pharmaceutical composition according to the invention as described above.

[0147] Preferably, the pharmaceutical dosage form is selected from tablets, microtablets, capsules, powders, granules, suspensions, emulsions.

[0148] In a particularly preferred embodiment, the pharmaceutical dosage form is a tablet, which is preferably granulated, more preferably wet granulated. Preferably, the first and second liquids preferably used for the preparation of the nanoparticles according to the invention described above serve as granulation liquids for the wet granulation.

[0149] Thus, preferably, wet granulation involves a liquid containing water and a solvent selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol, isopropanol, and acetonitrile, preferably tetrahydrofuran or acetone.

[0150] In a preferred embodiment, the pharmaceutical dosage form according to the invention is a film-coated tablet.

[0151] 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.

[0152] 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, even more preferably 750 mg or less, most preferably 700 mg or less, especially 650 mg or less.

[0153] The dose of enzalutamide contained in the pharmaceutical dosage form according to the present invention is not particularly limited and may typically depend on the age and weight of the patient, as well as the severity of the disease or disorder or condition to be treated.

[0154] In a preferred embodiment, the pharmaceutical dosage form according to the present invention contains enzalutamide at 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.

[0155] Preferably, the pharmaceutical dosage form according to the present invention has a disintegration time according to Ph.Eur of 8.0 minutes or less, preferably 7.0 minutes or less, more preferably 6.0 minutes or less, even more preferably 5.0 minutes or less, even more preferably 4.0 minutes or less, even more preferably 3.0 minutes or less, most preferably 2.0 minutes or less, especially 1.0 minute or less.

[0156] Preferably, the pharmaceutical dosage form according to the present invention provides immediate release of enzalutamide in accordance with Ph.Eur, such that under in vitro conditions at 37°C, pH 1.2 in 600 mL of artificial gastric fluid using a paddle apparatus with a rotation speed of 75 rpm, in each case at least 80% by weight, preferably at least 85% by weight, more preferably at least 90% by weight of the enzalutamide originally contained in the pharmaceutical dosage form is released after 30 minutes.

[0157] The preferred immediate release profiles A1-A40 of the pharmaceutical dosage forms according to the present invention under in vitro conditions of 37°C, pH 1.2 in 600 mL of artificial gastric fluid using a paddle apparatus with a rotation speed of 75 rpm are summarized in the following table: All percentages are based on the weight of enzalutamide originally contained in the pharmaceutical dosage form. [Table 2]

[0158] Preferably, the pharmaceutical dosage form according to the invention provides a mean oral bioavailability of enzalutamide of at least 5%, preferably at least 10%, more preferably at least 15%, even more preferably at least 20%, even more preferably at least 25%, even more preferably at least 30%, most preferably at least 35%, and especially at least 40%. Preferably, the pharmaceutical dosage form according to the invention provides a mean oral bioavailability of enzalutamide of at least 50%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and especially at least 98%.

[0159] Preferably, the pharmaceutical dosage form according to the invention when administered orally comprises: - C of 0.4 ± 0.1 μg / mL at a dose of 30 mg max and / or t in the range of 0.4 to 4 h max and / or an AUC of 54 ± 21 μg·h / mL ∞provide; and / or - C of 0.9 ± 0.5 μg / mL at a dose of 40 mg max and / or t in the range of 0.4 to 4 h max and / or an AUC of 65 ± 30 μg·h / mL ∞ provide; and / or - C of 1.7 ± 0.5 μg / mL at a 60 mg dose max and / or t in the range of 0.5 to 1 h max and / or an AUC of 94 ± 17 μg·h / mL ∞ provide; and / or - C of 2.2 ± 0.8 μg / mL at an 80 mg dose max and / or t in the range of 0.5 to 2 h max and / or an AUC of 120 ± 40 μg·h / mL ∞ provide; and / or - C of 3.4 ± 0.8 μg / mL at a dose of 150 mg max and / or t in the range of 0.5 to 2 h max and / or an AUC of 334 ± 50 μg·h / mL ∞ provide; and / or - C of 3.5 ± 0.8 μg / mL at a dose of 160 mg max and / or t in the range of 0.5 to 2 h max and / or an AUC of 400 ± 50 μg·h / mL ∞ to provide.

[0160] In another preferred embodiment of the present invention, a pharmaceutical dosage form comprising the nanoparticles according to the present invention provides a controlled release, preferably a sustained release (sustained release, delayed release), of enzalutamide. The sustained release is preferably achieved by a matrix retardation, although other known means for achieving delayed release are also contemplated, such as by a suitable coating, which may optionally contain a suitable pore-forming agent, etc. Preferably, the pharmaceutical dosage form comprises a controlled release matrix material in which the nanoparticles according to the present invention are embedded. Preferably, the controlled release matrix material comprises one or more retarding polymers.

[0161] In a preferred embodiment, the controlled release matrix material comprises one or more polysaccharides, independently of one another, selected from cellulose derivatives such as cellulose ethers or cellulose esters, including, but not limited to, methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcellulose (HEC), ethylhydroxyethylcellulose (EHEC), hydroxyethylmethylcellulose (HEMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydrophobically modified hydroxyethylcellulose (HMHEC), hydrophobically modified ethylhydroxyethylcellulose (HMEHEC), carboxymethyl hydrophobically modified hydroxyethylcellulose (CMHMHEC); guar and guar derivatives; pectin; carrageenan; xanthan gum; locust bean gum; agar; algin and its derivatives, gellan gum, acacia, starch and modified starches; or any combination of the foregoing.

[0162] In preferred embodiments, the controlled release matrix material comprises one or more synthetic polymers such as, 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.

[0163] The controlled release matrix material may include additional pharmaceutical excipients such as fillers, binders, disintegrants, surfactants, lubricants, glidants, and any combination thereof, as defined above.

[0164] Preferred controlled release profiles B1 to B40 of pharmaceutical dosage forms according to the present invention under in vitro conditions of 37°C, pH 1.2 in 600 mL of artificial gastric fluid using a paddle apparatus with a rotation speed of 75 rpm are summarized in the following table: All percentages are based on the weight of enzalutamide originally contained in the pharmaceutical dosage form. [Table 3]

[0165] Another aspect of the present invention is a method for producing a semiconductor device comprising: (i) providing nanoparticles according to the invention as described above; (ii) granulating, preferably wet granulating, the nanoparticles with one or more pharmaceutical excipients; and (iii) compressing the granules; a method for preparing the pharmaceutical dosage form according to the invention as described above, comprising:

[0166] Preferably, the process for preparing the pharmaceutical dosage form comprises the process for preparing the nanoparticles according to the invention as described above.

[0167] In a preferred embodiment, step (ii) involves wet granulating a mixture of the first and second liquids with a third liquid containing the defined precipitated nanoparticles, preferably obtained in step (c) of the method for preparing nanoparticles according to the invention described above.

[0168] In another preferred embodiment, step (ii) involves wet granulating a mixture of the third and fourth liquids with a fifth liquid comprising the defined precipitated coated nanoparticles, preferably obtained in step (E) of the method for preparing nanoparticles according to the invention described above.

[0169] Another aspect of the present invention relates to a pharmaceutical dosage form according to the present invention as described above for use in treating a hyperproliferative disorder. Another aspect of the present invention relates to a method for treating a hyperproliferative disorder, 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 treating a hyperproliferative disorder.

[0170] 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-resistant prostate cancer and hormone-sensitive prostate cancer.

[0171] Preferably, the pharmaceutical dosage form according to the invention is administered orally.

[0172] Preferably, the pharmaceutical dosage form according to the invention is administered once a day or twice a day; preferably once a day, optionally with simultaneous administration of multiple pharmaceutical dosage forms. In this context, "simultaneous administration" means that the subject takes multiple pharmaceutical dosage forms within a relatively short time period, for example within 10 minutes, preferably within 5 minutes.

[0173] 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.

[0174] The following examples further illustrate the present invention but should not be construed as limiting its scope. [Example]

[0175] Example 1 - Pluronic vs. SDS and Soluplus vs. PVP vs. TPGS vs. HPMC - Pre-precipitation Experiments Eight formulations containing enzalutamide in non-salt form and various excipients were prepared. Precipitation experiments were performed. Acetone was used as the solvent and water as the non-solvent, and precipitation was carried out under stirring. The particle size of the precipitates thus obtained was measured. The composition of the various formulations and the results of particle size measurement are summarized in the following table: [Table 4]

[0176] The experimental design yielded a relatively broad particle size distribution. Formulations 1-1a, 1-lb, 1-2a, 1-2b, and 1-4a precipitated from acetone were at the lower end of the particle size distribution, with individual sizes of 800 nm or less, which was considered the upper target limit (minimum [nm]). Based on this preliminary testing, formulations 1-lb (Pluronic F127 / Soluplus), 1-2a (SDS / PVP K30), and 1-4a (SDS / HPMC) were determined to provide the best precipitates from acetone upon stirring.

[0177] Example 2 - Pluronic F127 / Soluplus - Acetone vs. THF - Pre-precipitation Experiment The Pluronic F127 / Soluplus system was further investigated. Eight formulations containing different amounts of enzalutamide in its unsalted form and different amounts of Pluronic F127 were prepared. The concentration of Soluplus was kept constant (70 mg / ml). Precipitation experiments were performed using acetone and tetrahydrofuran (THF) as the solvent and water as the nonsolvent, with a solvent to nonsolvent ratio of 1 / 3. The z-average particle size of the precipitates thus obtained was measured.

[0178] It was further investigated whether the particles thus obtained could be dispersed from the suspension into a fasting state simulated fluid (FaSSIF). To this end, 40 mg of particles were stirred in 900 ml of FaSSIF at 50 rpm and 37°C for 1 h. The dispersion was then filtered through a 0.45 μm PTFE filter, and the percentage of particles dispersed in the FaSSIF was quantified.

[0179] The composition of the various formulations, the solvent, the results of the particle size measurements, as well as the results of the dispersion experiments are summarized in the table below: [Table 5]

[0180] As a result, precipitation from THF generally gave better results than precipitation from acetone. Furthermore, formulations 2-6, 2-7, and 2-8 gave promising dispersion experiments in FaSSIF.

[0181] Example 3 - PVPK30 / SDS / THF - Pre-precipitation Experiment The PVP K30 / SDS (and PVP K30 / Pluronic F127) systems were also investigated. Five formulations containing different amounts of enzalutamide in its unsalted form and different amounts of PVP K30 were prepared. The concentration of SDS was kept constant. Precipitation experiments were performed with tetrahydrofuran (THF) as the solvent and water as the non-solvent, with a solvent to non-solvent ratio of 1 / 2. The z-average particle size of the precipitates thus obtained was measured.

[0182] It was further investigated according to Example 2 whether the particles thus obtained could be dispersed from the suspension into a fasting state simulated fluid (FaSSIF).

[0183] The composition of the various formulations, the solvent, the results of the particle size measurements, as well as the results of the dispersion experiments are summarized in the table below: [Table 6]

[0184] Example 4 - HMPC / SDS / THF - Pre-precipitation Experiment The HPMC / SDS system was also investigated. Three formulations containing enzalutamide in its non-salt form were prepared. The concentrations of SDS (60 mg / ml) and HPMC (25 mg / ml) were kept constant. Precipitation experiments were performed using acetone and tetrahydrofuran (THF) as solvents and water as non-solvents at different solvent to non-solvent ratios. The z-average particle size of the precipitates thus obtained was measured.

[0185] It was further investigated according to Example 2 whether the particles thus obtained could be dispersed from the suspension into a fasting state simulated fluid (FaSSIF).

[0186] The composition of the various formulations, the solvent, the results of the particle size measurements, as well as the results of the dispersion experiments are summarized in the table below: [Table 7]

[0187] As a result, Example 4-3 exhibits an excellent particle size (z-average: about 80 nm) and is highly dispersed (about 98%) from the suspension into FaSSIF.

[0188] Example 5 - PVPK30 / TPGS / THF - Pre-precipitation Experiment The PVP K30 / TPGS system was also investigated. Seven formulations containing enzalutamide in its non-salt form were prepared. The concentrations of PVP K30 (60 mg / ml) and enzalutamide (200 mg / ml) were kept constant. Precipitation experiments were performed using tetrahydrofuran (THF) as the solvent and water as the nonsolvent, with a solvent to nonsolvent ratio of 1 / 3. The nonsolvent contained TPGS. The z-average particle size of the precipitates thus obtained was measured.

[0189] It was further investigated according to Example 2 whether the particles thus obtained could be dispersed from the suspension into a fasting state simulated fluid (FaSSIF).

[0190] The composition of the various formulations, the solvent, the results of the particle size measurements, as well as the results of the dispersion experiments are summarized in the table below: [Table 8]

[0191] Example 6 - HPMC / TPGS / THF - Pre-precipitation Experiment The HPMC / TPGS system was also investigated. Seven formulations containing enzalutamide in its non-salt form were prepared. The concentrations of HPMC (60 mg / ml) and enzalutamide (200 mg / ml) were kept constant. Precipitation experiments were performed using tetrahydrofuran (THF) as the solvent and water as the nonsolvent, with a solvent to nonsolvent ratio of 1 / 3. The nonsolvent contained TPGS. The z-average particle size of the precipitates thus obtained was measured.

[0192] It was further investigated according to Example 2 whether the particles thus obtained could be dispersed from the suspension into a fasting state simulated fluid (FaSSIF).

[0193] The composition of the various formulations, the solvent, the results of the particle size measurements, as well as the results of the dispersion experiments are summarized in the table below: [Table 9]

[0194] As a result, Examples 6-5 to 6-7 exhibited excellent particle sizes and were highly dispersed from the suspension into FaSSIF.

[0195] Example 7 - HPMC-AS / Acetone - Coprecipitation with Pre-precipitation Experiment The HPMC / TPGS system was also investigated. Nine formulations containing enzalutamide in its non-salt form were prepared. The concentrations of HPMC-AS (15 mg / ml) and enzalutamide (none or 5 mg / ml) were kept constant. Precipitation experiments were performed using acetone as the solvent and water as the nonsolvent, with a solvent to nonsolvent ratio of 1 / 5. The water contained 50 mM buffer solutions with various pH values. The z-average particle size of the precipitates thus obtained was measured.

[0196] It was further investigated according to Example 2 whether the particles thus obtained could be dispersed from the suspension into a fasting state simulated fluid (FaSSIF).

[0197] The composition of the various formulations, the solvent, the results of the particle size measurements, as well as the results of the dispersion experiments are summarized in the table below: [Table 10]

[0198] Example 8 - Microjet Reactor Based on the above-mentioned screening by preliminary precipitation experiments, two representative systems, C-1 (Soluplus® / Pluronic® F127) and C-2 (HPMC / SDS), were identified, and the corresponding formulations were processed by nanojet technology. Nanoparticles were prepared from the non-salt form of enthalzamide dissolved in tetrahydrofuran as the solvent and water as the nonsolvent in a microjet reactor at 25°C.

[0199] The composition of the various formulations, the solvent, the results of the particle size measurements, as well as the results of the dispersion experiments are summarized in the table below: [Table 11]

[0200] The experimental results for the Soluplus® / Pluronic® F127 system are further shown in Figures 1-3.

[0201] Figure 1 shows the z-average particle size as a function of the concentration of enzalutamide (API) in suspension. The results of the preliminary precipitation experiments (beaker) are marked with the symbol "□", and the results of the microjet reactor technique (MJR) are marked with the symbol "■".

[0202] Figure 2 shows the percentage of dispersion in FaSSIF depending on the concentration of enzalutamide (API) in the suspension. The results of the preliminary precipitation experiments (beaker) are marked with the symbol "□" and the results of the microjet reactor technique (MJR) are marked with the symbol "■".

[0203] As shown, under the given experimental conditions, particle size is reduced by flash precipitation (MJR) compared to the pre-precipitation experiment (beaker). Furthermore, increasing the concentration of enzalutamide (API) increases particle size, thereby decreasing dispersion in FaSSIF.

[0204] Figure 3 shows the percentage of dispersion in FaSSIF depending on the z-average particle size. The results of the preliminary precipitation experiments (beaker) are marked with the symbol "□" and the results of the microjet reactor technique (MJR) are marked with the symbol "■".

[0205] As shown, the smaller particles disperse better than the larger particles.

[0206] Example 9 - Microjet Reactor Nanoparticles were prepared from enzalutamide in its non-salt form dissolved in tetrahydrofuran and the pharmaceutical excipients Soluplus® and Pluronic® F127 dissolved in water. Tetrahydrofuran was used as the solvent for the first liquid, and water was used as the antisolvent for the second liquid containing Soluplus® and Pluronic® F127. A temperature of 25°C was set for the first liquid, the second liquid, and the microjet reactor (400 μm pinhole, no pressure, flow rate 200 ml / min).

[0207] Particles with different particle sizes are produced, and the results are summarized in the table below: [Table 12]

[0208] Thus, Examples 9-1 to 9-4 exhibit excellent particle sizes and are highly dispersed from the suspension into FaSSIF.

Claims

1. Nanoparticles containing enzalutamide.

2. The nanoparticles of claim 1, wherein the enzalutamide has a crystallinity of at least 10%, preferably at least 20%, more preferably at least 30%.

3. The nanoparticles of claim 2, wherein the enzalutamide has a crystallinity of at least 40%, preferably at least 50%, more preferably at least 60%.

4. The nanoparticles of claim 3, wherein the enzalutamide has a crystallinity of at least 70%, preferably at least 80%, more preferably at least 90%, especially at least 95%.

5. The nanoparticle of any one of the preceding claims, wherein enzalutamide is the only pharmacologically active ingredient contained in the nanoparticle.

6. 10. The nanoparticles according to any one of the preceding claims, having a z-average particle size Dz of 1000 nm or less, preferably 900 nm or less, more preferably 800 nm or less, determined according to ISO 22412:2008 Particle size analysis—Dynamic light scattering.

7. 200±150 nm, or 200±100 nm, or 200±50 nm; or 300±150 nm, or 300±100 nm, or 300±50 nm; or 400±150 nm, or 400±100 nm, or 400±50 nm; or 500±150 nm, or 500±100 nm, or 500±50 nm; or 600±150 nm, or 600± 10. The nanoparticles of any one of the preceding claims, having a z-average particle size Dz in the range: 100 nm, or 600±50 nm; or 700±150 nm, or 700±100 nm, or 700±50 nm; or 800±150 nm, or 800±100 nm, or 800±50 nm; or 900±150 nm, or 900±100 nm, or 900±50 nm.

8. 8. The nanoparticles of claim 7, having a z-average particle size Dz in the range of 850±150 nm, or 850±100 nm, or 850±50 nm.

9. 10. The nanoparticles according to any one of the preceding claims, having a z-average particle size Dz of 700 nm or less, preferably 600 nm or less, more preferably 500 nm or less; or 400 nm or less, preferably 300 nm or less, more preferably 200 nm or less; or 150 nm or less, preferably 125 nm or less, more preferably 100 nm or less.

10. 10. The nanoparticle of any one of the preceding claims, further comprising one or more pharmaceutical excipients independently selected from the group consisting of surfactants and polymers.

11. 11. The nanoparticles of claim 10, wherein the total content of all pharmaceutical excipients contained in the nanoparticles is in each case 90% by weight or less, preferably 85% by weight or less, more preferably 80% by weight or less, relative to the total weight of the nanoparticles.

12. 12. The nanoparticles of claim 11, wherein the total content of all pharmaceutical excipients contained in the nanoparticles is in each case 75% by weight or less, preferably 70% by weight or less, more preferably 65% by weight or less, relative to the total weight of the nanoparticles.

13. 13. The nanoparticles of claim 12, wherein the total content of all pharmaceutical excipients contained in the nanoparticles is in each case 60% by weight or less, preferably 55% by weight or less, more preferably 50% by weight or less, relative to the total weight of the nanoparticles.

14. Nanoparticles according to any one of claims 10 to 13, which contain one or more surfactants.

15. 15. The nanoparticles according to claim 14, wherein the total content of the one or more surfactants contained in the nanoparticles is in each case 20% by weight or less, preferably 15% by weight or less, more preferably 10% by weight or less, relative to the total weight of the nanoparticles.

16. 16. The nanoparticles of claim 15, wherein the total content of the one or more surfactants contained in the nanoparticles is in each case 7.5% by weight or less, preferably 5.0% by weight or less, more preferably 2.5% by weight or less, relative to the total weight of the nanoparticles.

17. 17. The nanoparticles of claim 16, wherein the total content of the one or more surfactants contained in the nanoparticles is in each case 1.5% by weight or less, preferably 1.0% by weight or less, more preferably 0.5% by weight or less, relative to the total weight of the nanoparticles.

18. 18. The nanoparticles of any one of claims 14 to 17, wherein the one or more surfactants comprise or consist essentially of a surfactant having an HLB value of at least 10, preferably at least 15, more preferably at least 20.

19. 19. The nanoparticle of claim 18, wherein the one or more surfactants comprise or consist essentially of a surfactant having an HLB value of at least 25, preferably at least 30, more preferably at least 32.

20. 20. The nanoparticle of claim 19, wherein the one or more surfactants comprise or consist essentially of a surfactant having an HLB value of at least 34, preferably at least 36, more preferably at least 38.

21. 21. The nanoparticle of any one of claims 14 to 20, wherein the one or more surfactants comprise or consist essentially of a non-ionic surfactant.

22. The nonionic surfactant is linear or branched fatty alcohols; preferably chosen from cetyl alcohol, cetostearyl alcohol, stearyl alcohol, oleyl alcohol, octyldodecanol or 2-hexyldecan-1-ol; sterols; preferably cholesterol; - lanolin alcohol; 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, superglycerinated fully hydrogenated rapeseed oil; partial fatty acid esters of sorbitan; preferably selected from sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate; 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; such as monolauryl, trilauryl, 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, polyoxyethylene (20) sorbitan trioleate; polyoxyethylene glycerol fatty acid esters, such as mixtures of mono-, di- and triesters of glycerol with di- and monoesters of macrogols having a molecular weight in the range from 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, macrogolglycerol lysinolate; polyoxyethylene fatty acid esters, preferably selected from macrogol oleate, macrogol stearate, macrogol-15-hydroxystearate, polyoxyethylene esters of 12-hydroxystearic acid; - fatty alcohol ethers of polyoxyethylene; preferably selected from polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene cetostearyl ether, lauromacrogol 400, macrogol oleyl ether, macrogol stearyl ether; - reaction products of natural or hydrogenated castor oil with ethylene oxide, such as those commercialized under the trademark Cremophor®; - polyoxypropylene-polyoxyethylene block copolymers (poloxamers); preferably according to the general formula: 【Chemical 1】 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; - polyglycolized glycerides; preferably selected from those commercialized under the trademarks Gelucire®, Labrasol®; fatty acid esters of sucrose; preferably selected from sucrose distearate, sucrose dioleate, sucrose dipalmitate, sucrose monostearate, sucrose monopalmitate, sucrose monooleate, sucrose monomyristate, sucrose monolaurate; fatty acid esters of polyglycerol; preferably selected from polyglycerol oleate, polyglycerol dioleate, polyglycerol poly-12-hydroxystearate, triglycerol diisostearate; and - polyoxyethylene ester of D-α-tocopheryl succinate; preferably D-α-tocopherol polyethylene glycol 1000 succinate; 22. The nanoparticle of claim 21 selected from the group consisting of:

23. 23. Nanoparticles according to claim 22, wherein the non-ionic surfactant is a polyoxyethylene ester of D-α-tocophenyl succinate; preferably D-α-tocopherol polyethylene glycol 1000 succinate.

24. The non-ionic surfactant is a polyoxypropylene-polyoxyethylene block copolymer (poloxamer), preferably according to the following general formula: 【Chemistry 2】 23. The nanoparticle of claim 22, wherein a is independently an integer in the range of 2 to 130, preferably 90 to 110, more preferably about 101; and b is an integer in the range of 15 to 67, preferably 46 to 66, more preferably about 56; preferably poloxamer 407.

25. The nanoparticles of any one of claims 14 to 20, wherein the one or more surfactants comprise or consist essentially of an anionic surfactant.

26. The anionic surfactant is alkyl sulfates, preferably those selected from sodium lauryl sulfate (sodium dodecyl sulfate), sodium cetyl sulfate, sodium cetylstearyl sulfate, sodium stearyl sulfate, sodium dioctyl sulfosuccinate (sodium docusate); and the corresponding potassium or calcium salts thereof; fatty acid salts; preferably selected from stearates and oleates; salts of cholic acid; preferably selected from sodium deoxycholate, sodium glycocholate, sodium taurocholate and the corresponding potassium or ammonium salts; particularly preferably sodium deoxycholate; 26. The nanoparticle of claim 25, selected from the group consisting of:

27. The anionic surfactant is an alkyl sulfate; preferably, the anionic surfactant is represented by the general formula C ｎ H ２ｎ＋１ O-SO ３ － M ＋ wherein n is an integer from 8 to 30, preferably from 10 to 24, more preferably from 12 to 18; M is Li ＋ , Na ＋ , K. ＋ , N.H. ４ ＋ , 1 / 2Mg ２＋ , and 1 / 2Ca ２＋ 26. The nanoparticles according to claim 25, wherein the nanoparticles are selected from the group consisting of:

28. 28. The nanoparticle of claim 27, wherein the anionic surfactant is sodium dodecyl sulfate.

29. Nanoparticles according to any one of claims 10 to 28, which contain one or more polymers.

30. 30. The nanoparticles according to claim 29, wherein the total content of the one or more polymers contained in the nanoparticles is in each case 45% by weight or less, preferably 40% by weight or less, more preferably 35% by weight or less, relative to the total weight of the nanoparticles.

31. 31. The nanoparticles of claim 30, wherein the total content of the one or more polymers contained in the nanoparticles is in each case 30% by weight or less, preferably 25% by weight or less, more preferably 20% by weight or less, relative to the total weight of the nanoparticles.

32. 32. The nanoparticles of claim 31, wherein the total content of the one or more polymers contained in the nanoparticles is in each case 15% by weight or less, preferably 10% by weight or less, more preferably 5.0% by weight or less, relative to the total weight of the nanoparticles.

33. 33. Nanoparticles according to any one of claims 29 to 32, wherein the total content of the one or more polymers contained in the nanoparticles is in each case at least 1.0 wt.-%, preferably at least 2.5 wt.-%, more preferably at least 5.0 wt.-%, relative to the total weight of the nanoparticles.

34. 34. The nanoparticles according to claim 33, wherein the total content of the one or more polymers contained in the nanoparticles is in each case at least 7.5% by weight, preferably at least 10% by weight, more preferably at least 12.5% by weight, relative to the total weight of the nanoparticles.

35. 35. The nanoparticles according to claim 34, wherein the total content of the one or more polymers contained in the nanoparticles is in each case at least 15% by weight, preferably at least 17.5% by weight, more preferably at least 20% by weight, relative to the total weight of the nanoparticles.

36. 36. The nanoparticle of any one of claims 29 to 35, wherein the one or more polymers comprise or consist essentially of a polymer selected from the group consisting of: - neutral non-cellulosic polymers, preferably selected from vinyl polymers and copolymers with hydroxyl, alkylacyloxy and cyclic amide polyvinyl alcohol substituents, with at least a portion of the repeating units in non-hydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinylpyrrolidone; polyvinylpyrrolidone vinyl acetate; and polyethylene polyvinyl alcohol copolymers; - ionizable non-cellulosic polymers; preferably carboxylic acid-functionalized vinyl polymers; preferably those selected from carboxylic acid-functionalized polymethacrylates and carboxylic acid-functionalized polyacrylates; amine-functionalized polyacrylates and polymethacrylates; proteins; and carboxylic acid-functionalized starches; amphiphilic non-cellulosic polymers; preferably selected from acrylate and methacrylate copolymers and graft copolymers of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate; neutral cellulosic polymers having at least one ester- and / or ether-linked substituent; preferably selected from hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose; - ionizable cellulosic polymers having at least one ester- and / or ether-bonded substituent; preferably hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate succinate phthalate, hydroxypropyl selected from pyrmethylcellulose succinate phthalate, cellulose propionate phthalate, hydroxypropylcellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose acetate salicylate, hydroxypropylsalicylatecellulose acetate, ethylbenzoatecellulose acetate, hydroxypropylethylbenzoatecellulose acetate, ethylphthalatecellulose acetate, ethylnicotinatecellulose acetate, and ethylpicolinatecellulose acetate; and amphiphilic cellulosic polymers obtained by substituting cellulose on any or all of the three hydroxyl substituents present in each saccharide repeat unit with at least one hydrophobic substituent, said hydrophobic substituent being preferably selected from ether- and ester-linked alkyl groups, ether- and / or ester-linked aryl groups, and phenylates; in addition to the hydrophobic substituents, at least one hydrophilic substituent may also be present; said hydrophilic substituent is preferably selected from ether- or ester-linked non-ionizable groups, preferably hydroxyalkyl substituents, alkyl ether groups, carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates, or sulfonates.

37. 37. The nanoparticle of claim 36, wherein the one or more polymers comprise or consist essentially of polyvinylpyrrolidone (PVP).

38. 37. The nanoparticle of claim 36, wherein the one or more polymers comprise or consist essentially of hydroxypropylmethylcellulose (HPMC).

39. 37. The nanoparticle of claim 36, wherein the one or more polymers comprise or consist essentially of hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

40. 37. The nanoparticle of claim 36, wherein the one or more polymers comprise or consist essentially of a graft copolymer based on polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam (PVAc-PVCap-PEG).

41. 25. Nanoparticles according to any one of the preceding claims, comprising a polyoxypropylene-polyoxyethylene block copolymer, preferably a polyoxypropylene-polyoxyethylene block copolymer according to claim 24, in combination with a polyoxyethylene ester of D-α-tocopheryl succinate, preferably D-α-tocopherol polyethylene glycol 1000 succinate.

42. Nanoparticles according to any one of claims 1 to 40, comprising a polyoxypropylene-polyoxyethylene block copolymer, preferably a polyoxypropylene-polyoxyethylene block copolymer according to claim 24, in combination with a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG).

43. Nanoparticles according to any one of claims 1 to 40, comprising a polyoxypropylene-polyoxyethylene block copolymer, preferably a polyoxypropylene-polyoxyethylene block copolymer according to claim 24, in combination with polyvinylpyrrolidone (PVP).

44. Nanoparticles according to any one of claims 1 to 40, comprising a polyoxypropylene-polyoxyethylene block copolymer, preferably a polyoxypropylene-polyoxyethylene block copolymer according to claim 24, in combination with hydroxypropylmethylcellulose (HPMC).

45. Nanoparticles according to any one of claims 1 to 40, comprising a polyoxypropylene-polyoxyethylene block copolymer, preferably a polyoxypropylene-polyoxyethylene block copolymer according to claim 24, in combination with hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

46. Nanoparticles according to any one of claims 1 to 40, comprising an alkyl sulfate, preferably an alkyl sulfate according to claim 27, in combination with a polyoxyethylene ester of D-α-tocopheryl succinate, preferably D-α-tocopherol polyethylene glycol 1000 succinate.

47. Nanoparticles according to any one of claims 1 to 40, comprising an alkyl sulfate, preferably an alkyl sulfate according to claim 27, in combination with a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam (PVAc-PVCap-PEG).

48. Nanoparticles according to any one of claims 1 to 40, comprising an alkyl sulfate, preferably an alkyl sulfate according to claim 27, in combination with polyvinylpyrrolidone (PVP).

49. Nanoparticles according to any one of claims 1 to 40, comprising an alkyl sulfate, preferably an alkyl sulfate according to claim 27, in combination with hydroxypropylmethylcellulose (HPMC).

50. Nanoparticles according to any one of claims 1 to 40, comprising an alkyl sulfate, preferably an alkyl sulfate according to claim 27, in combination with hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

51. Nanoparticles according to any one of claims 1 to 40, comprising a polyoxyethylene ester of D-α-tocopheryl succinate, preferably a polyoxyethylene ester of D-α-tocopheryl succinate according to claim 23, in combination with polyvinylpyrrolidone (PVP).

52. Nanoparticles according to any one of claims 1 to 40, comprising a polyoxyethylene ester of D-α-tocopheryl succinate, preferably a polyoxyethylene ester of D-α-tocopheryl succinate according to claim 23, in combination with hydroxypropylmethylcellulose (HPMC).

53. Nanoparticles according to any one of claims 1 to 40, comprising a polyoxyethylene ester of D-α-tocopheryl succinate, preferably a polyoxyethylene ester of D-α-tocopheryl succinate according to claim 23, in combination with hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

54. 10. A method for preparing nanoparticles according to any one of the preceding claims, which involves precipitation of the nanoparticles from a liquid.

55. (i) (a) providing a solution of enzalutamide in a first liquid, optionally with one or more pharmaceutical excipients; (b) providing a second liquid containing one or more pharmaceutical excipients, optionally in dissolved form; and (c) contacting the first liquid with the second liquid, thereby obtaining a third liquid containing a mixture of the first liquid and the second liquid and precipitated nanoparticles; Contains; or (ii) (A) providing a solution of enzalutamide in a first liquid, preferably free of pharmaceutical excipients; (B) providing a second liquid that is free of pharmaceutical excipients; (C) contacting the first liquid with the second liquid, thereby obtaining a third liquid containing a mixture of the first liquid and the second liquid and precipitated nanoparticles; (D) providing a fourth liquid comprising one or more pharmaceutical excipients in dissolved form; and (E) contacting the third liquid with the fourth liquid, thereby obtaining a fifth liquid containing a mixture of the third liquid and the fourth liquid and precipitated coated nanoparticles coated with one or more pharmaceutical excipients; 55. The method of claim 54, comprising:

56. 56. The method of claim 55, wherein the solution provided in step (a) or (D) comprises a surfactant according to any one of claims 18 to 28 and / or a polymer according to any one of claims 36 to 40.

57. 57. The method of claim 55 or 56, wherein the second liquid provided in step (b) or the fourth liquid provided in step (D) comprises a surfactant according to any one of claims 18 to 28 and / or a polymer according to any one of claims 36 to 40.

58. A method according to any one of claims 55 to 57, wherein the amount of enzalutamide contained in the precipitated nanoparticles obtained in step (c) or the precipitated coated nanoparticles obtained in step (E) is in each case at least 82% by weight, preferably at least 84% by weight, and more preferably at least 86% by weight of the amount of enzalutamide contained in the solution prepared in step (a).

59. The method of claim 58, wherein the amount of enzalutamide contained in the precipitated nanoparticles obtained in step (c) or the precipitated coated nanoparticles obtained in step (E) is, in each case, at least 88% by weight, preferably at least 90% by weight, and more preferably at least 92% by weight of the amount of enzalutamide contained in the solution prepared in step (a).

60. The method of claim 59, wherein the amount of enzalutamide contained in the precipitated nanoparticles obtained in step (c) or the precipitated coated nanoparticles obtained in step (E) is, in each case, at least 94% by weight, preferably at least 96% by weight, and more preferably at least 98% by weight of the amount of enzalutamide contained in the solution prepared in step (a).

61. 61. The method of any one of claims 55 to 60, wherein the first and second liquids are mixed as impinging jets at a defined pressure and flow rate, resulting in immediate precipitation or co-precipitation during nanoparticle formation; and optionally, the third and fourth liquids are mixed as impinging jets at a defined pressure and flow rate, resulting in immediate precipitation or co-precipitation of one or more excipients contained in the fourth liquid, thereby coating the nanoparticles contained in the third liquid.

62. The particle diameter of the nanoparticles is the temperature at which the first liquid and the second liquid come into contact, and optionally the temperature at which the third liquid and the fourth liquid come into contact; and / or the flow rates of the first and second liquids, and optionally the flow rates of the third and fourth liquids; and / or the pressure of the gas supplied to the reactor space of the microjet reactor where the first liquid and the second liquid come into contact, and optionally the pressure of the gas supplied to the reactor space of the microjet reactor where the third liquid and the fourth liquid come into contact; and / or - the concentration of each compound in each of said solvents and antisolvents; The method according to any one of claims 55 to 61, wherein the control is performed by

63. (i) the first liquid comprises a solvent selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol, isopropanol, and acetonitrile, preferably tetrahydrofuran or acetone; and / or the second liquid comprises water; or (ii) the first liquid comprises glacial acetic acid; and / or the second liquid comprises or consists essentially of an aqueous base; preferably the second liquid comprises or consists essentially of aqueous sodium hydroxide, potassium hydroxide, or ammonia, in each case together with pharmaceutical excipients which may optionally be present; 63. The method of any one of claims 55 to 62.

64. The method of any one of claims 55 to 63, wherein the first liquid comprises a solvent for enzalutamide and the second liquid comprises an anti-solvent for enzalutamide, and the contact of the first liquid with the second liquid in step (c) or (C) produces the nanoparticles by controlled precipitation against an anti-solvent using microjet reactor technology.

65. 65. The method of any one of claims 55 to 64, wherein in step (a) or (A), enthalzamide is used in a non-salt form.

66. 66. The method of any one of claims 54 to 65, carried out in a microjet reactor.

67. Nanoparticles obtainable by the method according to any one of claims 54 to 66.

68. A pharmaceutical composition comprising the nanoparticles of any one of claims 1 to 53 or 67 and one or more pharmaceutical excipients.

69. 69. The pharmaceutical composition of claim 68, wherein the one or more pharmaceutical excipients form a matrix in which the nanoparticles are dispersed.

70. 70. The pharmaceutical composition of claim 68 or 69, wherein the pharmaceutical excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a lubricant, a glidant, and any combination thereof.

71. A pharmaceutical composition according to any one of claims 68 to 70, wherein the weight content of enzalutamide is in each case at least 1.0% by weight, preferably at least 2.5% by weight, and more preferably at least 5.0% by weight, relative to the total weight of the pharmaceutical composition.

72. A pharmaceutical composition described in claim 71, wherein the weight content of the enzalutamide is, in each case, at least 10% by weight, preferably at least 15% by weight, more preferably at least 20% by weight, even more preferably at least 25% by weight, even more preferably at least 30% by weight, even more preferably at least 35% by weight, even more preferably at least 40% by weight, most preferably at least 45% by weight, and in particular at least 50% by weight, relative to the total weight of the pharmaceutical composition.

73. A pharmaceutical dosage form comprising nanoparticles according to any one of claims 1 to 53 or 67 or a pharmaceutical composition according to any one of claims 69 to 73.

74. 74. The pharmaceutical dosage form of claim 73, selected from tablets, microtablets, capsules, powders, granules, suspensions, emulsions.

75. 75. A pharmaceutical dosage form according to claim 73 or 74, which is a tablet.

76. 76. The pharmaceutical dosage form of claim 75, wherein the tablet is wet granulated.

77. 77. The pharmaceutical dosage form of claim 76, wherein the wet granulation requires a liquid comprising water and a solvent selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol, isopropanol, and acetonitrile, preferably tetrahydrofuran or acetone.

78. 78. The pharmaceutical dosage form according to any one of claims 75 to 77, which is film coated.

79. 79. A pharmaceutical dosage form according to any one of claims 73 to 78, 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, even more preferably not more than 750 mg, most preferably not more than 700 mg, especially not more than 650 mg.

80. 80. The pharmaceutical dosage form of any one of claims 73 to 79, comprising enzalutamide at 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.

81. 81. The pharmaceutical dosage form according to any one of claims 75 to 80, having a disintegration time according to Ph.Eur of 8.0 minutes or less, preferably 7.0 minutes or less, more preferably 6.0 minutes or less, even more preferably 5.0 minutes or less, even more preferably 4.0 minutes or less, even more preferably 3.0 minutes or less, most preferably 2.0 minutes or less, and in particular 1.0 minute or less.

82. The pharmaceutical dosage form according to any one of claims 75 to 81, which provides an immediate release of the enzalutamide in accordance with Ph. Eur, such that at least 80% by weight of the enzalutamide originally contained in the pharmaceutical dosage form is released after 30 minutes under in vitro conditions of 37°C, pH 1.2 in 600 mL of artificial gastric fluid using a paddle apparatus at a rotation speed of 75 rpm.

83. A pharmaceutical dosage form according to any one of claims 73 to 82, which provides an average oral bioavailability of enzalutamide of at least 5%, preferably at least 10%, more preferably at least 15%, even more preferably at least 20%, even more preferably at least 25%, even more preferably at least 30%, most preferably at least 35%, and particularly at least 40%.

84. When administered orally, - C of 0.4 ± 0.1 μg / mL at a dose of 30 mg ｍａｘ and / or t in the range of 0.4 to 4 h ｍａｘ and / or an AUC of 54±21 μg·h / mL ∞ and / or - C of 0.9 ± 0.5 μg / mL at a dose of 40 mg ｍａｘ and / or t in the range of 0.4 to 4 h ｍａｘ and / or an AUC of 65±30 μg·h / mL ∞ and / or - C of 1.7 ± 0.5 μg / mL at a dose of 60 mg ｍａｘ and / or t in the range of 0.5 to 1 h ｍａｘ and / or an AUC of 94±17 μg·h / mL ∞ and / or - At a dose of 80 mg, C of 2.2 ± 0.8 μg / mL ｍａｘ and / or t in the range of 0.5 to 2 h ｍａｘ and / or an AUC of 120±40 μg·h / mL ∞ and / or - At a dose of 150 mg, C of 3.4 ± 0.8 μg / mL ｍａｘ and / or t in the range of 0.5 to 2 h ｍａｘ and / or an AUC of 334±50 μg·h / mL ∞ and / or - C of 3.5 ± 0.8 μg / mL at a dose of 160 mg ｍａｘ and / or t in the range of 0.5 to 2 h ｍａｘ and / or an AUC of 400±50 μg·h / mL ∞ provide; 84. A pharmaceutical dosage form according to any one of claims 73 to 83.

85. 85. A method for preparing a pharmaceutical dosage form according to any one of claims 75 to 84, comprising the steps of: (i) providing nanoparticles according to any one of claims 1 to 53 or 68; (ii) granulating, preferably wet granulating, the nanoparticles with one or more pharmaceutical excipients; and (iii) compressing the granules.

86. 86. The method of claim 85, comprising the method of any one of claims 54 to 67.

87. 87. The method of claim 85 or 86, wherein step (ii) involves wet granulating a mixture of the first and second liquids defined in step (c) of claim 55 and a third liquid comprising the precipitated nanoparticles.

88. A pharmaceutical dosage form according to any one of claims 73 to 84 for use in the treatment of a hyperproliferative disorder.

89. 89. The pharmaceutical dosage form for use according to claim 88, wherein the hyperproliferative disorder is selected from the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer.

90. 90. The pharmaceutical dosage form for use according to claim 89, wherein the hyperproliferative disorder is prostate cancer selected from hormone-resistant prostate cancer and hormone-sensitive prostate cancer.

91. 91. The pharmaceutical dosage form for use according to any one of claims 88 to 90, wherein the pharmaceutical dosage form is administered orally.

92. 92. The pharmaceutical dosage form for use according to any one of claims 88 to 91, wherein the pharmaceutical dosage form is administered once daily, optionally requiring simultaneous administration of multiple pharmaceutical dosage forms.

93. 93. The pharmaceutical dosage form for use according to any one of claims 83 to 92, wherein the pharmaceutical dosage form is administered orally after a meal.

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