Solid oral composition comprising vericiguat

Abstract

The invention relates to a solid dispersion comprising Vericiguat and a polymer matrix. The solid dispersion is preferably prepared by hot melt extrusion or melt granulation. The invention further relates to pharmaceutical dosage forms comprising the solid dispersion.

Description

Solid Oral Composition Comprising Vericiguat

[0001] Priority is claimed of patent application LU505684 that was filed with the patent office in Luxemburg on December 1, 2023.

[0002] The invention relates to a solid dispersion comprising Vericiguat and a polymer matrix. The solid dispersion is preferably prepared by hot melt extrusion or melt granulation. The invention further relates to pharmaceutical dosage forms comprising the solid dispersion.

[0003] Vericiguat, i.e. methyl {4,6-diamino-2-[5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyri- din-3-yl]pyrimidin-5-yl} carbamate (C19H16F2N8O2, BAY 1021189, CAS no. 1350653-20-1, ATC C01DX22), has the following structure:

[0004] Vericiguat shows a typical biopharmaceutical profile for a BCS class II drug. Vericiguat is commercially available as Verquvo®, and is used as an oral solid form to reduce the risk of cardiovascular death and hospitalization in certain patients with heart failure after a recent acute decompensation event.

[0005] Vericiguat as well as its hydrochloride, sulfate, phosphate, mesylate, ethane- 1,2-disulfonate, maleate and nitrate salts are disclosed in WO 2011 / 147809.

[0006] WO 2013 / 076168 discloses solid state forms of Vericiguat, particularly a di-dimethyl sulfoxide solvate, a dimethylformamide / water solvate, a triacetic acid solvate, a monohydrate and a dihydrate.

[0007] M. Follmann et al., J. Med. Chem. 2017, 60, 5146-5161 relates to discovery of the soluble guanylate cyclase stimulator vericiguat (BAY 1021189) for the treatment of chronic heart failure.

[0008] WO 2020 / 014504 relates to methods, uses, pharmaceutical compositions comprising an sGC stimulator or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents, for the treatment of a mitochondrial disorder.

[0009] WO 2020 / 126983 relates to an active compound product of methyl {4,6-diamino-2-[5-fluoro- l-(2-fluorobenzyl)-lH-pyrazolo[3,4- b]pyridin-3-yl]pyrimidin-5-yl} carbamate that is said to have improved properties, for example in respect of the isolability of the active compound product, the dischargeability of the active compound product after isolation and drying and also conveyability, sieveability and micronizability of the active compound product, and to processes for the production and formulation thereof.

[0010] WO 2021 / 069350 describes a process for producing a pharmaceutical formulation comprising the steps of: A) suspending a pharmaceutical active substance in an aqueous solution of a polymer; B) drying the mixture obtained in step A); wherein in step A) the pharmaceutical active substance is present in the form of particles having a d90 value in the particle size distribution of < 1 pm and before step B) the pharmaceutical active substance is further contacted with an ionic surfactant. Example 3 relates to freeze-dried nanosuspensions of Vericiguat, PVP K12, and sodium lauryl sulfate.

[0011] WO 2021 / 156223 discloses nanosuspensions of Vericiguat in crystalline form of modification I, processes for preparing the nanosuspensions, nanoparticles comprising Vericiguat, and pharmaceutical compositions in solid form made from these nanosuspensions.

[0012] S.V. Bhujbal et al., Acta Pharmaceutica, 2021, 11(8), 2505-2536 review manufacturing strategies regarding pharmaceutical amorphous solid dispersions.

[0013] C. Becker et al., AAPS Open (2022) 8: 16 relates to results from in vitro and in vivo studies evaluating the bioavailability, effects of food, and administration of crushed tablet suspension on vericiguat pharmacokinetics.

[0014] WO 2023 / 034364 discloses solid state forms of Vericiguat, crystalline polymorphs of Vericiguat, processes for preparation thereof, and pharmaceutical compositions thereof.

[0015] The properties of the pharmaceutical compositions of Vericiguat that are known from the prior art are not satisfactory in every respect and there is a demand for improvements.

[0016] K. Crowley et al., Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development and Manufacturing, (ed. S.C. Gad), Wiley 2015, pp. 1-23 relates to hot melt extrusion of amorphous solid dispersions.

[0017] A Agrawal et al., AAPS Pharm. Sci. Tech., Vol. 17, No. 1, 2016 relates to development of a tablet formulation of amorphous solid dispersions prepared by hot melt extrusion using quality by design approach.

[0018] JP 2023 165408 A relates to an amorphous solid dispersion including a drug in an amorphous state dispersed in a carrier. The drug includes a heterocyclic compound with a nitrogen atom in a ring structure, and the carrier includes methyl hesperidin.

[0019] It is an object of the invention to provide an oral solid pharmaceutical dosage form of Vericiguat that has advantages compared to the dosage forms of the prior art. The oral solid pharmaceutical dosage form should be easy to manufacture and exhibit increased stability.

[0020] This object has been achieved by the subject-matter of the patent claims.

[0021] A first aspect of the invention relates to a solid dispersion comprising or essentially consisting of (i) Vericiguat or a physiologically acceptable salt and / or solvate thereof and (ii) a polymer matrix.

[0022] Unless expressly stated otherwise, all percentages are expressed as weight percent.

[0023] Unless expressly stated otherwise, all amounts refer to Vericiguat or a physiologically acceptable salt and / or solvate thereof. Thus, the weight contribution of the salt and / or solvent is taken into account.

[0024] Unless expressly stated otherwise, all references to Ph. Eur. and USP refer to the version that is in force on January 1, 2024.

[0025] For the purpose of the specification, "essentially consisting of' means that specific further components can be present, namely those not materially affecting the essential characteristics of the compound or composition.

[0026] For the purpose of the specification, a "solid dispersion" is a mixture of two solid phases, wherein hydrophobic Vericiguat or a physiologically acceptable salt and / or solvate thereof is dispersed in a polymer matrix, preferably a hydrophilic polymer matrix, as inert carrier in a solid state. According to W.E. Chiou et al., Pharmaceutical Applications of Solid Dispersion Systems, Journal of Pharmaceutical Sciences, 60(9), 1971, 1281-1302, a "solid dispersion" is a "the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (fusion), solvent, or melting-solvent method" . This is also the preferred meaning of "solid dispersion" according to the present invention.

[0027] In preferred embodiments, the "solid dispersion" according to the invention is obtained by extrusion, preferably melt extrusion, more preferably hot melt extrusion.

[0028] In other preferred embodiments, the "solid dispersion" according to the invention is obtained by melt granulation (thermoplastic granulation).

[0029] For the purpose of the specification, "solid dispersions" can be divided on the basis of the carrier used. Solid dispersions of first generation are based upon crystalline carriers such as sugars and urea. Solid dispersions of second generation, involve amorphous carriers which are usually polymers. Solid dispersions of third generation involve carriers with surface active agent properties or mixtures of amorphous polymers and surfactants. Solid dispersions of fourth generation are controlled release solid dispersions containing poorly water-soluble drugs with a short biological half-life. Based upon thisclassification, the solid dispersions according to the present invention preferably belong to the second generation or the third generation.

[0030] For the purpose of the specification, "solid dispersions" can alternatively be divided on the basis of their molecular arrangement, namely into eutectic mixtures, solid solutions and amorphous precipitates. Solid solutions in turn may be subdivided into substitutional solid solutions, continuous solid solutions, interstitial solid solutions and discontinuous solid solutions. Based upon this classification, the solid dispersions according to the present invention preferably belong to solid solutions or amorphous precipitates.

[0031] Preferably, the solid dispersion is an amorphous solid dispersion.

[0032] For the purpose of the specification, "amorphous" means a non-crystalline state that lacks the long-range order which is characteristic of a crystal. A completely amorphous material neither shows XRPD reflections nor does it show thermal events during DSC analysis. Amorphous materials can be characterized by a complete disorder as well as a short-range order. They are distinguished from nanocrystalline materials which are characterized by an intermediate-range order and from crystalline or polycrystalline materials which are characterized by a long range order. Amorphous solids lack long- range orientational and positional atomic or molecular order (and corresponding symmetry operators), but usually exhibit some degree of short-range orientational and / or positional order. Amorphous solids can be regarded as frozen liquids: at the molecular level the structure is liquid like, while at the macroscopic level, they have viscosities and hardness typical for solids.

[0033] For further details, reference is made to e.g. S.V. Bhujbal et al., Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies, Acta Pharmaceutica Sinica B 2021; 1 l(8):2505- 2536; R Malkawi et al., Current Trends on Solid Dispersions: Past, Present, and Future, Advances in Pharmacological and Pharmaceutical Sciences, 2022, 1-17; L. Kumari et al., Advancement in Solubilization Approaches: A Step towards Bioavailability Enhancement of Poorly Soluble Drugs, Life, 2023, 13, 1099, 1-32; and J. Zhang et al., Advances in the development of amorphous solid dispersions: The role of polymeric carriers, Asian journal of Pharmaceutical Sciences 18 (2023) 100834, 1-35.

[0034] The term "excipient" as used herein refers to any pharmaceutically acceptable substance that has no therapeutic activity as such. Pharmaceutically acceptable excipients may for example be selected from diluents, binders, disintegrants, surfactants lubricants, and glidants. Pharmaceutically acceptable excipients are described e.g. in Remington: The Science and Practice of Pharmacy, edited by A. Adejare, Academic Press, 23rd edition, 2020; or Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry, edited by O.M.Y. Koo, Wiley, 1st edition 2016.

[0035] Individual excipients may have polyfunctional properties, e.g. may exert both disintegrating and binding properties, or both lubricating and gliding properties, or may exert filling, binding and disintegrating properties.

[0036] The term "milling" as used herein comprises any procedure resulting in a reduction of the size of the starting material subjected to milling. In an embodiment, milling can be carried out in one or more milling devices; milling devices, especially milling devices which may be used in the pharmaceutical field, are known to the skilled person.

[0037] The solid dispersion according to the invention comprises Vericiguat or a physiologically acceptable salt and / or solvate thereof.

[0038] Preferably, Vericiguat is present in the non-salt form.

[0039] Preferably, Vericiguat is present as an ansolvate.

[0040] Preferably, Vericiguat is present as ansolvate of the non-salt form.

[0041] Preferably, Vericiguat is the sole pharmacologically active ingredient that is contained in the solid dispersion and pharmaceutical dosage form according to the invention.

[0042] The solid dispersion according to the invention comprises a polymer matrix.

[0043] In preferred embodiments, the polymer matrix comprises or essentially consists of a polymer selected from(i) polyvinyl alcohol (PVAL);(ii) copolymers of vinylpyrrolidone with vinyl acetate (copovidone), and polyvinylpyrrolidone (povidone, PVP);(iii) poly(meth)acrylates and polyalkyl(meth)acrylates; preferably poly(methyl acrylate) (PMA);(iv) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;(v) cellulose, cellulose ethers, and cellulose esters; preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl methyl cellulose acetate succinate;(vi) polyethylene glycol (PEG), polyethylene oxide (PEO), and block copolymers of ethylene oxide and propylene oxide (poloxamers); and any mixtures thereof.

[0044] When the solid dispersion according to the invention is prepared by extrusion, preferably melt extrusion, more preferably hot melt extrusion, the polymer matrix comprises or essentially consists of a polymer selected from (i) polyvinyl alcohol (PVAL), (ii) copolymers of vinylpyrrolidone with vinyl acetate (copovidone), (iii) poly(methyl acrylate) (PMA), (iv) polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer, and mixtures thereof.

[0045] When the solid dispersion according to the invention is prepared by melt granulation, the polymer matrix comprises or essentially consists of a polymer selected from (vi) polyethylene glycol (PEG), poloxamers, and mixtures thereof.

[0046] In preferred embodiments, the polymer matrix comprises or essentially consists of a polymer selected from polyvinyl alcohol (PVAL). Polyvinyl alcohol (PVAL) is particularly useful for preparing the solid dispersion according to the invention by extrusion, preferably melt extrusion, more preferably hot melt extrusion. The polyvinyl alcohol is preferably in accordance with the corresponding monograph in the European Pharmacopoeia.

[0047] Polyvinyl alcohol is prepared by hydrolysis of polyvinyl acetate. In addition to nearly completely hydrolyzed types, partially hydrolyzed types are preferred. Partially hydrolyzed types may contain up to 15 wt.-% acetyl groups. Preferably, the ester value (as defined in Ph. Eur.) is not greater than 280.

[0048] Preferably, the molecular mass (as defined in Ph. Eur.) of the PVAL is within the range of from 20,000 to 200,000.

[0049] In preferred embodiments, the PVAL is in accordance with the following formula:wherein the indices m and n comply with the requirement 0 < n / m < 0.35.

[0050] Preferably, the grade of PVAL can be extruded, preferably melt extruded, more preferably hot melt extruded. The PVAL can be used as an extrudable PVAL powder. PVAL powder is commercially available and can be prepared by milling, especially cryo-milling.

[0051] Preferably, PVAL has both glass transition temperature and melting temperature. Preferably, the melting temperature of PVAL is 170°C or less.

[0052] Preferred grades of PVAL are selected from 4-88, 4-98, 5-88, 8-88, 18-88, 26-88, and 40-88. Grade 4-88 is particularly preferred.

[0053] PVAL is commercially available, and is for example marketed as Parteck® MXP by Merck KGaA.

[0054] In other preferred embodiments, the polymer matrix comprises essentially no polyvinyl alcohol (PVAL)

[0055] In preferred embodiments, the polymer matrix comprises or essentially consists of a polymer selected from copolymers of vinylpyrrolidone with vinyl acetate (copovidone), and polyvinylpyrrolidone (povidone, PVP). Copovidone is particularly preferred. Copovidone is particularly useful for preparing the solid dispersion according to the invention by extrusion, preferably melt extrusion, more preferably hot melt extrusion. The copovidone and povidone are preferably in accordance with the corresponding monographs in the European Pharmacopoeia.

[0056] The copovidone is preferably a linear random copolymer of N-vinyl-2 -pyrrolidone (VP, 1-eth- enylpyrrolidin-2-one) and vinyl acetate (VA), wherein the VA content is preferably 40 wt.-%, but may vary, for example, between 35 and 42 wt.-%. Preferably, the copovidone is a copolymer of 1-ethenylpyr- rolidin-2-one and ethenyl acetate in the mass proportion 3:2. Preferably, the K value of the copovidone is within the range of from 25.4 to 34.2. Preferably, the molecular mass (as defined in Ph. Eur.) of the copovidone is within the range of from 45,000 to 75,000. Copovidone is commercially available e.g. under the trade name Kollidon® VA 64 (BASF) and Plasdone® S630 (Ashland).

[0057] In other preferred embodiments, the polymer matrix comprises essentially no copovidone.

[0058] The povidone is preferably a linear polymer of N-vinyl-2-pyrrolidone (VP, 1-ethenylpyrrolidin- 2-one). Preferably, the K value of the povidone is within the range of from 25 to 90. Preferably, the molecular mass (as defined in Ph. Eur.) of the povidone is within the range of from 28,000 to 1,150,000. Preferably, the povidone is selected from grades K12, K15, K17, K25, K30, K33, K60, K80, and K90. The glass transition temperature is preferably within the range of from 110 to 180°C. Povidone is commercially available e.g. under the tradenames Kollidon® (BASF) and Plasdone® (Ashland).

[0059] In other preferred embodiments, the polymer matrix comprises essentially no povidone.

[0060] In preferred embodiments, the polymer matrix comprises or essentially consists of a polymer selected from poly(meth)acrylates; preferably poly(meth)acrylates and polyalkyl(meth)acrylates; more preferably poly(methyl acrylate) (PMA). Poly(methyl acrylate) (PMA) is particularly preferred. Poly(methyl acrylate) (PMA) is particularly useful for preparing the solid dispersion according to the invention by extrusion, preferably melt extrusion, more preferably hot melt extrusion. The poly(meth)acrylates and polyalkyl(meth)acrylates are preferably in accordance with the corresponding monograph in the European Pharmacopoeia.

[0061] Preferably, the poly(meth)acrylate is selected from poly(butyl methacrylate, (2 -dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2: 1 (e.g. Eudragit® E, Eudragit® E PO); poly(ethyl acrylate, methyl methacrylate) 2: 1 (e.g. Eudragit® NE, Eudragit® NM); poly (methacrylic acid, methyl methacrylate) 1: 1 (e.g. Eudragit® L); poly(methacrylic acid, ethyl acrylate) 1: 1 (e.g. Eudragit® L 100-55); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) l:2:0.2 (e.g. Eudragit® RL); and poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS).

[0062] In other preferred embodiments, the polymer matrix comprises essentially no poly(meth)acry- lates.

[0063] In preferred embodiments, the polymer matrix comprises or essentially consists of a polymer selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is particularly useful for preparing the solid dispersion according to the invention by extrusion, preferably melt extrusion, more preferablyhot melt extrusion. The polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is preferably in accordance with the corresponding monograph in the European Pharmacopoeia.

[0064] Preferred polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (PCA- PVA-PEG) comprise at least one caprolactam block, at least one polyvinyl acetate block, and at least one polyethylene glycol block, wherein at least one block branches from another of the type of blocks.

[0065] Preferred PCA-PVA-PEGs are represented by the structure below:wherein p is within the range of from 10 to 10,000; preferably 100 to 900; more preferably 100 to 500; still more preferably 500 to about 900; q is within the range of from 20 to 20,000; preferably 150 to 1500; more preferably 200 to 800; still more preferably 800 to 1500; and r is within the range of from 30 to 30,000; preferably 300 to 3000; more preferably 300 to 1000; still more preferably 1000 to 2000, or 2000 to 3000.

[0066] In preferred embodiments, the PCA-PVA-PEG has a weight ratio of comonomers of 57 / 30 / 13.

[0067] Preferably, the PCA-PVA-PEG has a glass transition temperature of about 70°C.

[0068] In preferred embodiments, the PCA-PVA-PEG has an average molecular weight (in particular a weight average molecular weight) within the range of from 1,000 to 5,000,000 g / mol; more preferably 10,000 to 500,000 g / mol; more preferably from 90,000 to 140,000 g / mol. Methods for determining the average molecular weight are known in the art, e.g. gel permeation chromatography.

[0069] For example, PCA-PVA-PEG can be a polymer represented by CAS No. 402932-23-4. Especially, PCA-PVA-PEG can be Soluplus®, available from BASF.

[0070] In other preferred embodiments, the polymer matrix comprises essentially no polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0071] In preferred embodiments, the polymer matrix comprises or essentially consists of a polymer selected from cellulose, cellulose ethers and cellulose esters; preferably hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC, hypromellose), and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS). The cellulose, cellulose ethers and cellulose esters are preferably in accordance with the corresponding monographs in the European Pharmacopoeia.

[0072] In other preferred embodiments, the polymer matrix comprises essentially neither cellulose, nor cellulose ethers, nor cellulose esters.

[0073] In preferred embodiments, the polymer matrix comprises or essentially consists of a polymer selected from polyethylene glycol (PEG), polyethylene oxide (PEO), and block copolymers of ethylene oxide and propylene oxide (poloxamers). Polyethylene glycol (PEG) and poloxamers are particularly preferred. Polyethylene glycol (PEG) and poloxamers are particularly useful for preparing the solid dispersion according to the invention by melt granulation. The macrogols (PEG, PEO) and poloxamers are preferably in accordance with the corresponding monographs in the European Pharmacopoeia.

[0074] It has been unexpectedly discovered that Vericiguat or physiologically acceptable salt and / or solvate thereof can be successfully dissolved in polyethylene glycol (PEG, macrogol), thereby achieving an amorphous solid dispersion. During e.g. thermoplastic granulation Vericiguat or physiologically acceptable salt and / or solvate thereof and PEG may be homogenized, preferably at elevated temperatures, specifically within a range extending from above 20°C to below 100°C. It is preferable to operate at temperatures below 90°C and above 30°C, more preferably below 80°C and above 40°C, and most preferably the temperature is maintained between 50°C and 70°C.

[0075] Preferred polyethylene glycols are selected from PEG 300, 400, 600, 1000, 1500, 3000, 3350, 4000, 6000, 8000, 20 000, and 35 000.

[0076] Preferred poloxamers are selected from poloxamer 188 (e.g. Pluronic® F68, Kolliphor® Pl 88, Lutrol® F68) and poloxamer 407 (e.g. Pluronic® F127, Kolliphor® P407, Lutrol® F127).

[0077] In other preferred embodiments, the polymer matrix comprises essentially neither macrogols (PEG, PEO) nor poloxamers.

[0078] Preferably, the polymer matrix essentially consists of a single polymer.

[0079] Preferably, the weight ratio of the Vericiguat or physiologically acceptable salt and / or solvate thereof and the polymer matrix is within the range of from 1 :2 to 1: 13, preferably from 1 :3 to 1: 12.

[0080] In preferred embodiments, the weight ratio of the Vericiguat or physiologically acceptable salt and / or solvate thereof and the polymer matrix is within the range of from 1 :4 to 1:6.

[0081] In other preferred embodiments, the weight ratio of the Vericiguat or physiologically acceptable salt and / or solvate thereof and the polymer matrix is within the range of from 1 :8 to 1: 10.

[0082] In preferred embodiments, the solid dispersion according to the invention is an extrudate, i.e. has been prepared by means of an extruder. Preferably, the extrudate is a melt extrudate, more preferably a hot melt extrudate, i.e. has been prepared by hot melt extrusion (HME).

[0083] In other preferred embodiments, the solid dispersion according to the invention is a granulate, preferably a melt granulate, i.e. has been prepared by means of melt granulation (thermoplastic granulation).

[0084] Melt granulation, spray-congealing, and hot melt extrusion are different processes providing different products.

[0085] Melt granulation involves partially or completely melting solid excipient(s), and then granulating with the pharmacologically active ingredient and other excipients, followed by reducing the mixture to granules by chilling and congealing. During this process, the pharmacologically active ingredient is subjected to heat, and may be partially or completely dissolved in the molten excipients. If the melting point is relatively low or the heating temperature is sufficiently high, the pharmacologically active ingredient may also melt during processing. Partially or completely melted pharmacologically active ingredient may also serve as a binder or congealing carrier. Subsequent cooling may induce phase transitions through the solid-state or melt mechanisms.

[0086] Spray-congealing involves a low melting point carrier to provide the fluidity necessary for spraying. At high temperatures, all or a fraction of the pharmacologically active ingredient may be solubilized in the molten carrier. During spray-congealing, the hot droplets cool rapidly and solidify. Since rapid cooling / congealing is required for the formation of small particles with a narrow size distribution, it is possible that the pharmacologically active ingredient may precipitate as an amorphous phase or as a metastable crystal form. Spray-congealing often requires higher temperature, longer extent and duration of heating as well as rate of cooling relative to high shear melt granulation. Thus, spray-congealing is more likely to initiate phase transitions.

[0087] Similar to spray-congealing, melt-extrusion also requires complete melting of the carrier excipients. Although the rate of cooling is slower, melt-extrusion may still induce phase transitions.

[0088] Methods for analyzing and identifying hot melt extrudates and melt granulates are known to the skilled person and include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), powder x-ray diffraction (PXRD), and also e.g. vibrational spectroscopy and microspectroscopy (see e.g. L. Netchacovitch et al., Vibrational spectroscopy and microspectroscopy analyzing qualitatively and quantitatively pharmaceutical hot melt extrudates, Journal of Pharmaceutical and Biomedical Analysis, 113(10) 2015 21-33).

[0089] Preferably, the solid dispersion according to the invention shows essentially no reflection in an XRPD spectrum in a 20 range of from 5 to 30 using Cm, radiation at 23°C. Thus, preferably neither theVericiguat or physiologically acceptable salt and / or solvate thereof, nor the polymer matrix has a long range order to diffract Cit, x-ray radiation.

[0090] Preferably, the solid dispersion according to the invention shows essentially no thermal event during DSC analysis in a temperature range of from 20 to 250°C. Thus, preferably neither the Vericiguat or physiologically acceptable salt and / or solvate thereof, nor the polymer matrix undergoes an endothermic or exothermic phase transformation upon heating.

[0091] Preferably, the solid dispersion according to the invention is an amorphous solid dispersion (ASD).

[0092] In preferred embodiments, the solid dispersion according to the invention comprises amorphous Vericiguat or physiologically acceptable salt and / or solvate thereof.

[0093] In other preferred embodiments, the solid dispersion according to the invention comprises amorphous Vericiguat or physiologically acceptable salt and / or solvate thereof in combination with crystalline Vericiguat or physiologically acceptable salt and / or solvate thereof, preferably modification I according to WO 2013 / 076168.

[0094] In preferred embodiments, at least 80 wt.-% of the total content of the Vericiguat or physiologically acceptable salt and / or solvate thereof is amorphous; preferably at least 85 wt.-%; more preferably at least 90 wt.-%; still more preferably at least 95 wt.-%; yet more preferably at least 96 wt.-%, even more preferably at least 97 wt.-%. most preferably at least 98 wt.-%, and in particular at least 99 wt.-%.

[0095] In preferred embodiments, the Vericiguat or physiologically acceptable salt and / or solvate thereof is homogeneously dispersed in the matrix polymer.

[0096] In preferred embodiments, the Vericiguat or physiologically acceptable salt and / or solvate thereof is molecularly dispersed in the matrix polymer.

[0097] In preferred embodiments, the solid dispersion according to the invention comprises or essentially consists of (i) amorphous Vericiguat or physiologically acceptable salt and / or solvate thereof and (ii) amorphous polymer matrix. These embodiments are particularly preferred when the solid dispersion is a hot melt extrudate.

[0098] In other preferred embodiments, the solid dispersion according to the invention comprises or essentially consists of (i) amorphous Vericiguat or physiologically acceptable salt and / or solvate thereof, (ii) amorphous polymer matrix, and (iii) one or more additional excipients. These embodiments are particularly preferred when the solid dispersion is a melt granulate.

[0099] In preferred embodiments the solid dispersion according to the invention comprises or essentially consists of- Vericiguat or physiologically acceptable salt and / or solvate thereof; preferably in essentially amorphous form;- polymer matrix; preferably in essentially amorphous form; and- one or more additional excipients.

[0100] In preferred embodiments, the solid dispersion is preferably a melt granulate. Preferred embodiments are reflected by Examples 7 to 11.

[0101] Preferably, the polymer matrix comprises or essentially consists of macrogol, poloxamer, hydroxypropyl cellulose or a combination thereof; preferably macrogol in combination with poloxamer or with hydroxypropyl cellulose.

[0102] Preferably, the one or more additional excipients are selected from diluents, surfactants, and binders.

[0103] Preferably, the one or more additional excipients comprise one or more diluents; preferably microcrystalline cellulose, lactose, mannitol, or a combination thereof; more preferably microcrystalline cellulose in combination with lactose or with mannitol.

[0104] Preferably, the one or more additional excipients comprise a surfactant; preferably an anionic surfactant; more preferably sodium lauryl sulfate (SLS).

[0105] Alternatively, the solid dispersion is first prepared by hot melt extrusion, i.e. is a hot melt extrudate, that is subsequently melt granulated together with additional excipients. Preferred embodiments are reflected by Examples 15 to 17.

[0106] Another aspect of the invention relates to a pharmaceutical dosage form for oral administration comprising the solid dispersion according to the invention as described above.

[0107] In preferred embodiments, the pharmaceutical dosage form is selected from capsules and sachets filled with powder or granules.

[0108] A pharmaceutical composition comprising or consisting of one or more granules, especially hot melt extruded granules, can be filled into capsule(s) or sachet(s), or can be compressed in one or more comprimate(s), preferably in one or more tablet(s) or microtablet(s), or may be formulated in one or more pellet(s), which comprimate(s) or pellet(s) optionally can be coated and / or optionally filled into capsule(s) or sachet(s).

[0109] In other preferred embodiments, the pharmaceutical dosage form is selected from comprimates; preferably tablets.

[0110] In particularly preferred embodiments, the pharmaceutical dosage form is a tablet.

[0111] Preferably, the pharmaceutical dosage form according to the invention is film coated; preferably with a functional film coating or with a non-fimctional film coating.

[0112] Preferred coatings are aqueous soluble film coatings, preferably having an average thickness of at least 0.8 pm, measured by scanning electron microscopy (SEM) of cross-section of coated solid dosage form.

[0113] Preferably, the film coating comprises an aqueous soluble polymer selected from cellulose ethers, polyvinyl alcohol, povidone, sodium carboxymethyl cellulose, waxy materials, acrylic polymers, or block polymers of polyvinyl alcohol and polyethylene glycol, such as those that are commercially available under trade name Kollicoat® IR and Kollicoat ® Protect.

[0114] Preferred cellulose ethers used in fdm coatings include hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) and methyl cellulose (MC).

[0115] Preferred acrylic polymers used in fdm coatings may have diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration / dissolution of the film.

[0116] The film coating may additionally contain excipients selected from lubricants, antitacking agents, pigments, colorants and / or plasticizers.

[0117] Preferred plasticizers for film coatings are selected from three groups: (i) polyols, e.g. glycerol, propylene glycol, macrogols; (ii) organic esters, e.g. phthalate esters, dibutyl sebacate, citrate esters, triacetin; and (iii) oils / glycerides, e.g. castor oil, acetylated monoglycerides, fractionated coconut oil.

[0118] Preferred lubricants and / or antitacking agents for film coatings are selected from (i) metal salts of fatty acids with 12 to 20 carbon atoms such as magnesium stearate, calcium stearate, aluminum stearate, zinc stearate, magnesium palmitate or magnesium oleate; (ii) fatty acids with 12 to 20 carbon atoms such as stearic acid, palmitic acid and oleic acid; (iii) hydrogenated vegetable oil; (iv) hydrogenated castor oil; (v) talc; (vi) meads wax or spermaceti; (vii) boric acid; (viii) sodium stearyl fumarate; and mixtures thereof.

[0119] Preferred colorants / opacifiers for film coatings are selected from organic dyes and their lakes, inorganic colors, and natural colors. Pigments can be selected from metal oxides such as iron or titanium oxides.

[0120] The composition of the coating layer of the pharmaceutical composition of the present invention preferably comprises at least one excipient selected from excipients with the function as defined of polymer and plasticizer.

[0121] Combination of different materials from each group can be combined, in particular in defined ratios.

[0122] Film coating suspensions can be used as ready-to-make preparations which are available on the market. Film coating dispersions can be prepared by using different solvents (e.g. water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.

[0123] A particularly preferred composition of coating suspension comprises (calculated on dry material relative to the total weight of the coating):1.0 to 99 wt.-% of polymer, preferably 1.0 to 95 wt.-%;0.8 to 50 wt.-% of plasticizer, preferably 1.0 to 40 wt.-%;0.1 to 20 wt.-% of lubricant, preferably 1.0 to 10 wt.-%; and0. 1 to 20 wt.-% of colorant / opacifier and / or pigment, preferably 0.1 to 10 wt.-%.

[0124] Preferably, the pharmaceutical dosage form according to the invention additionally comprises one or more excipients; preferably independently of one another selected from diluents, binders, disin- tegrants, surfactants, dispersants and lubricants.

[0125] Preferred diluents comprise but are not limited to- lactose (e.g. anhydrous or hydrate or amorphous (partially or completely));- polysaccharides, (e.g. starches or celluloses); starches may be selected from partially or wholly pregelatinized starch, com starch, wheat starch, rice starch, tapioca starch, potato starch and any mixture thereof; celluloses may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose co-processed with other excipients such as lactose, starch, silicon dioxide, mannitol, etc. and any mixture thereof;- monosaccharides (e.g. glucose, fructose);- disaccharides (e.g. sucrose, lactose monohydrate, anhydrous lactose, a-lactose, [3-lactose, isomaltose, trehalose);- oligosaccharides (e.g. raffinose, dextrates);- compressible sugars;- sugar alcohols (e.g. mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol);- inorganic salts of phosphoric acid;- inorganic salts.

[0126] Particularly preferred diluents according to the invention are selected from lactose, microcrystalline cellulose, mannitol, and mixtures thereof.

[0127] Preferred binders include but not limited to- povidone (polyvinylpyrrolidone);- copovidone (vinylpyrrolidone- vinyl acetate copolymer);- cellulose derivatives such as cellulose esters or cellulose ethers (e.g. hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), low substituted hydroxypropyl cellulose and hydroxypropyl methyl cellulose (HPMC)):- polyvinyl alcohol,- starch (e.g. com starch, potato starch, or rice starch); a-starch, pregelatinized starch;- dextrins;- gum arabic;- pullulan;- poly(meth)acrylates.

[0128] A particularly preferred binder according to the invention is hydroxypropyl cellulose (HPC).

[0129] Preferred disintegrants include but not limited to- crospovidone;- starch, maize starch, pregelatinized starch, sodium starch glycollate, modified starch, hydroxypropyl starch, carboxymethyl starch;- sodium and / or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. sodium croscarmellose and / or calcium croscarmellose);- polacrilin potassium;- alginic acid or alginates, sodium and / or calcium alginate;- polyacrylates;- docusate sodium;- methylcellulose; and- agar, gums, guar gum, chitosan.

[0130] A particularly preferred disintegrant according to the invention is sodium croscarmellose.

[0131] Preferred surfactants include but are not limited to- cationic surfactants;- anionic surfactants; such as carboxylates: alkyl carboxylates-fatty acid salts; carboxylate fluoro surfactants; sulfates: alkyl sulfates (e.g., sodium lauryl sulfate); alkyl ether sulfates (e.g., sodium laureth sulfate); sulfonates: docusates (e.g., dioctyl sodium sulfosuccinate); alkyl benzene sulfonates; phosphate esters: alkyl aryl ether phosphates; alkyl ether phosphates;- zwitterionic surfactants; and- non-ionic surfactants; such as polyol esters {e.g. glycol esters, glycerol esters, and sorbitan derivatives [such as fatty acid esters of sorbitan (generally referred to as Spans) and their ethoxylated derivatives (generally referred to as Tweens)]}, polyoxyethylene esters, poloxamers.

[0132] Particularly preferred surfactants according to the invention are sodium lauryl sulfate and polox- amer.

[0133] Preferred lubricants include but are not limited to- fatty acids (i.e. carboxylic acids with 12 to 20 carbon atoms);- faty acid esters including glyceride esters such as glyceryl monostearate, glyceryl tribehenate, or glyceryl dibehenate (e.g. Compritol® 888);- metal salts of faty acids, including magnesium, calcium, aluminum or zinc salts of faty acids (e.g. magnesium, calcium, aluminum or zinc stearate, magnesium palmitate, or magnesium oleate);- hydrogenated vegetable oil, hydrogenated castor oil;- waxes (e.g. Sterotex® NL, Lubriwax® [hydrogenated vegetable oil type], meads wax or spermaceti);- boric acid;- sodium stearyl fumarate;- polymers (e.g., PEG, macrogols);- sugar esters such as sorbitan monostearate and sucrose monopalmitate.

[0134] A particularly preferred lubricant according to the invention is magnesium stearate.

[0135] Preferred dispersants include but are not limited to colloidal silicon dioxide (e.g. Aerosil) and talcum.

[0136] A particularly preferred dispersant according to the invention is colloidal silicon dioxide.

[0137] Excipients may be present at different locations of the pharmaceutical dosage form, namely inside the solid dispersion or outside the solid dispersion. When the solid dispersion as such is part of an intragranular phase, excipients inside the solid dispersion become automatically intragranular, whereas excipients outside the solid dispersion may nonetheless be intragranular as well, or extragran- ular.

[0138] Preferably, the solid dispersion, preferably hot melt extrudate, comprises in addition to Vericig- uat, a physiologically acceptable salt and / or solvate thereof, and the polymer matrix as defined above, one or more further excipients, e.g. 1 or 2 or 3 or 4 or 5 or more further excipient(s), preferably independently selected from the group consisting of diluents, binders, disintegrants, dispersants, lubricants, glidants, surfactants, and antitacking agents.

[0139] In preferred embodiments, the solid dispersion is a granulate comprising one or more further excipients in addition to Vericiguat, a physiologically acceptable salt and / or solvate thereof, and the polymer matrix as defined above. The granulate comprising Vericiguat, a physiologically acceptable salt and / or solvate thereof and the polymer matrix can comprise one or more further excipients, e.g. 1 or 2 or 3 or 4 or 5 or more further excipient(s), preferably independently selected from the group consisting of diluents, binders, disintegrants, dispersants, lubricants, glidants, surfactants, and antitacking agents, as intragranular excipients.

[0140] In particular, a granulate preferably comprises Vericiguat, a physiologically acceptable salt and / or solvate thereof, the polymer matrix, and one or more intragranular excipients selected from- one or more diluents, e.g. lactose, preferably lactose monohydrate; cellulose, preferably microcrystalline cellulose; and mixtures thereof;- one or more disintegrants, e.g. sodium croscarmellose);- optionally, one or more lubricants, e.g. magnesium stearate;- optionally, one or more surfactants, e.g. sodium lauryl sulfate; and- optionally, one or more further excipients.

[0141] The pharmaceutical dosage form comprising Vericiguat, a physiologically acceptable salt and / or solvate thereof, and the polymer matrix, can furthermore comprise one or more further excipients, e.g. 1 or 2 or 3 or 4 or 5 or more further excipient(s), selected from the group of diluents, binders, disintegrants, dispersants, lubricants, glidants, surfactants, and antitacking agents, as extragranular excipients.

[0142] In particular, the pharmaceutical dosage form can comprise as extragranular excipients- one or more disintegrants, e.g. sodium croscarmellose);- optionally, one or more diluents, e.g. lactose, preferably anhydrous lactose; cellulose, preferably microcrystalline cellulose;, and mixtures thereof;- optionally, one or more dispersants, e.g. colloidal silicon dioxide;- optionally one or more lubricants, e.g. magnesium stearate;- optionally one or more surfactants, e.g. sodium lauryl sulfate; and- optionally one or more further excipients.

[0143] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises the solid dispersion as a hot melt extrudate that is blended with external excipients. Preferred embodiments are reflected by Examples 2 to 6.

[0144] According to these embodiments, the solid dispersion preferably essentially consists of- the Vericiguat, physiologically acceptable salt and / or solvate thereof and- the polymer matrix (which preferably essentially consists of copovidone, PCA-PVA-PEG, or PVAL), but preferably does not contain any additional excipients.

[0145] According to these embodiments, additional excipients are preferably all present outside the solid dispersion in an external phase. Preferably, said external phase comprises at least one, preferably all of the following:- one or more diluents; preferably lactose and / or microcrystalline cellulose;- one or more disintegrants; preferably sodium croscarmellose;- one or more surfactants; preferably sodium lauryl sulfate;- one or more dispersants; preferably colloidal silicon dioxide; and- one or more lubricants; preferably magnesium stearate.

[0146] In other preferred embodiments, the pharmaceutical dosage form according to the invention comprises the solid dispersion as a melt granulate as intragranular phase that is blended with external excipients forming an extragranular phase. Preferred embodiments are reflected by Examples 7 to 11.

[0147] According to these embodiments, the solid dispersion forms an intragranular phase preferably comprising- the Vericiguat, physiologically acceptable salt and / or solvate thereof,- a polymer matrix which preferably comprises polyethylene glycol in combination with poloxamer, or polyethylene glycol in combination with hydroxypropyl cellulose; and at least one, preferably all of the following:- one or more diluents; preferably microcrystalline cellulose in combination with lactose, or microcrystalline cellulose in combination with mannitol; and- one or more surfactants; preferably sodium lauryl sulfate.

[0148] According to these embodiments, additional excipients are preferably present in an extragranu- lar phase. Preferably, said extragranular phase comprises at least one, preferably all of the following:- one or more diluents; preferably microcrystalline cellulose;- one or more disintegrants; preferably sodium croscarmellose; and- one or more lubricants; preferably magnesium stearate.

[0149] In further preferred embodiments, the pharmaceutical dosage form according to the invention comprises the solid dispersion as a hot melt extrudate as component of an intragranular phase prepared by wet granulation (preferably using ethanol as granulation liquid) together with additional intragranular excipients, wherein said intragranular phase is then blended with external excipients forming an extra- granular phase. Preferred embodiments are reflected by Examples 12 to 14.

[0150] According to these embodiments, besides the solid dispersion, the intragranular phase preferably comprises at least one, preferably all of the following:- one or more diluents; preferably microcrystalline cellulose in combination with lactose;- one or more disintegrants; preferably sodium croscarmellose; and- one or more binders; preferably hydroxypropyl cellulose.

[0151] According to these embodiments, additional excipients are preferably present in an extragranular phase. Preferably, said extragranular phase comprises at least one, preferably all of the following:- one or more diluents; preferably microcrystalline cellulose in combination with lactose;- one or more disintegrants; preferably sodium croscarmellose;- one or more surfactants; preferably sodium lauryl sulfate;- one or more dispersants; preferably colloidal silicon dioxide; and- one or more lubricants; preferably magnesium stearate.

[0152] In still further preferred embodiments, the pharmaceutical dosage form according to the invention comprises the solid dispersion as a hot melt extrudate as component of an intragranular phase prepared by melt granulation together with additional intragranular excipients, wherein said intragranularphase is then blended with external excipients forming an extragranular phase. Preferred embodiments are reflected by Examples 15 to 17.

[0153] According to these embodiments, besides the solid dispersion, the intragranular phase preferably comprises at least one, preferably all of the following:- one or more diluents; preferably microcrystalline cellulose in combination with mannitol;- one or more surfactants; preferably sodium lauryl sulfate; and- a combination of polyethylene glycol and poloxamer.

[0154] According to these embodiments, additional excipients are preferably present in an extragranular phase. Preferably, said extragranular phase comprises at least one, preferably all of the following:- one or more diluents; preferably microcrystalline cellulose;- one or more disintegrants; preferably sodium croscarmellose;- one or more surfactants; preferably sodium lauryl sulfate;- one or more dispersants; preferably colloidal silicon dioxide; and- one or more lubricants; preferably magnesium stearate.

[0155] In yet further preferred embodiments, the pharmaceutical dosage form according to the invention comprises the solid dispersion as a hot melt extrudate as component of an intragranular phase prepared by dry granulation together with additional intragranular excipients, wherein said intragranular phase is then blended with external excipients forming an extragranular phase. Preferred embodiments are reflected by Examples 18 to 20.

[0156] According to these embodiments, besides the solid dispersion, the intragranular phase preferably comprises at least one, preferably all of the following:- one or more diluents; preferably microcrystalline cellulose in combination with lactose;- one or more disintegrants; preferably sodium croscarmellose;- one or more surfactants; preferably sodium lauryl sulfate; and- one or more lubricants; preferably magnesium stearate.

[0157] According to these embodiments, additional excipients are preferably present in an extragranular phase. Preferably, said extragranular phase comprises at least one, preferably all of the following:- one or more disintegrants; preferably sodium croscarmellose; and- one or more lubricants; preferably magnesium stearate.

[0158] Another aspect of the invention relates to a solid dispersion according to the invention or a pharmaceutical dosage form according to the invention for use in the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event requiring IV therapy. In preferred embodiments, the solid dispersion according to the invention or the pharmaceutical dosage form according to the invention are for use in the treatment and / or prophylaxis of heart failure, worsening chronic heart failure, worsening chronic heart failure withreduced ejection fraction, worsening chronic heart failure with preserved ejection fraction, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, cognitive disorders, kidney failure, thromboembolic disorders, fibrotic disorders and / or arteriosclerosis.

[0159] Another aspect of the invention relates to a process for preparing a solid dispersion according to the invention as described above.

[0160] Preferably, said process comprises or consists of extrusion, preferably melt extrusion, more preferably hot melt extrusion (HME).

[0161] Melt extrusion, especially HME, are procedures known to the skilled person. Hot melt extrusion comprises moving of material at a temperature of preferably at least 110°C, more preferably at least 190°C, still more preferably at least 210°C, through a nozzle.

[0162] Melt extrusion, in particular HME, can be carried out in an extruder which can comprise a filling device and a shaft ensuring movement of the material to be extruded through a heated section and an extruding device, e.g. an extruding head.

[0163] The time period that the material to be extruded remains in the extruder (residence time) can be e.g. less then 9 minutes, especially 6 to 8 minutes.

[0164] Preferably, HME comprises pumping to the mixture to be subjected to HME at elevated temperature, preferably of at least 180°C, more preferably at least 210°C, through a heated barrel to obtain an extrudate. An extruder can consist of one or two rotating screws inside a barrel that is usually cylindrical.

[0165] The hot melt extruded solid dispersion may be obtained as granules of any shape, especially particles of any shape, including but not limited to the shape of granules obtainable by wet granulation, dry granulation, melt granulation, especially hot-melt extrusion, optionally in combination with milling and / or sieving procedures.

[0166] Preferably, the process for the preparation of a solid dispersion according to the invention comprises the steps of(A) preparing a mixture comprising or essentially consisting of- Vericiguat or a physiologically acceptable salt and / or solvate thereof;- one or more polymers for the polymer matrix; preferably selected from (i) polyvinyl alcohol (PVAL); (ii) copolymers of vinylpyrrolidone with vinyl acetate (copovidone), and polyvinylpyrrolidone (povidone, PVP); (iii) poly(meth)acrylates and polyalkyl(meth)acrylates; preferably poly (methyl acrylate) (PMA); (iv) polyvinyl caprolactam-poly vinyl acetate-poly ethylene glycol graft copolymer; (v) cellulose, cellulose ethers, and cellulose esters; preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl methyl cellulose acetatesuccinate; (vi) polyethylene glycol (PEG), polyethylene oxide (PEO), and block copolymers of ethylene oxide and propylene oxide (poloxamers); and mixtures thereof; and- optionally, one or more additional excipients;(B) subjecting the mixture obtained from step (A) to extrusion, preferably melt extrusion, more preferably hot melt extrusion; preferably wherein the hot melt extrusion is carried out at a temperature of at least 180°C; and(C) optionally, comminuting the extrudate obtained in step (B) to obtain a comminuted extrudate, and optionally sieving and / or milling the comminuted extrudate.

[0167] The mixing of Vericiguat or a physiologically acceptable salt and / or solvate thereof and one or more matrix polymers and optionally one or more additional excipients may be effected in conventional devices used for mixing of powder or powders, e.g. motionless (passive) mixers, fluidized bed, diffusion, biconic diffusion, uni- or biconic, tubular, cubic, planetary, Y-, V-shaped or high-shear mixers.

[0168] The same equipment may be used in subsequent preparation of the pharmaceutical dosage form, e.g. for compression mixture with the prior step of a granulate preparation by granulation, e.g. wet granulation, melt granulation or dry granulation.

[0169] Without wishing to be bound by theory, it appears that the combination of Vericiguat or a physiologically acceptable salt and / or solvate thereof and a polymer matrix and processing by hot melt extrusion contributes to the formation of amorphous Vericiguat in the extrudate. In particular, Vericiguat forms different from amorphous Vericiguat can be transformed during hot melt extrusion into amorphous Vericiguat.

[0170] Step (C) of comminuting the extrudate may be carried out according to conventional milling methods or micronization methods. For example, comminuting can be milling or milling and sieving. Comminuting can be e.g. carried out in an air jet mill, a hammer and screen mill, a fine impact mill, a ball mill or a vibrator mill or combinations thereof. Micronization can be effected by known methods using an ultrasonic disintegrant, e.g. of the BRANSON Sonifier type, or by stirring a suspension with a high speed agitator, for example with a stirrer of the HOMOREX type.

[0171] Another aspect of the invention relates to an extrudate obtained or obtainable by step (B) of the process for the preparation of a solid dispersion according to the invention as described above.

[0172] Another aspect of the invention relates to a comminuted extrudate obtained or obtainable by step (C) of the process for the preparation of a solid dispersion according to the invention as described above.

[0173] The extrudate, in particular the hot-melt extrudate, is obtainable from a process comprising extrusion, in particular hot melt extrusion, carried out at a temperature of at least 180°C, especially at a temperature in the range from 200°C to 240°C.

[0174] Another aspect of the invention relates to a process for the preparation of a pharmaceutical dosage form according to the invention as described above.

[0175] Preferably, the process for the preparation of a pharmaceutical dosage form according to the invention comprises the process for the preparation of a solid dispersion according to the invention as described above (steps (A), (B) and optionally (C)).

[0176] Preferably, the process for preparing a pharmaceutical dosage form according to the invention comprises the steps of(A) preparing a mixture comprising or essentially consisting of- Vericiguat or a physiologically acceptable salt and / or solvate thereof;- one or more polymers for the polymer matrix; preferably selected from (i) polyvinyl alcohol (PVAL); (ii) copolymers of vinylpyrrolidone with vinyl acetate (copovidone), and polyvinylpyrrolidone (povidone, PVP); (iii) poly(meth)acrylates and polyalkyl(meth)acrylates; preferably poly (methyl acrylate) (PMA); (iv) polyvinyl caprolactam-poly vinyl acetate-poly ethylene glycol graft copolymer; (v) cellulose, cellulose ethers, and cellulose esters; preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl methyl cellulose acetate succinate; (vi) polyethylene glycol (PEG), polyethylene oxide (PEO), and block copolymers of ethylene oxide and propylene oxide (poloxamers); and mixtures thereof; and- optionally, one or more additional excipients;(B) subjecting the mixture obtained from step (A) to extrusion, preferably melt extrusion, more preferably hot melt extrusion; preferably wherein the hot melt extrusion is carried out at a temperature of at least 180°C;(C) optionally, comminuting the extrudate obtained in step (B) to obtain a comminuted extrudate, and optionally sieving and / or milling the comminuted extrudate;(D) optionally, converting the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) to form a granulate;(E) optionally, mixing the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) or the granulate obtained in step (D) with at least one excipient to obtain a compression mixture;(F) optionally, compressing the compression mixture to obtain a comprimate, in particular tablet; and(G) optionally, applying a coating onto the comprimate.

[0177] In preferred embodiments, step (D) of converting the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) to form a granulate can comprise or essentially consist of the sub-steps:(di) combining the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) with at least one excipient to obtain an extrudate-containing mixture;(d2) compacting the extrudate-containing mixture to obtain a compacted extrudate-containing mixture, especially a granulate, e.g. in the form of a ribbon; and(ds) optionally, further comminuting the compacted extrudate-containing mixture, especially the granulate, obtained in sub-step (ds).

[0178] In other preferred embodiments, step (D) of converting the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) to form a granulate can comprise or essentially consist of the sub-steps:(di) combining the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) with at least one excipient to obtain a extrudate-containing mixture; and(d4) subjecting the extrudate-containing mixture to wet granulation, e.g. using a granulation liquid comprising or consisting of a solvent selected from methanol, ethanol, propanol, water, and mixtures thereof.

[0179] For drying of the granulate prepared by wet granulation, conventional drying devices such as a fluid-bed dryer or drying chambers can be used.

[0180] In further preferred embodiments, step (D) of converting the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) to form a granulate can comprise or essentially consist of the sub-steps:(di) combining the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) with at least one excipient to obtain a extrudate-containing mixture; and(ds) subjecting the extrudate-containing mixture to melt granulation, e.g. using a high shear mixer.

[0181] In still further preferred embodiments, step (D) of converting the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) to form a granulate can comprise or essentially consist of the sub-steps:(di) combining the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) with at least one excipient to obtain a extrudate-containing mixture; and(de) subjecting the extrudate-containing mixture to dry granulation, e.g. using slugging or roller compaction.

[0182] Compaction may be carried out using a slugging or roller compaction technique. The preferred method of dry granulation can be roller compaction. Roller compaction is known in the art. Roller compaction (essentially) utilizes two rollers which roll towards each other. A hydraulic ram forces one of the rollers against the other roller to exert a compacting force against the ground particles fed into theroller compactor via a screw conveyor system. A compaction force of minimal 10 kN can be used. The comprimate can be in the form of a ribbon, e.g. in segments, depending on the surface of the rollers. The comprimate may be milled and / or sieved to produce the granulate.

[0183] Granulation can be performed using granulator(s) (especially state of the art granulator(s)) such as high shear granulator, low shear granulator, or a fluid bed granulator.

[0184] It is particularly preferred that the pharmaceutical dosage form according to the invention comprises granulate (i.e. intragranular phase) and an extragranular phase. Intra- and extragranular phase together comprise a compression mixture. The compression mixture can comprise or can consist of intragranular and extragranular phase.

[0185] In optional step (G), conventional equipment can be used for applying a fdm coating, such as a Wurster coating system or conventional perforated or non-perforated coating pans for use in pharmaceutical industry.

[0186] The following examples further illustrate the invention but are not to be construed as limiting its scope:Example 1 to DSC preparation of solid dispersion:

[0187] To optimize the preparation of solid dispersions using hot melt extrusion (HME), the melting behavior of the active ingredient and excipients in different ratios was investigated. This preliminary assessment, conducted through differential scanning calorimetry (DSC) studies, provided insights into the feasibility of the solid dispersion preparation.

[0188] In the synthesis of solid dispersions, a high-precision DSC 1 Mettler Toledo Differential Scanning Calorimeter was utilized, operated under a constant nitrogen gas flow of 40 mL / min to maintain an inert atmosphere. The drug and polymer matrix are weighed in a 1:9 or 1:5 ratio, the sample was then placed in a 40 pL aluminum crucible, which was then sealed with a perforated aluminum lid. The sample was subjected to a controlled thermal analysis, beginning with a heating cycle where the temperature was increased from 30°C to 220-250°C at a rate of lOK / min. Upon reaching final temperature in range of 220-250°C, an isothermal hold was applied for 5 minutes to ensure the complete amalgamation of the sample components. This was followed by a rapid cooling phase, where the temperature was lowered from 220-250°C to 20°C at a rate of 20K / min.

[0189] To confirm the formation and stability of the sample, a second heating cycle was initiated, raising the temperature from 20°C to 260°C at lOK / min. This step was crucial to analyze the thermal behavior and to verify the absence of any crystalline attributes in the sample, indicating a successful transition to an amorphous state as well as measuring glass transition temperature of the prepared sample.n.d.: not determined

[0190] Upon examination of the experimental data, a surprising observation has been made regarding the formation of amorphous solid dispersions using various polymers. Despite subjecting Vericiguat to heating at high temperatures ranging from 230°C to 250°C, followed by an isothermal hold for 5 minutes, it has been found that polymers such as hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) do not facilitate the formation of completely amorphous solid dispersions. This was evidenced by the DSC thermograms, which indicated that a significant proportion of Vericiguat remained in a crystalline form when these polymers were used.

[0191] Figure 1 (Ex 1-14) and Figure 2 (Ex 1-12) show melting of crystalline Vericiguat upon second heating at temperatures in range from 240 - 260°C.

[0192] Conversely, for polymers like polyvinyl alcohol (PVAL), copovidone, poly(methyl acrylate) (PMA), and Soluplus®, the results demonstrate the successful attainment of fully amorphous solid solutions under the same conditions of heating to temperatures between 230°C and 250°C and applying an isothermal hold for 5 minutes. This distinction underscores the differential efficacy of various polymers in the formation of amorphous solid dispersions, particularly in the context of hot melting process.

[0193] The specific observations from the table are as follows:

[0194] Samples 1-3, 1-5, 1-8, 1-12, 1-14, and 1-17 with HPMC, PVP, and HPMC-AS exhibited only partial transition to an amorphous state.

[0195] Conversely, samples 1-4, 1-6, 1-7, 1-9, 1-13, 1-15, 1-16, and 1-18 using PVAL, copovidone, PMA, and PCA-PVA-PEG achieved a pure amorphous state.

[0196] The compounds of the present invention were characterized by their powder X-ray diffraction patterns (obtained using a PANalytical X'Pert PRO diffractometer using CuKa radiation with a wavelength of 1.541874 A).

[0197] Figure 1: DSC of Vericiguat : Povidone K30, first and second heating in ratio 1:9 according to Ex. 1-14

[0198] Figure 2: DSC of Vericiguat : HPMC 6CP, first and second heating, ratio 1:9 according to Ex. 1-12

[0199] Figure 3: DSC of Vericiguat : PCA-PVA-PEG, first and second heating, ratio 1:9, DSC thermogram according to Ex. 1-18

[0200] Figure 4: DSC of Vericiguat : PVAL 4-88, first and second heating, ratio 1:9 according to Ex. 1-15

[0201] Figure 5: DSC of Vericiguat : Copovidone, first and second heating, ratio 1:9 according to Ex 1-13

[0202] Figure 6: XRPD of solid dispersion after thermoplastic granulation of vericiguat and PEG according to Ex 9

[0203] Figure 7: XRPD of Vericiguat : Soluplus®, after second heating ratio 1:9 according to Ex. 1-18

[0204] Figure 8: XRPD of Vericiguat : Copovidone, after second heating ratio 1:9 according to Ex 1- 13Examples 2 to 6 - hot-melt extrudate blended with external excipients:

[0205] The size of laboratory experiments was 5.000 tablets.

[0206] The table here below summarizes the ingredients used for preparing the pharmaceutical compositions according to Examples 2 to 6:

[0207] Vericiguat was mixed with polymer at the investigated ratio in a suitable mixer. A twin screw extruder was used to extrude the mixture at the desired temperature and feed rate. A standard configuration of the screws was used and the speed was set to 60 to 120 rpm. The hot-melt extrudate was extruded through a die with 1.5 to 3.0 mm in diameter, cooled on a cooling belt and grinded to smaller size. The grinded extrudate was then sieved and subjected to stability testing under controlled conditions of 40 to 50°C and 65 to 75 % RH.

[0208] Hot-melt extrudate of Vericiguat was prepared by using polymers, which formed pure amorphous form of Vericiguat on DSC.

[0209] A tableting mixture was prepared by first mixing the sieved extrudate (prepared as per example 2) with surfactant, diluent or mixture of diluents, disintegrant, and glidant. Then magnesium stearate was added. Tableting was performed on a rotary tablet press. Tablet cores were then coated using standard coating procedure until the desired mass gain was achieved.Examples 7 to 11 - melt granulation (thermoplastic granulation):

[0210] The size of laboratory experiments was 8.000 tablets.

[0211] The table here below summarizes the ingredients used for preparing the pharmaceutical compositions according to Examples 7 to 11:IG intragranular; EG extragranular

[0212] A granulate was prepared by first mixing lactose monohydrate or mannitol; microcrystalline cellulose, macrogol; poloxamer or HPC; and sodium lauryl sulfate. Then the powder mixture was filled into a high-shear granulator and then thermoplastically granulated at a heated jacket temperature of 50 to 80°C. The granulate was than sieved through a sieve and cooled down to below 30°C in a fluid-bed dryer. After cooling was finished, the granulate was again sieved through a sieve with openings of about 0.5 to 1.9 mm.

[0213] A tableting mixture was prepared by mixing the sieved extrudate with a mixture of diluent and disintegrant. Then magnesium stearate was added. Tableting was performed on a rotary tablet press. Tablet cores were then coated using standard coating procedure until the desired mass gain was achieved.Examples 12 to 14 - wet granulation of extrudate:

[0214] The size of laboratory experiments was 5.000 tablets.

[0215] The table here below summarizes the ingredients used for preparing the pharmaceutical compositions of Examples 12 to 14:IG intragranular; EG extragranular

[0216] A granulating liquid was prepared by dissolving hydroxypropyl cellulose (HPC) in a sufficient amount of ethanol 96 %. A granulating mixture was prepared by mixing the sieved extrudate (prepared as per Example 1) with lactose monohydrate, microcrystalline cellulose type 101 and sodium croscar- mellose. The granulating mixture was then put into a 10 L high-shear mixer where it was first dry blended for 3 min. The granulating liquid was then sprayed onto the mixture until sufficient agglomeration was obtained. After kneading of the granulate for 1 min, the granulate was dried in a fluid-bed at an inlet air temperature of at least 35°C until less than 4 % loss on drying (105°C, 5 min) was achieved. The dried granulate was then sieved through a mesh with screen size 0.8 mm.

[0217] A tableting mixture was prepared by first mixing the sieved extrudate (prepared as per example 1) with surfactant, diluent or mixture of diluents, disintegrant, and glidant. Then magnesium stearate was added. Tableting was performed on a rotary tablet press. Tablet cores were then coated using standard coating procedure until the desired mass gain was achieved.Examples 15 to 17 - thermoplastic granulation of extrudate:

[0218] The size of laboratory experiments was 5.000 tablets.

[0219] The table here below summarizes the ingredients used for preparing the pharmaceutical compositions according to Examples 15 to 17:IG intragranular; EG extragranular

[0220] A triturate was prepared by first mixing the sieved extrudate (prepared as per Example 1) with sodium lauryl sulfate and microcrystalline cellulose type 101. Then mannitol, polyethylene glycol and poloxamer were added and the mixture was sieved through a mesh with screen size 0.6 mm. The granulating mixture was then put into a 10 L high-shear mixer with temperature regulation. During the mixing, the heating was applied until sufficient agglomeration was obtained. The granulate was cooled on a tray and sieved through a mesh with screen size 0.8 mm.

[0221] A tableting mixture was prepared by first mixing the granulate with sodium croscarmellose and colloidal silicon dioxide (Aerosil) and then magnesium stearate was added. Tableting was performed on a rotary tablet press. Tablet cores were then coated using standard coating procedure until the desired mass gain was achieved.Examples 18 to 20 - dry compaction of extrudate:

[0222] The size of laboratory experiments was 5.000 tablets.

[0223] The table here below summarizes the ingredients used for preparing the pharmaceutical compositions according to Examples 18 to 20:IG intragranular; EG extragranular

[0224] A compacting mixture was prepared by mixing the sieved extrudate (prepared as per Example 2-6) with lactose monohydrate, microcrystalline cellulose type 802, sodium croscarmellose and sodium lauryl sulfate and then magnesium stearate was added. The compacting mixture was compressed on a roller compactor with a pressure sufficient to obtain ribbons with appropriate density. Ribbons were then milled through a mesh with screen size 18.

[0225] A tableting mixture was prepared by first mixing the granulate with sodium croscarmellose and then magnesium stearate was added. Tableting was performed on a rotary tablet press. Tablet cores were then coated using standard coating procedure until the desired mass gain was achieved.

Claims

Patent claims:

1. A solid dispersion comprising or essentially consisting of(i) Vericiguat or a physiologically acceptable salt and / or solvate thereof and(ii) a polymer matrix.

2. The solid dispersion according to claim 1, wherein the polymer matrix comprises or essentially consists of a polymer selected from(i) polyvinyl alcohol (PVAL);(ii) copolymers of vinylpyrrolidone with vinyl acetate (copovidone), and polyvinylpyrrolidone (povidone, PVP);(iii) poly(meth)acrylates and polyalkyl(meth)acrylates; preferably poly(methyl acrylate) (PMA);(iv) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;(v) cellulose, cellulose ethers, and cellulose esters; preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl methyl cellulose acetate succinate;(vi) polyethylene glycol (PEG), polyethylene oxide (PEO), and block copolymers of ethylene oxide and propylene oxide (poloxamers); and any mixtures thereof.

3. The solid dispersion according to claim 1 or 2, wherein the polymer matrix comprises or essentially consists of a polymer selected from polyvinyl alcohol (PVAL).

4. The solid dispersion according to any of the preceding claims, wherein the polymer matrix comprises or essentially consists of a polymer selected from copolymers of vinylpyrrolidone with vinyl acetate (copovidone), and polyvinylpyrrolidone (povidone, PVP).

5. The solid dispersion according to any of the preceding claims, wherein the polymer matrix comprises or essentially consists of a polymer selected from poly(meth)acrylates and poly- alkyl(meth)acrylates; preferably poly(methyl acrylate) (PMA).

6. The solid dispersion according to any of the preceding claims, wherein the polymer matrix comprises or essentially consists of a polymer selected from polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer.

7. The solid dispersion according to any of the preceding claims, wherein the polymer matrix comprises or essentially consists of a polymer selected from cellulose, cellulose ethers and cellulose esters; preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl methyl cellulose acetate succinate.

8. The solid dispersion according to any of the preceding claims, wherein the polymer matrix comprises or essentially consists of a polymer selected from polyethylene glycol (PEG), polyethylene oxide (PEO), and block copolymers of ethylene oxide and propylene oxide (poloxamers).

9. The solid dispersion according to any of the preceding claims, wherein the polymer matrix essentially consists of a single polymer.

10. The solid dispersion according to any of the preceding claims, wherein the weight ratio of the Vericiguat or physiologically acceptable salt and / or solvate thereof and the polymer matrix is within the range of from 1:2 to 1: 13, preferably from 1:3 to 1: 12.

11. The solid dispersion according to any of the preceding claims, wherein the weight ratio of the Vericiguat or physiologically acceptable salt and / or solvate thereof and the polymer matrix is within the range of from 1:4 to 1:6.

12. The solid dispersion according to any of claims 1 to 9, wherein the weight ratio of the Vericiguat or physiologically acceptable salt and / or solvate thereof and the polymer matrix is within the range of from 1:8 to 1: 10.

13. The solid dispersion according to any of the preceding claims, which is an extrudate; preferably a melt extrudate; more preferably a hot melt extrudate.

14. The solid dispersion according to any of claims 1 to 11, which is a granulate; preferably a melt granulate.

15. The solid dispersion according to any of the preceding claims, which shows essentially no reflection in an XRPD spectrum in a 20 range of from 5 to 30 using Cti?,, radiation at 23°C.

16. The solid dispersion according to any of the preceding claims, which shows essentially no thermal event during DSC analysis in a temperature range of from 20 to 250°C.

17. The solid dispersion according to any of the preceding claims, which is an amorphous solid dispersion (ASD).

18. The solid dispersion according to claim 17, which comprises or essentially consists of amorphous Vericiguat or physiologically acceptable salt and / or solvate thereof and amorphous polymer matrix.

19. The solid dispersion according to claim 17, which comprises or essentially consists of amorphous Vericiguat or physiologically acceptable salt and / or solvate thereof, amorphous polymer matrix, and one or more additional excipients.

20. The solid dispersion according to claim 19, which is a melt granulate.

21. The solid dispersion according to claim 19 or 20, wherein the polymer matrix comprises or essentially consists of macrogol, poloxamer, hydroxypropyl cellulose or a combination thereof; preferably macrogol in combination with poloxamer or with hydroxypropyl cellulose.

22. The solid dispersion according to any of claims 19 to 21, wherein the one or more additional excipients are selected from diluents, surfactants, and binders.

23. The solid dispersion according to any of claims 19 to 22, wherein the one or more additional excipients comprise one or more diluents; preferably microcrystalline cellulose, lactose, mannitol, or a combination thereof; more preferably microcrystalline cellulose in combination with lactose or with mannitol.

24. The solid dispersion according to any of claims 19 to 22, wherein the one or more additional excipients comprise a surfactant; preferably an anionic surfactant; more preferably sodium lauryl sulfate (SLS).

25. The solid dispersion according to any of the preceding claims, which comprises amorphous Vericiguat or physiologically acceptable salt and / or solvate thereof.

26. The solid dispersion according to any of the preceding claims, which comprises amorphous Vericiguat or physiologically acceptable salt and / or solvate thereof in combination with Vericiguat modification I according to WO 2013 / 076168.

27. The solid dispersion according to any of the preceding claims, wherein at least 80 wt.-% of the total content of the Vericiguat or physiologically acceptable salt and / or solvate thereof is amorphous; preferably at least 85 wt.-%; more preferably at least 90 wt.-%; still more preferably at least 95 wt.-%; yet more preferably at least 96 wt.-%, even more preferably at least 97 wt.-%. most preferably at least 98 wt.-%, and in particular at least 99 wt.-%.

28. The solid dispersion according to any of the preceding claims, wherein the Vericiguat or physiologically acceptable salt and / or solvate thereof is homogeneously dispersed in the matrix polymer.

29. The solid dispersion according to any of the preceding claims, wherein the Vericiguat or physiologically acceptable salt and / or solvate thereof is molecularly dispersed in the matrix polymer.

30. The solid dispersion according to any of the preceding claims, wherein Vericiguat is present in the non-salt form.

31. The solid dispersion according to any of the preceding claims, wherein Vericiguat is present as an ansolvate.

32. A pharmaceutical dosage form for oral administration comprising the solid dispersion according to any of the preceding claims.

33. The pharmaceutical dosage form according to claim 32, which is selected from capsules and sachets filled with powder or granules.

34. The pharmaceutical dosage form according to claim 32, which is selected from comprimates; preferably tablets.

35. The pharmaceutical dosage form according to claim 34, which is a tablet.

36. The pharmaceutical dosage form according to any of claims 34 or 35, which is film coated.

37. The pharmaceutical dosage form according to claim 36, which is coated with a functional film coating or a non-functional film coating.

38. The pharmaceutical dosage form according to any of claims 32 to 37, which additionally comprises one or more excipients independently of one another selected from diluents, binders, dis- integrants, surfactants, dispersants and lubricants.

39. The pharmaceutical dosage form according to any of claims 32 to 38, which comprises one or more diluents independently of one another selected from polysaccharides, oligosaccharides, disaccharides, monosaccharides, compressible sugars, sugar alcohols, inorganic salts and mixtures thereof.

40. The pharmaceutical dosage form according to claim 39, wherein the one or more diluents are selected from lactose, microcrystalline cellulose, mannitol, and mixtures thereof.

41. The pharmaceutical dosage form according to any of claims 32 to 40, which comprises one or more binders independently of one another selected from povidone, copovidone, cellulose esters, polyvinyl alcohol, starch, dextrins, gum arabic, pullulan poly(meth)acrylates, and mixtures thereof.

42. The pharmaceutical dosage form according to claim 41, wherein the one or more binders comprise hydroxypropyl cellulose.

43. The pharmaceutical dosage form according to any of claims 32 to 42, which comprises one or more disintegrants independently of one another selected from crospovidone, starch, maize starch, pregelatinized starch, sodium starch gly collate, modified starch, hydroxypropyl starch, carboxymethyl starch, sodium and / or calcium salts of carboxymethyl cellulose, sodium and / or calcium salts of cross-linked carboxymethylcellulose, polacrilin potassium, alginic acid, alginates, polyacrylates, docusate sodium, methylcellulose, gums, chitosan, and mixtures thereof.

44. The pharmaceutical dosage form according to claim 43, wherein the one or more disintegrants comprise sodium croscarmellose.

45. The pharmaceutical dosage form according to any of claims 32 to 44, which comprises one or more surfactants independently of one another selected from cationic surfactants, anionic surfactants, zwitterionic surfactants, nonionic surfactants, and mixtures thereof.

46. The pharmaceutical dosage form according to claim 45, wherein the one or more surfactants comprise sodium lauryl sulfate.

47. The pharmaceutical dosage form according to any of claims 32 to 46, which comprises one or more dispersants independently of one another selected from silica and talcum; preferably colloidal silicon dioxide.

48. The pharmaceutical dosage form according to any of claims 32 to 43, which comprises one or more lubricants independently of one another selected from fatty acids, fatty acid esters, metal salts of fatty acids, hydrogenated vegetable oil, hydrogenated castor oil, waxes, boric acid, sodium stearyl fumarate, macrogols, sugar esters, and mixtures thereof.

49. The pharmaceutical dosage form according to claim 48, wherein the one or more lubricants comprise magnesium stearate.

50. The pharmaceutical dosage form according to any of claims 32 to 49, which is granulated.

51. The pharmaceutical dosage form according to any of claims 32 to 50, which comprises an intra- granular phase and an extragranular phase.

52. The pharmaceutical dosage form according to claim 51, wherein the intragranular phase comprises or essentially consists of the solid dispersion.

53. The pharmaceutical dosage form according to any of claims 32 to 52, which is dry granulated.

54. The pharmaceutical dosage form according to any of claims 32 to 52, which is wet granulated.

55. The pharmaceutical dosage form according to any of claims 32 to 52, which is melt granulated (thermoplastically granulated).

56. The pharmaceutical dosage form according to any of claims 32 to 55, wherein Vericiguat is the sole pharmacologically active ingredient that is contained in the solid dispersion and pharmaceutical dosage form.

57. A process for the preparation of a solid dispersion according to any of claims 1 to 31 comprising the steps of(A) preparing a mixture comprising or essentially consisting of(a) Vericiguat or a physiologically acceptable salt and / or solvate thereof;(b) one or more polymers for the polymer matrix; preferably selected from (i) polyvinyl alcohol (PVAL); (ii) copolymers of vinylpyrrolidone with vinyl acetate (copovidone), and polyvinylpyrrolidone (povidone, PVP); (iii) poly(meth)acrylates and poly- alkyl(meth)acrylates; preferably poly(methyl acrylate) (PMA); (iv) polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (v) cellulose, cellulose ethers, and cellulose esters; preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl methyl cellulose acetate succinate; (vi) polyethylene glycol (PEG), polyethylene oxide (PEO), and block copolymers of ethylene oxide and propylene oxide (poloxamers); and mixtures thereof; and(c) optionally, one or more additional excipients;(B) subjecting the mixture obtained from step (A) to extrusion, preferably melt extrusion, more preferably hot melt extrusion; preferably wherein the hot melt extrusion is carried out at a temperature of at least 180°C; and(C) optionally, comminuting the extrudate obtained in step (B) to obtain a comminuted extrudate, and optionally sieving and / or milling the comminuted extrudate.

58. A solid dispersion obtainable by the process according to claim 57.

59. A process for the preparation of a pharmaceutical dosage form according to any of claims 32 to 56 comprising the steps of one or more of the steps of(A) preparing a mixture comprising or essentially consisting of(a) Vericiguat or a physiologically acceptable salt and / or solvate thereof;(b) one or more polymers for the polymer matrix; preferably selected from (i) polyvinyl alcohol (PVAL); (ii) copolymers of vinylpyrrolidone with vinyl acetate (copovidone), and polyvinylpyrrolidone (povidone, PVP); (iii) poly(meth)acrylates and poly- alkyl(meth)acrylates; preferably poly(methyl acrylate) (PMA); (iv) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (v) cellulose, cellulose ethers, and cellulose esters; preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl methyl cellulose acetate succinate; (vi) polyethylene glycol (PEG), polyethylene oxide (PEG), and block copolymers of ethylene oxide and propylene oxide (poloxamers); and mixtures thereof; and(c) optionally, one or more additional excipients;(B) subjecting the mixture obtained from step (A) to extrusion, preferably melt extrusion, more preferably hot melt extrusion; preferably wherein the hot melt extrusion is carried out at a temperature of at least 180°C;(C) optionally, comminuting the extrudate obtained in step (B) to obtain a comminuted extrudate, and optionally sieving and / or milling the comminuted extrudate;(D) optionally, converting the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) to form a granulate;(E) optionally, mixing the extrudate obtained in step (B) or the comminuted extrudate obtained in step (C) or the granulate obtained in step (D) with at least one excipient to obtain a compression mixture;(F) optionally, compressing the compression mixture to obtain a comprimate, in particular tablet; and(G) optionally, applying a coating onto the comprimate.

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