Formulations comprising crystalline nanosized encorafenib

Abstract

The invention relates to pharmaceutical compositions comprising crystalline nanosized Encorafenib, one or more polymers, and optionally one or more surfactants. The invention further relates to a process for the preparation of such pharmaceutical compositions. The invention further relates to pharmaceutical dosage forms comprising the pharmaceutical compositions.

Description

Formulations comprising crystalline nanosized Encorafenib

[0001] Priority is claimed of European patent application no. 24 183 689.9 that was filed on June 21, 2024.

[0002] The invention relates to pharmaceutical compositions comprising crystalline nanosized Encorafenib, one or more polymers, and optionally one or more surfactants. The invention further relates to a process for the preparation of such pharmaceutical compositions. The invention further relates to pharmaceutical dosage forms comprising the pharmaceutical compositions.

[0003] Encorafenib, (methyl [(2S)-l-{[4-(3-{5-chloro-2-fluoro-3-[(methylsulfonyl)amino]phenyl}-l- isopropyl-lH-pyrazol-4-yl)-2-pyrimidinyl]amino}-2-propanyl]carbamate))is marketed under the trade name Braftovi® as oral capsule for the treatment of patients with metastatic melanoma in combination with Binimetinib and of patients with metastatic colorectal cancer with a BRAF V600E mutation in combination with Cetuximab. Encorafenib is practically insoluble in aqueous media over a wide range of pH values.

[0004] The known pharmaceutical dosage forms of Encorafenib are not satisfactory in every respect.

[0005] The Braftovi® capsules include Encorafenib as an amorphous solid dispersion (ASD). Each Braftovi® capsule has considerable size and contains a dose of only 75 mg Encorafenib, whereas the necessary daily dose of Encorafenib amounts to 450 mg. Thus, a patient needs to swallow 6 large Braftovi® capsules per day. This is disadvantageous with respect to patient compliance. As in Braftovi® capsules the Encorafenib is provided as an amorphous solid dispersion, a considerable amount of excipients is needed and it is not possible to further increase the dose from 75 mg - this would result in a capsule size that can hardly be swallowed thus further deteriorating patient compliance.

[0006] Solid solutions and amorphous solid dispersions (ASD) are susceptible to thermodynamic instability due to the higher free energy associated with the amorphous state. Numerous factors such as the improper selection of formulation components, thermal stress, environmental stress such as humidity, and manufacturing stress contribute to the physical instability of solid solutions and amorphous solid dispersions. The proper selection of formulation ingredients, manufacturing process, processparameters, and packaging components are deemed essential to obtain a stable solid solution or amorphous solid dispersion drug product. Furthermore, a solid solution or an amorphous solid dispersion dosage form must include a significant amount of polymer increasing the size of the dosage form.

[0007] US 2015 0342896 Al relates to a formulation for treating a patient with hepatocellular carcinoma. The formulation comprises therapeutic agents in the form of nanoparticles containing one or more proteins or polysaccharides. The therapeutic agent is conjugated to an active targeting agent causing the formulation to preferentially segregate to the hepatocellular carcinoma tissue to release the therapeutic agents.

[0008] US 2017 0056327 Al relates to micro / nano composite drug delivery compositions for use in diagnosis, prophylaxis, treatment and / or amelioration of one or more symptoms of a mammalian disease, disorder, dysfunction, or abnormal condition.

[0009] US 2020 0405778 Al relates to therapeutic compositions and methods for treating cancer patients. The compositions and methods can increase efficacy of an anti-cancer therapy, or treat, prevent, or inhibit an oncology-treatment induced condition (OTIC) induced by an anti-cancer therapy.

[0010] US 2021 0263032 Al and US 2024 0103011 Al relate to methods, kits, systems, and compositions or liquid biopsy yield enhancement.

[0011] US 2024 0026294 Alrelates target cancer cell specific immunotherapy compositions, methods of making and use thereof.

[0012] US 2024 0173380 Al relates to Cx43, preferably in combination with an inhibitor of a mitogen- activated protein kinase (MAPK) selected from the list consisting of: BRAF, RAS, MEK or ERK, for use in the treatment of cancer wherein the cancer is characterized by the activation of mitogen-activated protein kinase (MAPK) selected from the list consisting of: BRAF, RAS, MEK or ERK.

[0013] US 2025 0032413 Al relates to an ultrasonically-enhanced continuous and large-scale production method for nano-formulations.

[0014] L. Fattore et al., Oncogene (2023) 42:293 - 307, https: / / doi.org / 10.1038 / s41388-022-02547-9 relates to oncosuppressive miRNAs loaded in lipid nanoparticles that potentiate targeted therapies in BRAF -mutant melanoma by inhibiting core escape pathways of resistance.

[0015] Th.S.C. Ng et al., Sci. Adv. 8, eabl6339 (2022) 29 April 2022 relates to overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy.

[0016] H. Chen et al., Frontiers in Oncology, June 2022, vol. 12, 928797, doi: 10.3389 / fonc.2022. 928797 relates to nanoparticle-based combination therapy for melanoma.

[0017] S. Battacharya et al., materialstoday Communications, vol. 31, June 2022, 103757, https: / / doi.Org / 10.1016 / j.mtcomm.2022.103757 relates to the development and characterization of hyaluronic acid surface scaffolds Encorafenib loaded polymeric nanoparticles for colorectal cancertargeting, such as Encorafenib-polycaprolactone nanoparticles, Encorafenib-polyhydroxybutyrate nanoparticles, hyaluronic acid-Encorafenib-polycaprolactone nanoparticles, and hyaluronic acid-Encoraf- enib- polyhydroxybutyrate nanoparticles.

[0018] R. Sen et al., https: / / 2025.biomaterials.org / sites / sfb / files / abstracts / 3P532.pdf, report about fabrication of PLGA-based nanoparticles co-loaded with Encorafenib and Trametinib (ETNPs) using a nanoprecipitation method for the treatment of CRC in a preclinical setting

[0019] There is a demand for stable bioavailable forms of Encorafenib.

[0020] It is an object of the invention to provide pharmaceutical compositions, especially pharmaceutical dosage forms, of Encorafenib that have advantages compared to the prior art.

[0021] This object has been achieved by the subject-matter of the patent claims.

[0022] A first aspect of the invention relates to a pharmaceutical composition comprising(i) nanoparticles of crystalline Encorafenib (i.e. crystalline nanosized Encorafenib), and(ii) one or more polymers; preferably selected from homopolymers, random copolymers, alternating copolymers, block copolymers and graft copolymers, and any combinations thereof; more preferably selected from cellulose ethers, cellulose esters, (co-)povidones, polyoxyalkylenes, polyoxyalkylene graft copolymers, acrylates, and any combinations thereof; still more preferably selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinylpyrrolidone, vinyl acetate) (PVP / VA), polyvinylpyrrolidone (PVP), poloxamers (PEO-PPO-PEO), polyvinyl ca- prolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)), poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) (BA / DMAEMA / MMA), poly(ethyl acrylate, methyl methacrylate) (EA / MMA), poly(meth- acrylic acid, methyl methacrylate) (MAA / MMA), poly(methacrylic acid, ethyl acrylate) (MAA / EA), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (EA / MMA / TMAEMA), and any combinations thereof; yet more preferably hydroxypropyl methyl cellulose acetate succinate (HPMCAS), or hydroxypropyl cellulose (HPC); even more preferably hydroxypropyl methyl cellulose (HPMC), poloxamers (PEO-PPO-PEO), or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g- (PVAc-co-PVCL)); more preferably poloxamers (PEO-PPO-PEO); and(iii) optionally one or more surfactants.

[0023] It has been surprisingly found that when amorphous nanosized Encorafenib is contacted with aqueous solutions comprising certain polymers, crystalline nanosized Encorafenib is obtained.

[0024] Further, it has been surprisingly found that the particle size of the amorphous nanosized Encorafenib (starting material) does not significantly increase in the course of crystallization, i.e. that the particle size of the crystalline nanosized Encorafenib (product) is not significantly greater than the particle size of the amorphous nanosized Encorafenib (starting material).

[0025] In the pharmaceutical compositions according to the invention, the crystalline nanosized Encorafenib is embedded in one or more polymers (crystalline polymer embedded nanoparticles, cPeNs). The morphology of the pharmaceutical compositions according to the invention is distinguished from the morphology of amorphous solid dispersions and solid solutions.

[0026] In preferred embodiments, the nanosized Encorafenib is present in form of particles that essentially consist of Encorafenib.

[0027] In preferred embodiments, the crystalline nanosized Encorafenib and the one or more polymers are crystalline polymer embedded nanoparticles, i.e. crystalline nanoparticles that are polymer embedded.

[0028] Several exemplifying and non-limiting embodiments of the invention are described in accompanied dependent claims.

[0029] Various exemplifying and non-limiting embodiments of the invention and methods of operation, together with additional objects and advantages thereof, are best understood from the following description of specific exemplifying embodiments.

[0030] The specific examples provided in the description given below should not be construed as limiting the scope and / or the applicability of the appended claims. Lists and groups of examples provided in the description given below are not exhaustive unless otherwise explicitly stated.

[0031] The features recited in dependent claims are mutually freely combinable unless otherwise explicitly stated. Furthermore, it is to be understood that the use of "a" or "an", i.e., a singular form, throughout this document does not exclude a plurality.

[0032] The verbs "to comprise" and "to include" are used as open limitations that neither exclude nor require the existence of also unrecited features.

[0033] As defined herein, "essentially consisting of' means that specific further components can be present, namely those not materially affecting the essential characteristics of the compound or pharmaceutical composition. Preferably, "essentially consisting of' means at least 98.0 wt.-% of the specified component, more preferably at least 98.5 wt.-%, still more preferably at least 99.0 wt.-%, yet more preferably at least 99.5 wt.-%, even more preferably about 100 wt.-%.

[0034] As defined herein, a "suspension" is Encorafenib suspended in liquid; preferably in an aqueous solution comprising one or more polymers and optionally one or more surfactants.

[0035] As defined herein, the expression "one or more polymers" refers homopolymers and copolymers, e.g. bipolymers or terpolymers, whereas copolymers can be random, alternating block or graft. The expression "one or more polymers" refers to a polymeric component that may consist of a single polymer or a mixture of two or more polymers. Unless expressly stated otherwise, when the pharmaceutical composition according to the invention comprises a combination of polymers, i.e., more than a single polymer, all quantities refer to the total amount of polymers.

[0036] As defined herein, the expression "one or more surfactants" refers to an amphiphilic component that may consist of a single surfactant or a mixture of two or more surfactants. Unless expressly stated otherwise, when the pharmaceutical composition according to the invention comprises a combination of surfactants, i.e., more than a single surfactant, all quantities refer to the total amount of surfactants.

[0037] As defined herein, an "aqueous solution" is water that contains one or more dissolved substances. In their neat state, the dissolved substances may be solids, liquids, or gases.

[0038] Unless expressly stated otherwise, all percentages are by weight (wt.-%) and relative to the total weight of the composition or formulation to which it is referred.

[0039] Unless expressly stated otherwise, the term "Encorafenib" refers to Encorafenib, its non-salt form, its physiologically acceptable salts, co-crystals, polymorphs and / or solvates thereof.

[0040] Unless expressly stated otherwise, a "pharmaceutical composition" according to the invention is a formulation comprising or essentially consisting of the pharmacologically active ingredient, one or more polymers and optionally one or more surfactants, which satisfies regulatory standards with respect to pharmaceuticals and medicaments, e.g. according to EMA, FDA, and the like. The "pharmaceutical composition" according to the invention is distinguished from a "pharmaceutical dosage form" according to the invention in that the latter is a dose unit that is devoted for administration to a patient in need thereof, whereas a "pharmaceutical composition" can be a bulk material. Thus, unless expressly stated otherwise, a "pharmaceutical dosage form" contains a therapeutic dose of the pharmacologically active ingredient that complies with the intended administration frequency to ensure that the desired therapeutic effect can be achieved.

[0041] Unless expressly stated otherwise, all references to standards and pharmacopoeias preferably refer to the version / edition that is effective / valid on June 21, 2025.

[0042] The pharmaceutical composition according to the invention comprises crystalline nanosized Encorafenib.

[0043] The expressions "nanoparticles of Encorafenib" and "nanosized Encorafenib" are used interchangeably. The expressions "nanoparticles of amorphous Encorafenib" and "amorphous nanosizedEncorafenib" are used interchangeably. The expressions "nanoparticles of crystalline Encorafenib" and "crystalline nanosized Encorafenib" are used interchangeably.

[0044] As defined herein, "nanosized Encorafenib" refers to a plurality of particles, either crystalline, or partially crystalline, or amorphous, preferably having a Dv90 value of at most 1000 nm, i.e., 90% of the volume fraction of said plurality of particles has a diameter of at most 1000 nm.

[0045] Preferably, Encorafenib is the sole active pharmaceutical ingredient (API) contained in the pharmaceutical composition according to the invention. Preferably, Encorafenib is likewise the sole active pharmaceutical ingredient (API) contained in the pharmaceutical dosage form according to the invention

[0046] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a Dv90 value of at most 950 nm, more preferably at most 900 nm, still more preferably at most 850 nm, yet more preferably at most 800 nm, even more preferably at most 750 nm, most preferably at most 700 nm, and in particular at most 650 nm.

[0047] Preferably, the Dv90 value is determined in accordance with ISO 22412:2008 Particle Size Analysis - Dynamic Light Scattering. The z-average particle size Dz is the intensity based harmonic mean. Dynamic light scattering (DLS) measurements are preferably performed with a Malvern Zetasizer Nano device, e.g. Zetasizer Nano ZS. The pharmaceutical composition according to the invention (dry powder of slurry / suspension) is redispersed into water or into 0.1% HPMC (aq.), stirred and measured after the sample is completely dispersed. Backscattering measurement setup is preferably used, and CUMULANTS -algorithm is preferably used to obtain z-average particle size (diameter) and polydispersity index (PI). For details, reference is made e.g. to the user manual Zetasizer nano series, NANO485 Issue 1.1 April 2013.

[0048] Preferably, the z-average particle size of the nanosized Encorafenib according to the invention, preferably of the crystalline nanosized Encorafenib according to the invention, is within the range of from 10 to 1000 nm.

[0049] In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a z-average particle size of at most 950 nm, more preferably at most 900 nm, still more preferably at most 850 nm, yet more preferably at most 800 nm, even more preferably at most 750 nm, most preferably at most 700 nm, and in particular at most 650 nm. In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a z-average particle size of at most 600 nm, more preferably at most 550 nm, still more preferably at most 500 nm, yet more preferably at most 450 nm, even more preferably at most 400 nm, most preferably at most 350 nm, and in particular at most 300 nm. In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a z-average particle size of at most 250 nm, more preferably at most 200 nm, still more preferably at most 150 nm, yet more preferably at most 100 nm, even more preferably at most 50 nm.

[0050] In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a z-average particle size of at least 50 nm, more preferably at least 100 nm, still more preferably at least 150 nm, yet more preferably at least 200 nm, even more preferably at least 250 nm, most preferably at least 300 nm, and in particular at least 350 nm. In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a z-average particle size of at least 400 nm, more preferably at least 450 nm, still more preferably at least 500 nm, yet more preferably at least 550 nm, even more preferably at least 600 nm, most preferably at least 650 nm, and in particular at least 700 nm. In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a z-average particle size of at least 750 nm, more preferably at least 800 nm, still more preferably at least 850 nm, yet more preferably at least 900 nm, even more preferably at least 950 nm.

[0051] In preferred embodiments, the z-average particle size of the nanosized Encorafenib according to the invention, preferably of the crystalline nanosized Encorafenib according to the invention, is within the range of from 10 to 200 nm, preferably 10 to 150 nm, more preferably 10 to 100 nm, still more preferably 50±40 nm, 100±40 nm, or 150±40 nm.

[0052] In other preferred embodiments, the z-average particle size of the nanosized Encorafenib according to the invention, preferably of the crystalline nanosized Encorafenib according to the invention, is within the range of from 150 to 550 nm, preferably 200 to 500 nm, more preferably 300±100 nm, or 400±100 nm.

[0053] In further preferred embodiments, the z-average particle size of the nanosized Encorafenib according to the invention, preferably of the crystalline nanosized Encorafenib according to the invention, is within the range of or from 500 to 900 nm, preferably 600±100 nm, 700±100 nm, or 800±100 nm.

[0054] The z-average particle size and the Dv90 value can be tuned as desired.

[0055] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a D90 value determined by scanning electron microscope (SEM) image analysis (i.e. a Dn90 value) of at most 950 nm, more preferably at most 900 nm, still more preferably at most 850 nm, yet more preferably at most 800 nm, even more preferably at most 750 nm, most preferably at most 700 nm, and in particular at most 650 nm.

[0056] Preferably, the mean diameter and the D90 value (i.e., Dn90 value) are determined in accordance with the method described by Sh. Zhang and Ch. Wang, Methods Protoc. 2023, 6, 63. https: / / doi.org / 10.3390 / mps6040063. Preferably, image analysis is performed by means of a software for particle analytics, ImageJ (version 1.46r, National Institute of Health, Bethesda, MD, USA), calibrating in advance each particular micrograph and using a thresholding approach to separate particlesfrom background. The output result is a number of nanoparticles and their individual areas. The mean diameter and the D90 value of the PSD are calculated.

[0057] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a Dn90 value determined by scanning electron microscope (SEM) image analysis of at most 600 nm, more preferably at most 550 nm, still more preferably at most 500 nm, yet more preferably at most 450 nm, even more preferably at most 400 nm, most preferably at most 380 nm, and in particular at most 360 nm.

[0058] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a Dn90 value determined by scanning electron microscope (SEM) image analysis of at least 60 nm, more preferably at least 80 nm, still more preferably at least 100 nm, yet more preferably at least 120 nm, even more preferably at least 140 nm, most preferably at least 160 nm, and in particular at least 180 nm.

[0059] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a Dn90 value determined by scanning electron microscope (SEM) image analysis within the range of 270±90 nm, more preferably 270±80 nm, still more preferably 270±70 nm, yet more preferably 270±60 nm, even more preferably 270±50 nm, most preferably 270±40 nm, and in particular 270±30 nm.

[0060] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a Dn50 value determined by scanning electron microscope (SEM) image analysis of at most 380 nm, more preferably at most 360 nm, still more preferably at most 340 nm, yet more preferably at most 320 nm, even more preferably at most 300 nm, most preferably at most 280 nm, and in particular at most 260 nm.

[0061] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a Dn50 value determined by scanning electron microscope (SEM) image analysis of at least 50 nm, more preferably at least 60 nm, still more preferably at least 70 nm, yet more preferably at least 80 nm, even more preferably at least 90 nm, most preferably at least 100 nm, and in particular at least 110 nm.

[0062] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a Dn50 value determined by scanning electron microscope (SEM) image analysis within the range of 185±90 nm, more preferably 185±80 nm, still more preferably 185±70 nm, yet more preferably 185±60 nm, even more preferably 185±50 nm, most preferably 185±40 nm, and in particular 185±30 nm.

[0063] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a DnlO value determined by scanning electron microscope (SEM) image analysis of at most 300 nm, more preferablyat most 280 nm, still more preferably at most 260 nm, yet more preferably at most 240 nm, even more preferably at most 220 nm, most preferably at most 200 nm, and in particular at most 180 nm.

[0064] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a DnlO value determined by scanning electron microscope (SEM) image analysis of at least 45 nm, more preferably at least 50 nm, still more preferably at least 55 nm, yet more preferably at least 60 nm, even more preferably at least 65 nm, most preferably at least 70 nm, and in particular at least 75 nm.

[0065] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a particle size distribution (PSD) with a DnlO value determined by scanning electron microscope (SEM) image analysis within the range of 145±90 nm, more preferably 145±80 nm, still more preferably 145±70 nm, yet more preferably 145±60 nm, even more preferably 145±50 nm, most preferably 145±40 nm, and in particular 145±30 nm.

[0066] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a span determined by scanning electron microscope (SEM) image analysis (i.e. a value for (Dn90-Dnl0) / Dn50) of at most 1.65, more preferably at most 1.60, still more preferably at most 1.55, yet more preferably at most 1.50, even more preferably at most 1.45, most preferably at most 1.40, and in particular at most 1.35.

[0067] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a span determined by scanning electron microscope (SEM) image analysis (i.e. a value for (Dn90-Dnl0) / Dn50) of at least 0.40, more preferably at least 0.45, still more preferably at least 0.50, yet more preferably at least 0.55, even more preferably at least 0.60, most preferably at least 0.65, and in particular at least 0.70.

[0068] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a span determined by seaming electron microscope (SEM) image analysis (i.e. a value for (Dn90-Dnl0) / Dn50) within the range of 1 ,00±0.35, more preferably 1.00±0.30, still more preferably 1.00±0.25, yet more preferably 1.00±0.20, even more preferably 1.00±0.15, most preferably 1.00±0.10, and in particular 1.00±0.05.

[0069] Preferably, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a mean particle size determined by scanning electron microscope (SEM) image analysis within the range of from 10 to 1000 nm.

[0070] The mean particle size (arithmetic mean) determined by scanning electron microscope (SEM) image analysis is number based. Thus, unless expressly stated otherwise, all mean particle sizes determined by scanning electron microscope (SEM) according to the invention are number based. Preferably, the image analysis is performed in accordance with Ph. Eur. 2.9.48 "Particle size and shape determination by image analysis" .

[0071] In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a mean particle size determined by scanning electron microscope (SEM) image analysis of at most 950 nm, more preferably at most 900 nm, still more preferably at most 850 nm, yet more preferably at most 800 nm, even more preferably at most 750 nm, most preferably at most 700 nm, and in particular at most 650 nm. In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a mean particle size determined by scanning electron microscope (SEM) image analysis of at most 600 nm, more preferably at most 550 nm, still more preferably at most 500 nm, yet more preferably at most 450 nm, even more preferably at most 400 nm, most preferably at most 350 nm, and in particular at most 300 nm. In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a mean particle size determined by scanning electron microscope (SEM) image analysis of at most 250 nm, more preferably at most 200 nm, still more preferably at most 150 nm, yet more preferably at most 100 nm, even more preferably at most 50 nm.

[0072] In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a mean particle size determined by scanning electron microscope (SEM) image analysis of at least 50 nm, more preferably at least 100 nm, still more preferably at least 150 nm, yet more preferably at least 200 nm, even more preferably at least 250 nm, most preferably at least 300 nm, and in particular at least 350 nm. In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a mean particle size determined by scanning electron microscope (SEM) image analysis of at least 400 nm, more preferably at least 450 nm, still more preferably at least 500 nm, yet more preferably at least 550 nm, even more preferably at least 600 nm, most preferably at least 650 nm, and in particular at least 700 nm. In preferred embodiments, the nanosized Encorafenib according to the invention, preferably the crystalline nanosized Encorafenib according to the invention, has a mean particle size determined by scanning electron microscope (SEM) image analysis of at least 750 nm, more preferably at least 800 nm, still more preferably at least 850 nm, yet more preferably at least 900 nm, even more preferably at least 950 nm.

[0073] In preferred embodiments, the mean particle size determined by scanning electron microscope (SEM) image analysis of the nanosized Encorafenib according to the invention, preferably of the crystalline nanosized Encorafenib according to the invention, is within the range of from 10 to 200 nm, preferably 10 to 150 nm, more preferably 10 to 100 nm, still more preferably 50±40 nm, 100±40 nm, or 150±40 nm.

[0074] In other preferred embodiments, the mean particle size determined by scanning electron microscope (SEM) image analysis of the nanosized Encorafenib according to the invention, preferably of the crystalline nanosized Encorafenib according to the invention, is within the range of from 150 to 550 nm, preferably 200 to 500 nm, more preferably 300±100 nm, or 400±100 nm.

[0075] In further preferred embodiments, the mean particle size determined by scanning electron microscope (SEM) image analysis of the nanosized Encorafenib according to the invention, preferably of the crystalline nanosized Encorafenib according to the invention, is within the range of or from 500 to 900 nm, preferably 600±100 nm, 700±100 nm, or 800±100 nm.

[0076] The mean particle size determined by scanning electron microscope (SEM) image analysis and the D90 value of the PSD can be tuned as desired.

[0077] Preferably, Encorafenib is not conjugated to an active targeting agent, preferably not conjugated at all.

[0078] The pharmaceutical composition according to the invention comprises or essentially consists of nanoparticles of crystalline Encorafenib and one or more polymers.

[0079] In preferred embodiments, the one or more polymers comprise or essentially consist of a homopolymer.

[0080] Preferably, the pharmaceutical composition comprises crystalline nanosized Encorafenib and homopolymer, wherein the weight ratio Encorafenib : homopolymer is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3 : 1 to 1:3, most preferably 3 : 1 to 1: 1, such as 2 : 1 or 1 : 1.

[0081] In preferred embodiments, the one or more polymers comprise or essentially consist of a random copolymer.

[0082] Preferably, the pharmaceutical composition comprises crystalline nanosized Encorafenib and random copolymer, wherein the weight ratio Encorafenib : random copolymer is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0083] In preferred embodiments, the one or more polymers comprise or essentially consist of an alternating copolymer.

[0084] Preferably, the pharmaceutical composition comprises crystalline nanosized Encorafenib and alternating copolymer, wherein the weight ratio Encorafenib : alternating copolymer is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4 : 1 to 1:4, even more preferably 3 : 1 to 1:3, most preferably 3 : 1 to 1: 1, such as 2 : 1 or 1 : 1.

[0085] In preferred embodiments, the one or more polymers comprise or essentially consist of a block copolymer.

[0086] Preferably, the pharmaceutical composition comprises crystalline nanosized Encorafenib and block copolymer, wherein the weight ratio Encorafenib : block copolymer is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3 : 1 to 1:3, most preferably 3 : 1 to 1: 1, such as 2 : 1 or 1 : 1.

[0087] In preferred embodiments, the one or more polymers comprise or essentially consist of a graft copolymer.

[0088] Preferably, the pharmaceutical composition comprises crystalline nanosized Encorafenib and graft copolymer, wherein the weight ratio Encorafenib : graft copolymer is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0089] Besides the crystalline nanosized Encorafenib, the pharmaceutical composition according to the invention comprises or essentially consists of one or more polymers.

[0090] Preferably, the one or more polymers is / are selected from(I) cellulose ethers; preferably hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC);(II) cellulose esters; preferably hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP);(III) (co-)povidones; preferably polyvinylpyrrolidone, vinyl acetate) (PVP / VA). polyvinylpyrrolidone (PVP);(IV) polyoxyalkylenes and polyoxyalkylene graft copolymers; preferably poloxamers (PEO-PPO-PEO), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co- PVCL));(V) acrylates; preferably poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) (BA / DMAEMA / MMA), poly(ethyl acrylate, methyl methacrylate) (EA / MMA), poly(methacrylic acid, methyl methacrylate) (MAA / MMA), poly(methacrylic acid, ethyl acrylate) (MAA / EA), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (EA / MMA / TMAEMA); and any combinations thereof.

[0091] Preferably, the one or more polymers are solids at 23°C in the neat state and have a HLB value (hydrophilic-lipophilic balance) of at least 6, preferably at least 8, more preferably at least 10, still more preferably at least 12, yet more preferably at least 14, even more preferably at least 16, most preferably at least 18, and in particular at lest 20.

[0092] Preferred polymers according to the invention that are solids at 23 °C in the neat state and have a HLB value of at least 10 are compiled in the below table:

[0093] In preferred embodiments, the pharmaceutical composition according to the invention additionally comprises one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS. Preferably, the surfactant is non-polymeric.

[0094] For the purpose of the specification, poloxamers (PEO-PPO-PEO) and polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)) are preferably not regarded as "surfactants" according to the invention, whereas tocofersolan (TPGS) is to be regarded as a "surfactant" according to the invention.

[0095] In other preferred embodiments, the pharmaceutical composition according to the invention does not additionally comprise any non-polymeric surfactant.

[0096] In preferred embodiments, the one or more polymers comprise or essentially consist of HPC. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPC.

[0097] Various grades of hydroxypropyl cellulose (HPC) are commercially available, e.g. under the tradenames Klucel®.

[0098] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPC, wherein the weight ratio Encorafenib : HPC is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0099] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, HPC, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0100] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPC, but does not additionally contain any surfactant.

[0101] In preferred embodiments, the one or more polymers comprise or essentially consist of HPMC. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMC. Preferably, the HPMC has a substitution type according to Ph. Eur. selected from 1828, 2208, 2906 and 2910.

[0102] Preferred substitution types of HPMC (hypromellose) are in accordance with Ph. Eur. and selected from HPMC 1828, HPMC 2208 (K-type), HPMC 2906 (F-type) and HPMC 2910 (E-type).

[0103] HPMC is a cellulose substituted with methoxy groups and hydroxypropoxy groups:

[0104] Preferably, the HPMC has a viscosity of at most 5040 mPa s, more preferably at most 2100 mPa s, still more preferably at most 1050 mPa s, yet more at most 300 mPa s, even more preferably at most 120 mPa s, and most preferably within the range of 80-120 mPa s (e.g. Benecel® K100LV PH CR, Ashland). Preferably, the viscosity is determined in accordance with Ph. Eur.

[0105] Various grades of hydroxypropyl methyl cellulose (HPMC, hypromellose) are commercially available, e.g. under the tradenames Benecel®, Metolose® and Tylopur®.

[0106] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMC, wherein the weight ratio Encorafenib : HPMC is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1 : 1, such as 2: 1 or 1: 1.

[0107] In preferred embodiments, the weight ratio of Encorafenib : HPMC is within the range of (2.5±1.6): 1.0, preferably (2.5±1.4): 1.0, more preferably (2.5±1.2): 1.0, still more preferably (2.5± 1.0): 1.0, yet more preferably (2.5±0.8): 1.0, even more preferably (2.5±0.6): 1.0, most preferably (2.5±0.4): 1.0, and in particular (2.5±0.2): 1.0.

[0108] In other preferred embodiments, the weight ratio of Encorafenib : HPMC is within the range of (5.0±3.2): 1.0, preferably (5.0±2.8): 1.0, more preferably (5.0±2.4): 1.0, still more preferably (5.0±2.0): 1.0, yet more preferably (5.0±1.6): 1.0, even more preferably (5.0±1.2): 1.0, most preferably (5.0±0.8): 1.0, and in particular (5.0±0.4): 1.0.

[0109] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, HPMC, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0110] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMC, but does not additionally contain any surfactant.

[0111] In preferred embodiments, the one or more polymers comprise or essentially consist of HPM- CAS. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMCAS.

[0112] Various grades of hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and commercially available, e.g. under the tradename AquaSolve®.

[0113] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMCAS, wherein the weight ratio Encorafenib : HPMCAS is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0114] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, HPMCAS, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0115] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMCAS, but does not additionally contain any surfactant.

[0116] In preferred embodiments, the one or more polymers comprise or essentially consist of HPMCP. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMCP.

[0117] Various grades of hydroxypropyl methyl cellulose phthalate (HPMCP) are commercially available e.g. under the tradename AQOAT®.

[0118] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMCP, wherein the weight ratio Encorafenib : HPMCP is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0119] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, HPMCP, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the groupconsisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0120] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and HPMCP, but does not additionally contain any surfactant.

[0121] In preferred embodiments, the one or more polymers comprise or essentially consist of PVP / VA. In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PVP / VA. Preferably, the PVP / VA is a copolymer of 1 -vinyl-2 -pyrrolidon (PVP) and vinyl acetate (VA) in a weight ratio of about 3:2.

[0122] Various grades of poly( vinylpyrrolidone, vinyl acetate) (PVP / VA, copovidone) are commercially available, e.g. under the tradenames Kollidon® VA and Vivapharm®.

[0123] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PVP / VA, wherein the weight ratio Encorafenib : PVP / VA is from 10: l to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0124] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, PVP / VA, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0125] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PVP / VA, but does not additionally contain any surfactant.

[0126] In preferred embodiments, the one or more polymers comprise or essentially consist of PVP. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PVP.

[0127] Various grades of polyvinylpyrrolidone (PVP, povidone) are commercially available e.g. under the tradenames Kollidon® and Plasdone®.

[0128] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PVP, wherein the weight ratio Encorafenib : PVP is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yetmore preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0129] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, PVP, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0130] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PVP, but does not additionally contain any surfactant.

[0131] In preferred embodiments, the one or more polymers comprise or essentially consist of PEO- PPO-PEO. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PEO-PPO-PEO.

[0132] Various grades ofpoloxamers (PEO-PPO-PEO) are commercially available e.g. under the trade- name Pluronic®.

[0133] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PEO-PPO-PEO, wherein the weight ratio Encorafenib : PEO-PPO-PEO is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0134] In preferred embodiments, the weight ratio of Encorafenib : PEO-PPO-PEO, preferably polox- amer 407, is within the range of (1.0±1.6): 1.0, preferably (1.0±1.4): 1.0, more preferably (1.0±1.2): 1.0, still more preferably (1.0±1.0): 1.0, yet more preferably (1.0±0.8): 1.0, even more preferably (1.0±0.6): 1.0, most preferably (1.0±0.4): 1.0, and in particular (1.0±0.2): 1.0.

[0135] In other preferred embodiments, the weight ratio of Encorafenib : PEO-PPO-PEO, preferably poloxamer 188, is within the range of 1.0:(2.0±1.6), preferably 1.0:(2.0±1.4), more preferably 1.0:(2.0±1.2), still more preferably 1.0:(2.0±1.0), yet more preferably 1.0:(2.0±0.8), even more preferably 1.0:(2.0±0.6), most preferably 1.0:(2.0±0.4), and in particular 1.0:(2.0±0.2).

[0136] In further preferred embodiments, the weight ratio of Encorafenib : PEO-PPO-PEO, preferably poloxamer 188, is within the range of (1.0±1.6): 1.0, preferably (1.0±1.4): 1.0, more preferably (1.0±l .2): 1.0, still more preferably (1 ,0±l .0): 1.0, yet more preferably (1 ,0±0.8): 1.0, even more preferably (1.0±0.6): 1.0, most preferably (1.0±0.4): 1.0, and in particular (1.0±0.2): 1.0.

[0137] In still further preferred embodiments, the weight ratio of Encorafenib : PEO-PPO-PEO, preferably poloxamer 188, is within the range of (5.0±3.2): 1.0, preferably (5.0±2.8): 1.0, more preferably(5.0±2.4): 1.0, still more preferably (5.0±2.0): 1.0, yet more preferably (5.0±1.6):1.0, even more preferably (5.0±1.2): 1.0, most preferably (5.0±0.8): 1.0, and in particular (5.0±0.4): 1.0.

[0138] Preferably, the PEO-PPO-PEO is selected from poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407 (preferably according to Ph. Eur.), more preferably selected from poloxamer 188 and poloxamer 407, still more preferably poloxamer 188.

[0139] Poloxamers are triblock copolymers according to general formula (PEO)a-(PPO)b-(PEO)a:

[0140] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, PEO-PPO-PEO, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0141] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PEO-PPO-PEO, but does not additionally contain any surfactant.

[0142] In preferred embodiments, the one or more polymers comprise or essentially consist of PEG-g- (PVAc-co-PVCL). Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PEG-g-(PVAc-co-PVCL).

[0143] Various grades of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)) are commercially available, e.g. under the tradename Soluplus®.

[0144] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PEG-g-(PVAc-co-PVCL), wherein the weight ratio Encorafenib : PEG-g-(PVAc-co-PVCL) is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0145] In other preferred embodiments, the weight ratio of Encorafenib : PEG-g-(PVAc-co-PVCL) is within the range of (5.0±3.2): 1.0, preferably (5.0±2.8): 1.0, more preferably (5.0±2.4): 1.0, still more preferably (5.0±2.0): 1.0, yet more preferably (5.0±1.6): 1.0, even more preferably (5.0±1.2): 1.0, most preferably (5.0±0.8): 1.0, and in particular (5.0±0.4): 1.0.

[0146] Preferably, the PEG-g-(PVAc-co-PVCL) is according to CAS no. 402932-23-4. Preferably, the PEG-g-(PVAc-co-PVCL) is according to general formula (I)

[0147] Preferred is PEG 6000 / vinyl caprolactam / vinyl acetate 13 / 57 / 30. Preferably, the average molecular weight determined by gel permeation chromatography is nominally in the range of from 90 000 to 140 000 g / mol, more preferably approximately 118,000 g / mol.

[0148] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, PEG-g-(PVAc-co-PVCL), and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0149] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and PEG-g-(PVAc-co-PVCL), but does not additionally contain any surfactant.

[0150] In preferred embodiments, the one or more polymers comprise or essentially consist of BA / DMAEMA / MMA. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and BA / DMAEMA / MMA.

[0151] Various grades of poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) (BA / DMAEMA / MMA) are commercially available, e.g. under the tradenames Eudragit® E 100, Eudragit® E 12.5, and Eudragit® E PO.

[0152] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and BA / DMAEMA / MMA, wherein the weight ratio Encorafenib : BA / DMAEMA / MMA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0153] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, BA / DMAEMA / MMA, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0154] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and BA / DMAEMA / MMA, but does not additionally contain any surfactant.

[0155] In preferred embodiments, the one or more polymers comprise or essentially consist of EA / MMA. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and EA / MMA.

[0156] Various grades of poly(ethyl acrylate, methyl methacrylate) (EA / MMA) are commercially available, e.g. under the tradenames Eudragit® NE 30 D, Eudragit® NE 40 D, and Eudragit® NM 30 D.

[0157] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and EA / MMA, wherein the weight ratio Encorafenib : EA / MMA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0158] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, EA / MMA, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0159] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and EA / MMA, but does not additionally contain any surfactant.

[0160] In preferred embodiments, the one or more polymers comprise or essentially consist of MAA / MMA. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and MAA / MMA.

[0161] Various grades of poly(methacrylic acid, methyl methacrylate) (MAA / MMA) are commercially available, e.g. under the tradenames Eudragit® L 12.5 and Eudragit® L 12.5 P.

[0162] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and MAA / MMA, wherein the weight ratio Encorafenib :MAA / MMA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0163] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, MAA / MMA, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0164] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and MAA / MMA, but does not additionally contain any surfactant

[0165] In preferred embodiments, the one or more polymers comprise or essentially consist of MAA / EA. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and MAA / EA.

[0166] Various grades of poly(methacrylic acid, ethyl acrylate) (MAA / EA) are commercially available, e.g. under the tradename Eudragit® L 100-55.

[0167] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and MAA / EA, wherein the weight ratio Encorafenib : MAA / EA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0168] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, MAA / EA, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0169] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and MAA / ES, but does not additionally contain any surfactant

[0170] In preferred embodiments, the one or more polymers comprise or essentially consist of EA / MMA / TMAEMA. Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and EA / MMA / TMAEMA.

[0171] Various grades of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (EA / MMA / TMAEMA) are commercially available, e.g. under the tradenames Eudragit® RL 100, Eudragit® RL PO, Eudragit® RL 30 D, Eudragit® RL 12.5, Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30 D, or Eudragit® RS 12.5.

[0172] Preferably, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and EA / MMA / TMAEMA, wherein the weight ratio En- corafenib : EA / MMA / TMAEMA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

[0173] In preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib, EA / MMA / TMAEMA, and one or more surfactants. The surfactant may be cationic, anionic or nonionic. The surfactant is preferably selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and combinations thereof; more preferably SLS.

[0174] In other preferred embodiments, the pharmaceutical composition according to the invention comprises or essentially consists of crystalline nanosized Encorafenib and EA / MMA / TMAEMA, but does not additionally contain any surfactant.

[0175] Preferably, the pharmaceutical composition according to the invention has a weight content of Encorafenib of at least 5.0 wt.-%, preferably at least 10 wt.-%, more preferably at least 15 wt.-%, still more preferably at least 20 wt.-%, yet more preferably at least 25 wt.-%, even more preferably at least 30 wt.-%, most preferably at least 35 wt.-%, and in particular preferably at least 40 wt.-%, relative to the total dry solids content of the pharmaceutical composition.

[0176] Preferably, the pharmaceutical composition according to the invention has a weight content of Encorafenib of at least 45 wt.-%, preferably at least 50 wt.-%, more preferably at least 55 wt.-%, still more preferably at least 60 wt.-%, yet more preferably at least 65 wt.-%, even more preferably at least 70 wt.-%, most preferably at least 75 wt.-%, and in particular preferably at least 80 wt.-%, relative to the total dry solids content of the pharmaceutical composition.

[0177] Preferably, the pharmaceutical composition according to the invention has a weight content of Encorafenib of at least 5.0 wt.-%, preferably at least 10 wt.-%, more preferably at least 15 wt.-%, still more preferably at least 20 wt.-%, yet more preferably at least 25 wt.-%, even more preferably at least 30 wt.-%, most preferably at least 35 wt.-%, and in particular preferably at least 40 wt.-%, relative to the total dry solids content of the sum of the content of Encorafenib and the content of the one or more polymers that are contained in the pharmaceutical composition.

[0178] Preferably, the pharmaceutical composition according to the invention has a weight content of Encorafenib of at least 45 wt.-%, preferably at least 50 wt.-%, more preferably at least 55 wt.-%, still more preferably at least 60 wt.-%, yet more preferably at least 65 wt.-%, even more preferably at least 70 wt.-%, most preferably at least 75 wt.-%, and in particular preferably at least 80 wt.-%, relative to the total dry solids content of the sum of the content of Encorafenib and the content of the one or more polymers that are contained in the pharmaceutical composition.

[0179] For the purpose of the specification, the "loading degree" is preferably defined as weight of Encorafenib / total dry solids weight multiplied with 100.

[0180] In preferred embodiments, the pharmaceutical composition according to the invention is a suspension, preferably an aqueous suspension.

[0181] In other preferred embodiments, the pharmaceutical composition according to the invention is a powder, preferably a free flowing powder.

[0182] Another aspect of the invention relates to a process for the preparation of a pharmaceutical composition according to the invention as described above.

[0183] Preferably, the process comprises the steps of(a) providing nanoparticles of amorphous Encorafenib (i.e. amorphous nanosized Encorafenib); preferably as a solid;(b) providing an aqueous solution comprising one or more polymers; preferably selected from homopolymers, random copolymers, alternating copolymers, block copolymers and graft copolymers, and any combinations thereof; more preferably selected from cellulose ethers, cellulose esters, (co-)povidones, polyoxyalkylenes, polyoxyalkylene graft copolymers, acrylates, and any combinations thereof; still more preferably selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), poly (vinylpyrrolidone, vinyl acetate) (PVP / VA), polyvinylpyrrolidone (PVP), poloxamers (PEO-PPO-PEO), polyvinyl ca- prolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)), poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) (BA / DMAEMA / MMA), poly(ethyl acrylate, methyl methacrylate) (EA / MMA), poly(meth- acrylic acid, methyl methacrylate) (MAA / MMA), poly(methacrylic acid, ethyl acrylate) (MAA / EA), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (EA / MMA / TMAEMA), and any combinations thereof; yet more preferably hydroxypropyl methyl cellulose acetate succinate (HPMCAS), or hydroxypropyl cellulose (HPC);even more preferably hydroxypropyl methyl cellulose (HPMC), poloxamers (PEO-PPO-PEO), or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g- (PVAc-co-PVCL)); more preferably poloxamers (PEO-PPO-PEO); and optionally one or more surfactants;(c) contacting the nanoparticles of amorphous Encorafenib (i.e. amorphous nanosized Encorafenib) and the aqueous solution to form an admixture thereby obtaining a suspension comprising nanoparticles of crystalline Encorafenib (i.e. crystalline nanosized Encorafenib).

[0184] In preferred embodiments, the amorphous nanosized Encorafenib that is used as the starting material in step (a) of the process for the preparation of the crystalline nanosized Encorafenib according to the invention has a mean particle size determined by scanning electron microscope (SEM) image analysis of at most 200 nm, preferably at most 180 nm, more preferably at most 160 nm, still more preferably at most 140 nm, yet more preferably at most 120 nm, even more preferably at most 100 nm, most preferably at most 90 nm, and in particular at most 80 nm.

[0185] Preferably, the amorphous nanosized Encorafenib that is used as the starting material in step (a) of the process for the preparation of the crystalline nanosized Encorafenib according to the invention has a specific surface area determined according to BET surface area analysis, preferably according to ISO 9277:2022, of at least 50 m2 / g, preferably at least 60 m2 / g, more preferably at least 70 m2 / g, still more preferably at least 80 m2 / g, yet more preferably at least 90 m2 / g, most preferably at least 100 m2 / g, and in particular at least 110 m2 / g.

[0186] In other preferred embodiments, the amorphous nanosized Encorafenib that is used as the starting material in step (a) of the process for the preparation of the crystalline nanosized Encorafenib according to the invention has a mean particle size determined by scanning electron microscope (SEM) image analysis within the range of 300±280 nm, preferably 300±260 nm, more preferably 300±240 nm, still more preferably 300±220 nm, yet more preferably 300±200 nm, most preferably 300±180 nm, and in particular 300±160 nm.

[0187] Preferably, the amorphous nanosized Encorafenib that is used as the starting material in step (a) of the process for the preparation of the crystalline nanosized Encorafenib according to the invention has a specific surface area determined according to BET surface area analysis, preferably according to ISO 9277:2022, within the range of 40±38 m2 / g, preferably 40±35 m2 / g, more preferably 40±32 m2 / g, still more preferably 40±29 m2 / g, yet more preferably 40±26 m2 / g, most preferably 40±23 m2 / g, and in particular 40±20 m2 / g.

[0188] In further preferred embodiments, the amorphous nanosized Encorafenib that is used as the starting material in step (a) of the process for the preparation of the crystalline nanosized Encorafenibaccording to the invention has a mean particle size determined by scanning electron microscope (SEM) image analysis of at least 200 nm, preferably at least 250 nm, more preferably at least 300 nm, still more preferably at least 350 nm, yet more preferably at least 400 nm, even more preferably at least 450 nm, most preferably at least 500 nm, and in particular at least 550 nm.

[0189] Preferably, the amorphous nanosized Encorafenib that is used as the starting material in step (a) of the process for the preparation of the crystalline nanosized Encorafenib according to the invention has a specific surface area determined according to BET surface area analysis, preferably according to ISO 9277:2022, of at most 20 m2 / g, preferably at most 17.5 m2 / g, more preferably at most 15 m2 / g, still more preferably at most 12.5 m2 / g, yet more preferably at most 10 m2 / g, most preferably at most 7.5 m2 / g, and in particular at most 5.0 m2 / g.

[0190] Preferably, the mean particle size determined by scanning electron microscope (SEM) image analysis of the nanosized Encorafenib does not increase significantly upon crystallization. Preferably, compared to the mean particle size determined by scanning electron microscope (SEM) image analysis of the amorphous nanosized Encorafenib provided in step (a), the increase of the mean particle size determined by scanning electron microscope (SEM) image analysis of the crystalline nanosized Encorafenib obtained in step (c) is at most 5 -fold, more preferably at most 4-fold, still more preferably at most 3-fold, yet more preferably at most 2-fold, even more preferably at most 1.5-fold, most preferably at most 1.3-fold, and in particular at most 1.2-fold.

[0191] Preferably, the content of nanoparticles of amorphous Encorafenib in the admixture is higher than the solubility of the nanoparticles of amorphous Encorafenib (i.e. amorphous nanosized Encorafenib) in the aqueous solution. To form a suspension, the content of the amorphous nanosized Encorafenib in the admixture should be higher than its solubility in the aqueous solution comprising the one or more polymers and optionally the one or more surfactants. Preferably, content of the amorphous nanosized Encorafenib in the admixture is at least 10 times higher, more preferably at least 50 times higher, still more preferably at least 100 times higher, yet more preferably at least 500 times higher than its solubility in the aqueous solution comprising the one or more polymers and optionally the one or more surfactants.

[0192] Accordingly, the amount of the amorphous Encorafenib needed as starting material is dependent on its solubility in the aqueous solution comprising the one or more polymers and optionally the one or more surfactants. The solubility can be measured by any method known in the art.

[0193] Preferably, the amorphous nanosized Encorafenib provided in step (a) is obtained from solution of Encorafenib in supercritical CO2 by means of CESS™ technology, e.g. in analogy to Example 1 of US 10,098,842.

[0194] Preferably, water is the only solvent of the aqueous solution provided in step (b).

[0195] Too high polymer content may lead to slow crystal formation. The optimal polymer content is dependent on the one or more polymers.

[0196] When the one or more polymers comprise or essentially consist of PVP / VA. the content of PVP / VA in the aqueous solution is preferably within the range of from 0.2 to 50 wt.-%, more preferably 2.0 to 45wt.-%, still more preferably 10 to 45 wt.-%.

[0197] When the one or more polymers comprise or essentially consist of HPMC, the content of HPMC in the aqueous solution is preferably within the range of from 0.2 to 5 wt.-%.

[0198] In preferred embodiments, the aqueous solution provided in step (b) comprises one or more surfactants. Preferred surfactants include but are not limited to sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), tocofersolan (TPGS), and any combinations thereof. A preferred surfactant is SLS.

[0199] The surfactant enhances the wetting efficiency.

[0200] The overall content of the one or more surfactants in the aqueous solution is preferably within the range of from 0.0025 to 1.5 wt.-%.

[0201] In other preferred embodiments, the aqueous solution provided in step (b) does not comprise any surfactant.

[0202] Preferably, the contacting in step (c) is performed at a temperature within the range of from 15 to 40°C, more preferably from 20 to 40°C, such as at 30°C.

[0203] Preferably, the contacting in step (c) comprises mixing the suspension. The contacting, preferably by mixing, is performed preferably at least 10 h, more preferably 16 h, still more preferably at least 24 h. Relatively long mixing time is preferred to achieve complete wetting and good dispersion. The mixing can be done e.g. by shaking, stirring, or using a spatula.

[0204] The mixing and wetting can be facilitated by ultrasonication. Thus, the contacting in step (c) preferably comprises subjecting the suspension to ultrasound. However, high-intensity ultrasound is typically not needed.

[0205] If the mixing is omitted, the contacting in step (c) is performed preferably for at least 24 h.

[0206] The weight ratio Encorafenib : polymer is preferably within the range of from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1 : 1, such as 2: 1 or 1: 1, wherein the amount of Encorafenib is calculated as mg / mL of the suspension, and wherein the amount of the one or more polymers is calculated as wt.-% of the suspension. For example, 25 mg / mL of amorphous nanosized Encorafenib with a weight ratio of 1 : 1 API : one or more polymers produces desired crystalline nanosized Encorafenib in 24 h at 20°C.

[0207] In preferred embodiments, the process according to the invention comprises the additional step of(d) drying the suspension obtained in step (c) to provide a solid pharmaceutical composition comprising the crystalline nanosized Encorafenib, the one or more polymers, and optionally the one or more surfactants.

[0208] Drying can be achieved by using methods known in the art. Exemplary drying methods include heating, evaporating, vacuum drying, using a fluidized bed dryer, and freeze drying. Preferably, drying involves evaporation.

[0209] In preferred embodiments, the process according to the invention comprises the additional step of(e) crushing or grinding the solid pharmaceutical composition provided in step (d) to provide a powder.

[0210] Crushing or grinding of the solid pharmaceutical composition can be achieved by using methods known in the art. For example, crushing or grinding can be achieved by means of a mortar. The thus crushed or grinded solid pharmaceutical composition is preferably a powder ready for tableting. Preferably, the crushing or grinding has no significant effect on the particle size of the crystalline nanosized Encorafenib.

[0211] In preferred embodiments, the process according to the invention comprises the additional step of(f) removing the one or more polymers from the suspension obtained in step (c).

[0212] When the process according to the invention comprises optional step (f), it preferably does not comprise any of optional steps (d) and (e).

[0213] Removing the one or more polymers from the suspension can be achieved by methods known in the art e.g., by filtering with hydrophilic filter, or by centrifuging and subsequently discarding the supernatant.

[0214] Preferably, the thus obtained material is washed, e.g., with water.

[0215] The procedure of filtering or of centrifuging / discarding can be repeated as many times as needed. It is contemplated that the one or more polymers are only partially removed. It is further contemplated that the optional one or more surfactants are partially or completely removed.

[0216] Another aspect of the invention relates to a pharmaceutical dosage form comprising or essentially consisting of an effective amount of the pharmaceutical composition according to the invention as described above, and preferably at least one additional physiologically acceptable excipient.

[0217] The one or more polymers and the optional one or more surfactants described above may already be considered as physiologically acceptable excipients, whereas according to the invention they(additionally) serve the preferred purpose of promoting the conversion of the amorphous nanoparticles into crystalline particles. The conventional utility of these polymers as physiologically acceptable excipients is known to the skilled person. For example, hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC) can be used e.g. as binder, film coating agent and controlled release matrix. Hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), and various acrylates can be used e.g. for providing enteric release. Polyvinylpyrrolidone, vinyl acetate) (PVP / VA) and polyvinylpyrrolidone (PVP) can be used e.g. as binder. Polox- amers (PEO-PPO-PEO) can be used e.g. as non-ionic polymeric surfactants. Polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)) can be used e.g. as micellar solubilizer or matrix forming polymer.

[0218] Preferably, the pharmaceutical dosage form is for oral administration, i.e. an oral pharmaceutical dosage form.

[0219] In preferred embodiments, the pharmaceutical dosage form is a tablet, which may optionally be film coated.

[0220] In other preferred embodiments, the pharmaceutical dosage form is a capsule, e.g. a hard gelatin capsule.

[0221] Preferably, the pharmaceutical dosage form has a total weight of at most 2.0 g, preferably at most 1.8 g, still more preferably at most 1.6 g, yet more preferably at most 1.4 g, even more preferably at most 1.2 g, most preferably at most 1.0 g, and in particular at most 0.8 g.

[0222] Preferably, the pharmaceutical dosage form contains Encorafenib at a dose of at least 75 mg, preferably at least 150 mg, still more preferably at least 225 mg, yet more preferably at least 300 mg, even more preferably at least 375 mg, and most preferably at least 450 mg.

[0223] Preferably, the weight content of the pharmaceutical composition is at least 50 wt.-%, more preferably at least 60 wt.-%, still more preferably at least 70 wt.-%, yet more preferably at least 75 wt.- %, even more preferably at least 80 wt.-%, most preferably at least 85 wt.-%, and in particular at least 90 wt.-%, relative to the total weight of the pharmaceutical dosage form.

[0224] Preferably, the weight content of the pharmaceutical composition is at most 90 wt.-%, more preferably at most 85 wt.-%, still more preferably at most 80 wt.-%, yet more preferably at most 75 wt.- %, even more preferably at most 70 wt.-%, most preferably at most 65 wt.-%, and in particular at most 60 wt.-%, relative to the total weight of the pharmaceutical dosage form.

[0225] Preferably, the total weight content of Encorafenib and the one or more polymers of the pharmaceutical composition according to the invention is at least 50 wt.-%, more preferably at least 60 wt.- %, still more preferably at least 70 wt.-%, yet more preferably at least 75 wt.-%, even more preferably at least 80 wt.-%, most preferably at least 85 wt.-%, and in particular at least 90 wt.-%, relative to the total weight of the pharmaceutical dosage form.

[0226] Preferably, the total weight content of Encorafenib and the one or more polymers of the pharmaceutical composition according to the invention is at most 90 wt.-%, more preferably at most 85 wt.- %, still more preferably at most 80 wt.-%, yet more preferably at most 75 wt.-%, even more preferably at most 70 wt.-%, most preferably at most 65 wt.-%, and in particular at most 60 wt.-%, relative to the total weight of the pharmaceutical dosage form.

[0227] Besides the above one or more polymers and the optional one or more surfactants, the pharmaceutical dosage form according to the invention preferably comprises at least one additional physiologically acceptable excipient, which is preferably selected from fdlers / diluents, disintegrants, binders, glidants, lubricants, dispersants, film coating agents, preservatives, antioxidants, colorants, and the like, and combinations thereof.

[0228] Preferred fdlers / diluents include but are not limited to celluloses, microcrystalline cellulose, starches, calcium phosphates, sugars (e.g. sucrose, lactose, maltodextrins), sugar alcohols (e.g. mannitol, sorbitol).

[0229] Preferred disintegrants include but are not limited to (i) natural disintegrants, e.g. alginic acid, alginates, bentonite, microcrystalline cellulose, powdered cellulose, pregelatinized starches, guar, galactomannan; (ii) semi-synthetic disintegrants, e.g. carboxymethylcellulose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate (e.g. Type A or B), low-substituted carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose; and (iii) synthetic disintegrants, e.g. cro- spovidone.

[0230] Preferred binders include but are not limited to (i) natural polymers, e.g. Arabic gum, gelatin, sodium alginate, pullulan, starches, pregelatinized starches, tragacanth; (ii) semi-synthetic polymers, e.g. carboxymethylcellulose sodium, dextrin, maltodextrin; (iii) synthetic polymers, e.g. macro- gols, polyvinyl alcohols (PVA), cellulose acetate, cellulose acetate butyrate, chitosan, poly(vinyl acetate), shellack, zein.

[0231] Preferred glidants, lubricants, and / or dispersants include but are not limited to talc, colloidal silicon dioxide, starches, magnesium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol (PEG), calcium stearate.

[0232] Another aspect of the invention relates to a process for the preparation of pharmaceutical dosage form according to the invention as described above. Preferably, the process comprises the steps of(A) granulating, preferably wet-granulating, the pharmaceutical composition according to the invention as described above, i.e. the pharmaceutical composition comprising crystallized nanosized Encorafenib, with one or more pharmaceutical excipients thereby obtaining a granulate;(B) optionally, drying the granulate obtained in step (A) thereby obtaining a dry granulate; and(C) compressing the granulate obtained in step (A) or the dry granulate obtained in step (B).

[0233] The process for the preparation of a pharmaceutical dosage form according to the invention allows manufacture of pharmaceutical dosage forms and dosage forms, preferably oral dosage forms, that contain a comparatively high dose of the Encorafenib.

[0234] Accordingly, tablets and capsules can be produced that can be swallowed, i.e., tablets and capsules which have a total weight of not more than about 1000 mg but still a high drug load. Also, the tablet size can be reduced since less polymer is needed than in the corresponding solid solutions and amorphous solid dispersions.

[0235] Another aspect of the invention relates to the pharmaceutical dosage form according to the invention as described above for use in the treatment of patients with metastatic melanoma in combination with Binimetinib and of patients with metastatic colorectal cancer with a BRAF V600E mutation, optionally in combination with Cetuximab.

[0236] Another aspect of the invention relates to the use of crystalline nanosized Encorafenib for the manufacture of a pharmaceutical dosage form according to the invention as described above for use in the treatment of patients with metastatic melanoma in combination with Binimetinib and of patients with metastatic colorectal cancer with a BRAF V600E mutation, optionally in combination with Cetuximab.

[0237] Another aspect of the invention relates to a method for treating metastatic melanoma in combination with Binimetinib and of patients with metastatic colorectal cancer with a BRAF V600E mutation, optionally in combination with Cetuximab comprising administering the pharmaceutical dosage form according to the invention as described to a subject in need thereof.

[0238] Preferably, the pharmaceutical dosage form according to the invention as described above is administered orally.

[0239] Preferably, the pharmaceutical dosage form according to the invention as described above is administered once daily, i.e. contains a daily dose of Encorafenib.

[0240] The following examples further illustrate the invention but are not to be construed as limiting its scope:

[0241] Materials and methods:

[0242] SEM images were captured using the Zeiss Sigma 300 VP SEM instruments. Samples were dispersed into water and fdtered with 0. 1 pm fdter. Filters were dried, transferred to SEM sample holders and coated with a 5 nm thick layer of platinum.

[0243] XRPD measurements were carried out using the Malvern PANalytical Empyrean X-ray diffractometer equipped with a Cu Ka (1.54 A) source, Multi Core optics and a solid-state PIXcel3D detector. By using Kapton tape the samples were attached onto aluminum or polycrystalline silicon sample holders. Dried slurries were measured without further sample preparation under Kapton tape and suspensions were filtered, dried, and filters were attached with double sided tape. The samples were measured in thereflection geometry in a spinning measurement stage. The measurement range was 5 - 40 (°20). The step size and time per step values were varied depending on the counts per second obtained.

[0244] Dynamic light scattering (DLS) measurements were performed with Malvern Zetasizer. Slurries or dried powder were redispersed into water or 0.1% HPMC (aq.), stirred and measured after the sample was completely dispersed. Backscattering measurement setup was used, and CUMULANTS -algorithm was used to obtain average particle diameter (Z -average) and polydispersity index (PI).

[0245] Example 1 - preparing amorphous nanosized Encorafenib:

[0246] Amorphous nanosized Encorafenib was prepared from solutions of bulk Encorafenib in supercritical CO2 by Controlled Expansion of Supercritical Solutions (CESS™) (US 10,098,842, in analogy to Example 1 thereof).

[0247] The CESS™ process was performed by using an apparatus comprising a pressure vessel, a tube, and a depressurization vessel connected to one another in serial arrangement.

[0248] Figure 1 shows an electron micrograph, Figure 2 an XRPD spectrum of the amorphous nanosized Encorafenib thus prepared.

[0249] Example 2 - suspending amorphous nanosized Encorafenib in polymer solutions:

[0250] Amorphous nanosized Encorafenib was subjected to a polymer solution and crystalline nanosized Encorafenib was obtained.

[0251] Amorphous nanoparticles of Encorafenib obtained in accordance with Example 1 were weighted into small glass vials. Aqueous polymer solutions were added. The mixtures were mixed with magnetic stirrer and ultrasonicated until all Encorafenib was completely surrounded by water (wetted). The stirring of the intermediate was continued for 16-24 h. No (additional) surfactant was present.

[0252] The intermediates were dried to provide a solid pharmaceutical composition comprising the crystalline nanosized Encorafenib and the polymer.

[0253] Compositions and results are summarized in the table here below:[1]80-120 mPa s; API = Encorafenib; LD= Loading degree (API% / total so ids% * 100)

[0254] XRPD samples were prepared as described above. In each case, crystalline Encorafenib was clearly detected by XRPD.

[0255] Figure 3 shows an overlay XRPD spectrum of Examples #3, #8, #9 and #10.

[0256] SEM samples were prepared as described above. Measurements were performed after preparation (TO).

[0257] Example 3 - storage stability:

[0258] Samples of Examples #3, #8, #9 and #10 were stored at 2-8°C for 7 days (T7), 14 days (T14) and 30 days (T30) and again analyzed by XRPD and SEM.

[0259] The results for Example #3 are compiled in the below table:

[0260] Example #3: Poloxamer 407 ratio API : polymer 1: 1 storage condition 2-8°C:LD: loading degree

[0261] Figure 4 shows the XRPD spectra for Example #3 demonstrating storage stability for at least 30 days.

[0262] The results for Example #8 are compiled in the below table:

[0263] Example #8: Poloxamer 188 ratio API : polymer 1:2 storage condition 2-8°CLD: loading degree

[0264] Figure 5 shows the XRPD spectra for Example #8 demonstrating storage stability for at least 30 days.

[0265] The results for Example #9 are compiled in the below table:

[0266] Example #9: Poloxamer 188 ratio API : polymer 1: 1 storage condition 2-8°CLD: loading degree

[0267] Figure 6 shows the XRPD spectra for Example #9 demonstrating storage stability for at least 30 days.

[0268] The results for Example #10 are compiled in the below table:

[0269] Example #10: Poloxamer 188 ratio API : polymer 5: 1 storage condition 2-8°CLD: loading degree

[0270] Figure 7 shows the XRPD spectra for Example #10 demonstrating storage stability for at least 30 days.

[0271] Example 4 - in vitro dissolution:

[0272] In vitro dissolution in simulated gastric fluid (SGF) at a loading of 16 pl / ml was determined.

[0273] Components: Hydrochloric acid (37% HC1), deionized water (di. H2O).

[0274] Concentration: 0.025 M; pH: 1.6.

[0275] 1.026 mb of 37% HC1 were added to 450 mb di. H2O. After mixing the volume was made up to 500 mb. The pH of resulting solution was measured and confirmed (target -1.60).

[0276] Figure 8 shows in vitro dissolution profiles.

[0277] Example 5 - in vivo bioavailability

[0278] Pharmacokinetic properties of the formulations according to Examples #3, #8 and #10 were investigated in vivo in male Sprague Dawley rats and compared to bulk Encorafenib and to commercial product Braftovi®.

[0279] Results are compiled in the below table:

[0280] Figure 9 shows in vivo plasma concentration over time curves following oral administration of 10 mg / kg NF Encorafenib DP intermediate suspensions and 10 mg / kg RLD (50 mg Braftovi® capsule).

Claims

CLAIMS:

1. A pharmaceutical composition comprising(i) crystalline nanosized Encorafenib, and(ii) one or more polymers.

2. The pharmaceutical composition according to claim 1, wherein the crystalline nanosized Encorafenib has a Dn90 value of at most 1000 nm, determined by scanning electron microscope (SEM) image analysis.

3. The pharmaceutical composition according to claim 1 or 2, wherein the crystalline nanosized Encorafenib has a Dn90 value of at most 950 nm, more preferably at most 900 nm, still more preferably at most 850 nm, yet more preferably at most 800 nm, even more preferably at most 750 nm, most preferably at most 700 nm, and in particular at most 650 nm, determined by scanning electron microscope (SEM) image analysis.

4. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a Dn90 value of at most 600 nm, more preferably at most 550 nm, still more preferably at most 500 nm, yet more preferably at most 450 nm, even more preferably at most 400 nm, most preferably at most 380 nm, and in particular at most 360 nm, determined by scanning electron microscope (SEM) image analysis.

5. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a Dn90 value of at least 60 nm, more preferably at least 80 nm, still more preferably at least 100 nm, yet more preferably at least 120 nm, even more preferably at least 140 nm, most preferably at least 160 nm, and in particular at least 180 nm, determined by scanning electron microscope (SEM) image analysis.

6. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a Dn90 value within the range of 270±90 nm, more preferably 270±80 nm, still more preferably 270±70 nm, yet more preferably 270±60 nm, even more preferably 270±50 nm, most preferably 270±40 nm, and in particular 270±30 nm, determined by scanning electron microscope (SEM) image analysis.

7. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a Dn50 value of at most 380 nm, more preferably at most 360 nm, still more preferably at most 340 nm, yet more preferably at most 320 nm, even more preferably atmost 300 nm, most preferably at most 280 nm, and in particular at most 260 nm, determined by scanning electron microscope (SEM) image analysis.

8. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a Dn50 value of at least 50 nm, more preferably at least 60 nm, still more preferably at least 70 nm, yet more preferably at least 80 nm, even more preferably at least 90 nm, most preferably at least 100 nm, and in particular at least 110 nm, determined by scanning electron microscope (SEM) image analysis.

9. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a Dn50 value within the range of 185±90 nm, more preferably 185±80 nm, still more preferably 185±70 nm, yet more preferably 185±60 nm, even more preferably 185±50 nm, most preferably 185±40 nm, and in particular 185±30 nm, determined by scanning electron microscope (SEM) image analysis.

10. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a DnlO value of at most 300 nm, more preferably at most 280 nm, still more preferably at most 260 nm, yet more preferably at most 240 nm, even more preferably at most 220 nm, most preferably at most 200 nm, and in particular at most 180 nm, determined by scanning electron microscope (SEM) image analysis.

11. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a DnlO value of at least 45 nm, more preferably at least 50 nm, still more preferably at least 55 nm, yet more preferably at least 60 nm, even more preferably at least 65 nm, most preferably at least 70 nm, and in particular at least 75 nm, determined by scanning electron microscope (SEM) image analysis.

12. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a DnlO value within the range of 145±90 nm, more preferably 145±80 nm, still more preferably 145±70 nm, yet more preferably 145±60 nm, even more preferably 145±50 nm, most preferably 145±40 nm, and in particular 145±30 nm, determined by scanning electron microscope (SEM) image analysis.

13. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a span value of at most 1.65, more preferably at most 1.60, still more preferably at most 1.55, yet more preferably at most 1.50, even more preferably at most 1.45,most preferably at most 1.40, and in particular at most 1.35, determined by scanning electron microscope (SEM) image analysis.

14. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a span value of at least 0.40, more preferably at least 0.45, still more preferably at least 0.50, yet more preferably at least 0.55, even more preferably at least 0.60, most preferably at least 0.65, and in particular at least 0.70, determined by scanning electron microscope (SEM) image analysis.

15. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib has a span value within the range of 1.00±0.35, more preferably 1.00±0.30, still more preferably 1.00±0.25, yet more preferably 1.00±0.20, even more preferably 1.00±0.15, most preferably 1.00±0.10, and in particular 1.00±0.05, determined by scanning electron microscope (SEM) image analysis.

16. The pharmaceutical composition according to any of the preceding claims, wherein the mean particle size of the crystalline nanosized Encorafenib is within the range of from 10 to 1000 nm, determined by scanning electron microscope (SEM) image analysis.

17. The pharmaceutical composition according to claim 16, wherein the mean particle size is at most 950 nm, more preferably at most 900 nm, still more preferably at most 850 nm, yet more preferably at most 800 nm, even more preferably at most 750 nm, most preferably at most 700 nm, and in particular at most 650 nm.

18. The pharmaceutical composition according to claim 16 or 17, wherein the mean particle size is at most 600 nm, more preferably at most 550 nm, still more preferably at most 500 nm, yet more preferably at most 450 nm, even more preferably at most 400 nm, most preferably at most 350 nm, and in particular at most 300 nm.

19. The pharmaceutical composition according to any of claims 16 to 18, wherein the mean particle size is at most 250 nm, more preferably at most 200 nm, still more preferably at most 150 nm, yet more preferably at most 100 nm, even more preferably at most 50 nm.

20. The pharmaceutical composition according to any of claims 16 to 19, wherein the mean particle size is at least 50 nm, more preferably at least 100 nm, still more preferably at least 150 nm, yet more preferably at least 200 nm, even more preferably at least 250 nm, most preferably at least 300 nm, and in particular at least 350 nm.

21. The pharmaceutical composition according to any of claims 16 to 20, wherein the mean particle size is at least 400 nm, more preferably at least 450 nm, still more preferably at least 500 nm, yet more preferably at least 550 nm, even more preferably at least 600 nm, most preferably at least 650 nm, and in particular at least 700 nm.

22. The pharmaceutical composition according to any of claims 16 to 21, wherein the mean particle size is at least 750 nm, more preferably at least 800 nm, still more preferably at least 850 nm, yet more preferably at least 900 nm, even more preferably at least 950 nm.

23. The pharmaceutical composition according to any of claims 16 to 22, wherein the mean particle size is within the range of from 10 to 200 nm, preferably 10 to 150 nm, more preferably 10 to 100 nm, still more preferably 50±40 nm, 100±40 nm, or 150±40 nm24. The pharmaceutical composition according to any of claims 16 to 23, wherein the mean particle size is within the range of from 150 to 550 nm, preferably 200 to 500 nm, more preferably 300±100 nm, or 400±100 nm.

25. The pharmaceutical composition according to any of claims 16 to 24, wherein the mean particle size is within the range of or from 500 to 900 nm, preferably 600±100 nm, 700±100 nm, or 800±100 nm.

26. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of a homopolymer.

27. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of a homopolymer and wherein the weight ratio Encorafenib : homopolymer is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

28. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of a random copolymer.

29. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of a random copolymer and wherein the weight ratio Encorafenib : random copolymer is from 10: l to 1: 10, preferably 8: 1 to 1:8, more preferably6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

30. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of an alternating copolymer.

31. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of an alternating copolymer and wherein the weight ratio Encorafenib : alternating copolymer is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more pref- erably 6: l to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

32. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of a block copolymer.

33. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of a block copolymer and wherein the weight ratio Encorafenib : block copolymer is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

34. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of a graft copolymer.

35. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of a graft copolymer and wherein the weight ratio Encorafenib : graft copolymer is from 10: l to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

36. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers are independently of one another selected from cellulose ethers, cellulose esters, (co-)povidones, polyoxyalkylenes, polyoxyalkylene graft copolymers, acrylates, and any combinations thereof.

37. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers are independently of one another selected from the group consisting ofhydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinylpyrrolidone, vinyl acetate) (PVP / VA). polyvinylpyrrolidone (PVP), poloxamers (PEO- PPO-PEO), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)), poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) (BA / DMAEMA / MMA), poly(ethyl acrylate, methyl methacrylate) (EA / MMA), poly(methacrylic acid, methyl methacrylate) (MAA / MMA), poly(methacrylic acid, ethyl acrylate) (MAA / EA), poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (EA / MMA / TMAEMA), and any combinations thereof.

38. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers are independently of one another selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), poloxamers (PEO-PPO-PEO), or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)).

39. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPC.

40. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPC and wherein the weight ratio Encorafenib : HPC is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5 : 1 to 1:5, yet more preferably 4 : 1 to 1:4, even more preferably 3 : 1 to 1:3, most preferably 3 : 1 to 1: 1, such as 2: 1 or 1: 1.

41. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPMC.

42. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPMC and wherein the weight ratio Encorafenib : HPMC is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1 : 1.

43. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPMC and wherein the weight ratio Encorafenib : HPMC is within the range of (2.5±1.6): 1.0, preferably (2.5±1.4): 1.0, more preferably(2.5±1.2): 1.0, still more preferably (2.5±1.0): 1.0, yet more preferably (2.5±0.8): 1.0, even more preferably (2.5±0.6): 1.0, most preferably (2.5±0.4): 1.0, and in particular (2.5±0.2): 1.0.

44. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPMC and wherein the weight ratio Encoraf- enib : HPMC is within the range of (5.0±3.2): 1.0, preferably (5.0±2.8): 1.0, more preferably (5.0±2.4): 1.0, still more preferably (5.0±2.0): 1.0, yet more preferably (5.0±1.6): 1.0, even more preferably (5.0± 1.2): 1.0, most preferably (5.0±0.8): 1.0, and in particular (5.0±0.4): 1.0.

45. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPMCAS.

46. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPMCAS and wherein the weight ratio En- corafenib : HPMCAS is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

47. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPMCP.

48. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of HPMCP and wherein the weight ratio Encoraf- enib : HPMCP is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1 : 1.

49. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PVP / VA.

50. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PVP / VA and wherein the weight ratio Encoraf- enib : PVP / VA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1 : 1.

51. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PVP.

52. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PVP and wherein the weight ratio Encorafenib : PVP is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5 : 1 to 1:5, yet more preferably 4 : 1 to 1:4, even more preferably 3 : 1 to 1:3, most preferably 3 : 1 to 1: 1, such as 2: 1 or 1: 1.

53. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEO-PPO-PEO.

54. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEO-PPO-PEO and wherein the weight ratio Encorafenib : PEO-PPO-PEO is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

55. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEO-PPO-PEO, preferably poloxamer 407, and wherein the weight ratio Encorafenib : PEO-PPO-PEO is within the range of (1.0±1.6): 1.0, preferably (1.0±1.4): 1.0, more preferably (1.0±1.2): 1.0, still more preferably (1.0±1.0): 1.0, yet more preferably (1.0±0.8): 1.0, even more preferably (1.0±0.6): 1.0, most preferably (1.0±0.4): 1.0, and in particular ( 1.0±0.2) : 1.0.

56. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEO-PPO-PEO, preferably poloxamer 188, and wherein the weight ratio Encorafenib : PEO-PPO-PEO is within the range of 1.0:(2.0±1.6), preferably 1.0:(2.0±1.4), more preferably 1.0:(2.0±1.2), still more preferably 1.0:(2.0±1.0), yet more preferably 1.0:(2.0±0.8), even more preferably 1.0:(2.0±0.6), most preferably 1.0:(2.0±0.4), and in particular 1.0:(2.0±0.2).

57. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEO-PPO-PEO, preferably poloxamer 188, and wherein the weight ratio Encorafenib : PEO-PPO-PEO is within the range of (1.0±l .6): 1.0, preferably (1.0±1.4): 1.0, more preferably (1.0±1.2): 1.0, still more preferably (1.0±1.0): 1.0, yet morepreferably (1.0±0.8): 1.0, even more preferably (1.0±0.6): 1.0, most preferably (1.0±0.4): 1.0, and in particular ( 1.0±0.2) : 1.0.

58. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEO-PPO-PEO, preferably poloxamer 188, and wherein the weight ratio Encorafenib : PEO-PPO-PEO is within the range of (5.0±3.2): 1.0, preferably (5.0±2.8): 1.0, more preferably (5.0±2.4): 1.0, still more preferably (5.0±2.0): 1.0, yet more preferably (5.0±1.6): 1.0, even more preferably (5.0±1.2): 1.0, most preferably (5.0±0.8): 1.0, and in particular (5.0±0.4): 1.0.

59. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEG-g-(PVAc-co-PVCL).

60. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEG-g-(PVAc-co-PVCL) and wherein the weight ratio Encorafenib : PEG-g-(PVAc-co-PVCL) is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1 :5, yet more preferably 4: 1 to 1:4, even more preferably 3 : 1 to 1:3, most preferably 3 : 1 to 1: 1, such as 2 : 1 or 1 : 1.

61. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of PEG-g-(PVAc-co-PVCL) and wherein the weight ratio Encorafenib : PEG-g-(PVAc-co-PVCL) is within the range of (5.0±3.2): 1.0, preferably (5.0±2.8): 1.0, more preferably (5.0±2.4): 1.0, still more preferably (5.0±2.0): 1.0, yet more preferably (5.0±1.6): 1.0, even more preferably (5.0±1.2): 1.0, most preferably (5.0±0.8): 1.0, and in particular (5.0±0.4): 1.0.

62. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of BA / DMAEMA / MMA.

63. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of BA / DMAEMA / MMA and wherein the weight ratio Encorafenib : BA / DMAEMA / MMA is from 10: 1 to 1: 10, preferably 8: 1 to 1 :8, more pref- erably 6: l to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

64. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of EA / MMA.

65. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of EA / MMA and wherein the weight ratio En- corafenib : EA / MMA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

66. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of MAA / MMA.

67. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of MAA / MMA and wherein the weight ratio En- corafenib : MAA / MMA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1 :6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

68. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of MAA / EA.

69. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of MAA / EA and wherein the weight ratio Encoraf- enib : MAA / EA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more preferably 6: 1 to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1 : 1.

70. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of EA / MMA / TMAEMA.

71. The pharmaceutical composition according to any of the preceding claims, wherein the one or more polymers comprise or essentially consist of EA / MMA / TMAEMA and wherein the weight ratio Encorafenib : EA / MMA / TMAEMA is from 10: 1 to 1: 10, preferably 8: 1 to 1:8, more pref- erably 6: l to 1:6, still more preferably 5: 1 to 1:5, yet more preferably 4: 1 to 1:4, even more preferably 3: 1 to 1:3, most preferably 3: 1 to 1: 1, such as 2: 1 or 1: 1.

72. The pharmaceutical composition according to any of the preceding claims, which comprises one or more surfactants, preferably non-polymeric surfactants.

73. The pharmaceutical composition according to claim 72, wherein the one or more surfactants comprises or essentially consists of a cationic surfactant.

74. The pharmaceutical composition according to claim 72 or 73, wherein the one or more surfactants comprises or essentially consists of an anionic surfactant.

75. The pharmaceutical composition according to any of claims 72 to 74, wherein the one or more surfactants comprises or essentially consists of a nonionic surfactant.

76. The pharmaceutical composition according to any of claims 72 to 75, wherein the one or more surfactants are independently of one another selected from the group consisting of sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), dioctyl sulfosuccinate sodium salt (DOSS), and tocofersolan (TPGS); more preferably SLS.

77. The pharmaceutical composition according to any of the preceding claims, which comprises sodium lauryl sulfate (SLS).

78. The pharmaceutical composition according to any of the preceding claims, which comprises polysorbate 80 (Tween 80).

79. The pharmaceutical composition according to any of the preceding claims, which comprises polysorbate 20 (Tween 20).

80. The pharmaceutical composition according to any of the preceding claims, which comprises dioctyl sulfosuccinate sodium salt (DOSS).

81. The pharmaceutical composition according to any of the preceding claims, which comprises tocofersolan (TPGS).

82. The pharmaceutical composition according to any of claims 1 to 71, which does not additionally comprise a non-polymeric surfactant.

83. The pharmaceutical composition according to any of the preceding claims, which has a weight content of Encorafenib of at least 5.0 wt.-%, preferably at least 10 wt.-%, more preferably at least 15 wt.-%, still more preferably at least 20 wt.-%, yet more preferably at least 25 wt.-%, even more preferably at least 30 wt.-%, most preferably at least 35 wt.-%, and in particular preferably at least 40 wt.-%, relative to the total dry solids content of the pharmaceutical composition.

84. The pharmaceutical composition according to any of the preceding claims, which has a weight content of Encorafenib of at least 45 wt.-%, preferably at least 50 wt.-%, more preferably at least 55 wt.-%, still more preferably at least 60 wt.-%, yet more preferably at least 65 wt.-%, even more preferably at least 70 wt.-%, most preferably at least 75 wt.-%, and in particular preferably at least 80 wt.-%, relative to the total dry solids content of the pharmaceutical composition.

85. The pharmaceutical composition according to any of the preceding claims, which has a weight content of Encorafenib of at least 5.0 wt.-%, preferably at least 10 wt.-%, more preferably at least 15 wt.-%, still more preferably at least 20 wt.-%, yet more preferably at least 25 wt.-%, even more preferably at least 30 wt.-%, most preferably at least 35 wt.-%, and in particular preferably at least 40 wt.-%, relative to the total dry solids content of the sum of the content of Encorafenib and the content of the one or more polymers that are contained in the pharmaceutical composition.

86. The pharmaceutical composition according to any of the preceding claims, which has a weight content of Encorafenib of at least 45 wt.-%, preferably at least 50 wt.-%, more preferably at least 55 wt.-%, still more preferably at least 60 wt.-%, yet more preferably at least 65 wt.-%, even more preferably at least 70 wt.-%, most preferably at least 75 wt.-%, and in particular preferably at least 80 wt.-%, relative to the total dry solids content of the sum of the content of Encorafenib and the content of the one or more polymers that are contained in the pharmaceutical composition.

87. The pharmaceutical composition according to any of the preceding claims, which is a suspension, preferably an aqueous suspension.

88. The pharmaceutical composition according to any of claims 1 to 86, which is a powder, preferably a free flowing powder.

89. The pharmaceutical composition according to any of the preceding claims, wherein the nanosized Encorafenib is present in form of particles that essentially consist of Encorafenib.

90. The pharmaceutical composition according to any of the preceding claims, wherein the crystalline nanosized Encorafenib and the one or more polymers are crystalline polymer embedded nanoparticles.

91. The pharmaceutical composition according to any of the preceding claims, Encorafenib is not conjugated to an active targeting agent, preferably not conjugated at all.

92. A process for the preparation of the pharmaceutical composition according to any of the preceding claims comprising the steps of(a) providing amorphous nanosized Encorafenib; preferably as a solid;(b) providing an aqueous solution comprising one or more polymers; preferably selected from homopolymers, random copolymers, alternating copolymers, block copolymers and graft copolymers, and any combinations thereof; more preferably selected from cellulose ethers, cellulose esters, (co-)povidones, polyoxyalkylenes, polyoxyalkylene graft copolymers, acrylates, and any combinations thereof; still more preferably selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinylpyrrolidone, vinyl acetate) (PVP / VA), polyvinylpyrrolidone (PVP), poloxamers (PEO-PPO-PEO), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)), poly(butyl methacrylate, (2-dimethylami- noethyl)methacrylate, methyl methacrylate) (BA / DMAEMA / MMA), poly(ethyl acrylate, methyl methacrylate) (EA / MMA), poly(methacrylic acid, methyl methacrylate) (MAA / MMA), poly(methacrylic acid, ethyl acrylate) (MAA / EA), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (EA / MMA / TMAEMA), and any combinations thereof; yet more preferably hydroxypropyl methyl cellulose acetate succinate (HPMCAS), or hydroxypropyl cellulose (HPC); even more preferably hydroxypropyl methyl cellulose (HPMC), poloxamers (PEO-PPO- PEO), or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PEG-g-(PVAc-co-PVCL)); more preferably poloxamers (PEO-PPO-PEO); and optionally one or more surfactants;(c) contacting the amorphous nanosized Encorafenib and the aqueous solution to form an admixture thereby obtaining a suspension comprising crystalline nanosized Encorafenib.

93. The process according to claim 92, wherein content of the amorphous nanosized Encorafenib in the admixture is at least 10 times higher, more preferably at least 50 times higher, still more preferably at least 100 times higher, yet more preferably at least 500 times higher than itssolubility in the aqueous solution comprising the one or more polymers and optionally the one or more surfactants.

94. The process according to claim 92 or 93, wherein aqueous solution comprises one or more surfactants.

95. The process according to claim 94, wherein content of the one or more surfactants in the aqueous solution is within the range of from 0.0025 to 1.5 wt.-%.

96. The process according to any of claims 92 to 95, wherein the mean particle size of the crystalline nanosized Encorafenib obtained in step (c) is at most 50%, preferably at most 40%, more preferably at most 30%, still more preferably at most 20%, yet more preferably at most 10% larger than the mean particle size of the amorphous nanosized Encorafenib provided in step (a).

97. The process according to any of claims 92 to 96, wherein the contacting in step (c) comprises mixing the suspension.

98. The process according any of claims 92 to 97, wherein the contacting in step (c) comprises subjecting the suspension to ultrasound.

99. The process according to any of claims 92 to 98, wherein the contacting in step (c) is performed at least 10 h, preferably at least 16 h, more preferably at least 24 h.

100. The process according to any of claims 92 to 99, which comprises the additional step of(d) drying the suspension obtained in step (c) to provide a solid pharmaceutical composition comprising the crystalline nanosized Encorafenib and the one or more polymers; and optionally the one or more surfactants.

101. The process according to claim 100, which comprises the additional step of(e) crushing or grinding the solid pharmaceutical composition provided in step (d) to provide a powder.

102. A pharmaceutical dosage form comprising the pharmaceutical composition according to any of claims 1 to 91 and preferably at least one additional physiologically acceptable excipient.

103. The pharmaceutical dosage form according to claim 102, which is for oral administration.

104. The pharmaceutical dosage form according to claim 102 or 103, which is a tablet, which may optionally be fdm coated.

105. The pharmaceutical dosage form according to claim 102 or 103, which is a capsule, preferably a hard gelatin capsule.

106. The pharmaceutical dosage form according to any of claims 102 to 105, which has a total weight of at most 2.0 g, preferably at most 1.8 g, still more preferably at most 1.6 g, yet more preferably at most 1.4 g, even more preferably at most 1.2 g, most preferably at most 1.0 g, and in particular at most 0.8 g.

107. The pharmaceutical dosage form according to any of claims 102 to 106, wherein the at least one additional physiologically acceptable excipient is selected from fdlers / diluents, disintegrants, binders, glidants, lubricants, dispersants, film coating agents, preservatives, antioxidants, colorants, and the like, and combinations thereof.

108. The pharmaceutical dosage form according to claim 107, which comprises a filler / diluent selected from the group consisting of celluloses, microcrystalline cellulose, starches, calcium phosphates, sugars (e.g. sucrose, lactose, maltodextrins), sugar alcohols (e.g. mannitol, sorbitol).

109. The pharmaceutical dosage form according to claim 107 or 108, which comprises a disintegrant selected from the group consisting of (i) natural disintegrants, e.g. alginic acid, alginates, bentonite, microcrystalline cellulose, powdered cellulose, pregelatinized starches, guar, galactomannan; (ii) semi-synthetic disintegrants, e.g. carboxymethylcellulose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate (e.g. Type A or B), low-substituted carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose; and (iii) synthetic disintegrants, e.g. crospovidone.

110. The pharmaceutical dosage form according to any of claims 107 to 109, which comprises a binder selected from the group consisting of (i) natural polymers, e.g. Arabic gum, gelatin, sodium alginate, pullulan, starches, pregelatinized starches, tragacanth; (ii) semi-synthetic polymers, e.g. carboxymethylcellulose sodium, dextrin, maltodextrin; (iii) synthetic polymers, e.g. macrogols, polyvinyl alcohols (PVA), cellulose acetate, cellulose acetate butyrate, chitosan, poly(vinyl acetate), shellack, zein.

111. The pharmaceutical dosage form according to any of claims 102 to 110, wherein the total weight content of Encorafenib and the one or more polymers is at least 50 wt.-%, more preferably at least60 wt.-%, still more preferably at least 70 wt.-%, yet more preferably at least 75 wt.-%, even more preferably at least 80 wt.-%, most preferably at least 85 wt.-%, and in particular at least 90 wt.- %, relative to the total weight of the pharmaceutical dosage form.

112. The pharmaceutical dosage form according to any of claims 102 to 111, wherein the total weight content of Encorafenib and the one or more polymers is at most 90 wt.-%, more preferably at most 85 wt.-%, still more preferably at most 80 wt.-%, yet more preferably at most 75 wt.-%, even more preferably at most 70 wt.-%, most preferably at most 65 wt.-%, and in particular at most 60 wt.-%, relative to the total weight of the pharmaceutical dosage form.

113. The pharmaceutical dosage form according to any of claims 102 to 112, which contains Encorafenib at a dose of at least 75 mg, preferably at least 150 mg, still more preferably at least 225 mg, yet more preferably at least 300 mg, even more preferably at least 375 mg, and most preferably at least 450 mg.

114. The pharmaceutical dosage form according to any of claims 102 to 113, for use in the treatment of patients with metastatic melanoma in combination with Binimetinib and of patients with metastatic colorectal cancer with a BRAF V600E mutation, optionally in combination with Cetuximab.

115. The pharmaceutical dosage form for use according to claim 114, wherein the dosage form is administered twice daily.

116. The pharmaceutical dosage form for use according to claim 114, wherein the dosage form is administered once daily.

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