Solid dispersions comprising amorphous pimobendan and one or more stabilizing polymers

Abstract

The present invention relates to novel solid dispersions comprising amorphous pimobendan and one or more stabilizing polymers, as well as to processes for their preparation and to corresponding pharmaceutical compositions.

Description

[Technical Field]

[0001] Incorporation by Reference All references cited herein are incorporated by reference in their entirety. The present invention relates to the field of medicine, especially veterinary medicine. In particular, the present invention relates to a novel solid dispersion comprising amorphous pimobendan and one or more stabilizing polymers, as well as a process for its preparation and the corresponding pharmaceutical compositions. [Background technology]

[0002] Pimobendan (4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)-5-methyl-3(2H))-pyridazinone) is a benzimidazole pyridazone derivative and is described in EP 0008391 as a substance with cardiotonic, hypotensive and antithrombotic effects. Pimobendan is known to exhibit polymorphism, with more than 10 potential polymorphs and solvated polymorphs reported for chiral pimobendan (Rekis et al., 2018). EP 0439030 discloses that pimobendan has low solubility in aqueous environments, characterized by a high pH dependency. Depending on the buffer system used, approximately 100–300 mg / L of pimobendan dissolves at pH 1–3, but only about 1 mg / L of pimobendan dissolves at pH 5. In humans, this phenomenon results in highly variable, often too low, blood concentrations. These poor absorption characteristics are explained by the highly pH-dependent solubility of pimobendan in aqueous media and the variable pH conditions in the gastrointestinal tract of the test subjects. According to this patent publication, pimobendan's low solubility and high pH dependency can be overcome by using an essentially dry mixture of powdered pimobendan and powdered citric acid, with up to about 1 part by weight of pimobendan per at least about 5 parts by weight of citric acid and a pharmaceutically active carrier, which is then filled into capsules or compressed into tablets for oral administration. It is said that large fluctuations in blood concentration are prevented by the formation of acidic microspheres around the pimobendan particles caused by the dissolution rate of citric acid, which are always acidic and ensure a reliable and practically pH-independent dissolution and absorption of pimobendan.

[0003] WO 2005 / 084647 relates to a novel solid formulation containing pimobendan uniformly dispersed in a polyacid selected from the group consisting of citric acid, acetic acid, maleic acid, tartaric acid, or anhydride thereof, and a flavoring substance. According to the publication, the large amount of citric acid and its sour taste are not readily accepted by most animals. Therefore, these formulations must be force-fed to the animals or mixed with food before administration. According to the patent publication, these difficulties can be overcome by using the novel formulation, preferably in tablet form. Most preferred are tablets containing 1.25 mg, 2.5 mg, 5 mg, or 10 mg of pimobendan, more preferably 50 mg / g of citric acid, artificial beef flavor, and pharmaceutically acceptable excipients. WO2008 / 055871 relates to a liquid formulation comprising an etherified cyclodextrin derivative and pimobendan or a pharmaceutically acceptable salt thereof.

[0004] WO2010 / 010257 relates to the use of a coating composition for applying to a solid veterinary pharmaceutical composition prepared from pimobendan by a film coating method comprising a powdered appetite stimulant, a binder and a solvent. WO2010 / 055119 discloses a novel formulation comprising pimobendan and an organic carboxylic acid, wherein the only organic carboxylic acid is succinic acid and the mass ratio of succinic acid to pimobendan is at least 11:1. EP 2338493 provides a new crystalline form of pimobendan, the dissolution properties of which do not require the addition of organic acids or their anhydrides to ensure satisfactory absorption of the substance. WO2015 / 082389 relates to a composition in which pimobendan particles are integrally coated with a carrier matrix, which ensures rapid dissolution of the active substance and therefore reliable absorption in various pH conditions representative of the gastrointestinal tract, and to a method for microencapsulating pimobendan using spray congealing technology and incorporating the coated particles into oral formulations, such as tablets.

[0005] WO2017 / 103054 discloses a solid formulation comprising pimobendan or a pharmaceutically acceptable salt thereof dispersed in malic acid and a flavoring suitable for small animals, and also relates to a wet granulation process for preparing the formulation. WO2021 / 081366 relates to a chewable oral formulation comprising pimobendan in the form of granules, prepared by mixing pimobendan with lactose and / or dicalcium phosphate, granulating, and coating the mixture with a polyvinyl alcohol-polyethylene glycol graft copolymer. Further references include: CN112618505A describes a combined pharmaceutical composition containing benazepril and pimobendan for pets and its preparation method. W2011 / 042463 describes a pharmaceutical composition comprising at least one hyperbranched polymer and at least one pharmaceutically active ingredient, wherein the polymer and the pharmaceutically active ingredient are present in a specific mass ratio, and also describes a process for preparing the pharmaceutical composition. Vasconcelos T et al., Drug Discovery Today 2012, 12: 1068-1075, describes solid dispersions as a strategy to improve the oral bioavailability of poorly water-soluble drugs. Summary of the Invention

[0006] The object of the present invention is to provide an improved formulation of pimobendan which overcomes the problems of the prior art. Surprisingly, the present inventors have succeeded in overcoming the low solubility and high pH dependency of pimobendan and in ensuring very satisfactory solubility and transmembrane flux of pimobendan under various biologically relevant conditions by forming amorphous pimobendan into one or more stabilizing polymers as solid dispersions, in which pimobendan is present in a substantially amorphous form. Thus, in one aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion comprising, preferably consisting of, amorphous pimobendan, preferably substantially amorphous pimobendan, and one or more stabilizing polymers. Therefore, in another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion comprising amorphous pimobendan and one or more stabilizing polymers.

[0007] Therefore, in another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion consisting of amorphous pimobendan and one or more stabilizing polymers. Thus, in another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion comprising substantially amorphous pimobendan and one or more stabilizing polymers. Therefore, in another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion consisting of substantially amorphous pimobendan and one or more stabilizing polymers. In yet another aspect, the object of the present invention has surprisingly been solved by providing a process for preparing the solid dispersion as disclosed and / or claimed herein, wherein the solid dispersion is prepared by a melt-based process, preferably by hot-melt extrusion, or by a solvent evaporation-based process, preferably by spray drying.

[0008] Thus, in yet another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion comprising, preferably consisting of, amorphous pimobendan, preferably substantially amorphous pimobendan, and one or more stabilizing polymers, obtainable by the process disclosed and / or claimed herein. In yet another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion comprising amorphous pimobendan and one or more stabilizing polymers, obtainable by the process disclosed and / or claimed herein. In yet another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion comprising substantially amorphous pimobendan and one or more stabilizing polymers, obtainable by the process disclosed and / or claimed herein. In yet another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion of amorphous pimobendan and one or more stabilizing polymers, obtainable by the process disclosed and / or claimed herein. In yet another aspect, the object of the present invention has surprisingly been solved by providing a solid dispersion of substantially amorphous pimobendan and one or more stabilizing polymers, obtainable by the process disclosed and / or claimed herein.

[0009] In yet another aspect, the object of the present invention has surprisingly been solved by providing a pharmaceutical composition comprising the solid dispersion as disclosed and / or claimed herein and one or more pharmaceutically acceptable excipients, and optionally further comprising a crystalline form of pimobendan (preferably according to Figure 1), preferably wherein the pharmaceutical composition is a tablet, more preferably a chewable tablet. The amorphous state of pimobendan in the solid dispersion is crucial for enhancing its solubility. When the drug substance is in amorphous form, no energy is required to disrupt the drug's crystal lattice. Therefore, compared with the crystalline form, the amorphous form of pimobendan has been found to achieve substantially higher apparent solubility and significantly faster dissolution in various biologically relevant conditions characteristic of the gastrointestinal tract of dogs. The amorphous pimobendan solid dispersion described in the present invention has been found to have higher supersaturation, resulting in improved transmembrane flux and improved bioavailability of the drug substance. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is an XRPD diffractogram of a solid dispersion comprising crystalline pimobendan (AGC Pharma Chemicals, Spain) and substantially amorphous pimobendan prepared according to Examples 1 and 4. [Figure 2] Figure 1 shows the in vitro dissolution profiles at pH 3.0 and pH 6.5 of the pharmaceutical composition according to example 5 and the commercially available pimobendan tablets. Test conditions: equipment similar to USP apparatus 2, V=1000 ml, rotation speed=50 rpm, chromatography equipment: Agilent Infinity 1290 UHPLC, RP18, 50x3.0 mm, 1.7 μm column. [Figure 3]Figure 1 shows in vitro biorelevant volume dissolution and permeation of a pharmaceutical composition according to Example 5 and a commercial pimobendan tablet formulation under default pH conditions characteristic of the stomach (pH 3.0) and small intestine (pH 6.2) using simulated gastric and intestinal fluid for fasted dogs (Biorelevant, London, United Kingdom). Drug substance concentrations were measured by an immersion UV probe. [Figure 4] Figure 1 shows in vitro biorelevant volume dissolution and permeation of a pharmaceutical composition according to Example 5 and a commercial pimobendan tablet formulation under high pH conditions characteristic of the stomach (pH 6.5) and small intestine (pH 7.5) using simulated gastric and intestinal fluids for fasted dogs (Biorelevant, London, United Kingdom). Drug substance concentrations were measured by an immersion UV probe. [Figure 5] 1 is an XRPD diffractogram of a solid dispersion containing substantially amorphous pimobendan prepared according to Example 2. [Figure 6] 1 is an XRPD diffractogram of a solid dispersion containing substantially amorphous pimobendan prepared according to Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0011] Before describing embodiments of the present invention in further detail, it should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Because all given ranges and values ​​may vary by 1-5% unless otherwise indicated or known to one of ordinary skill in the art, the term "about" is typically omitted in the specification and claims. Although methods and materials similar or equivalent to any of those described herein can be used in the practice or testing of the present invention, preferred methods, devices, and materials are described herein. All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies reported in the publications that might be used in connection with the present invention. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0012] The term "drug" or "drug substance" as used herein refers to pimobendan (4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)-5-methyl-3(2H))-pyridazinone. The term "solid dispersion" refers to a solid-state system containing at least two components, one component dispersed throughout the other component. As used herein, the term "solid dispersion" in relation to "amorphous pimobendan" refers to a stable solid dispersion comprising amorphous pimobendan and one or more stabilizing polymers. The term "amorphous pimobendan" means that the solid dispersion contains pimobendan in a substantially amorphous solid state form. A solid in "amorphous" solid state form means in a non-crystalline state. The solid state form of a solid, such as pimobendan in a solid dispersion, can be determined by X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), or other standard techniques known to those skilled in the art.

[0013] The term "substantially amorphous pimobendan" or "pimobendan in substantially amorphous solid state form" means that no crystalline form of pimobendan is detectable in the material / solid dispersion by XRPD and / or DSC, for example and preferably using the conditions described in the examples herein. The term "stabilizing polymer" as disclosed and / or claimed herein refers to any one of the hydrophilic polymers known to those skilled in the art, preferably the polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate, particularly the polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate, and polymeric methacrylates, more preferably vinylpyrrolidone-vinyl acetate copolymers. The term is also understood to refer to mixtures of any two or more of the foregoing polymers. The term "pharmaceutically acceptable excipient" includes all excipients approved for use in human and / or veterinary medicine.

[0014] According to one embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein the one or more stabilizing polymers are selected from the group consisting of polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate; and / or polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate; and polymeric methacrylates. Polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate, and / or N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate, primarily include povidone (polyvinylpyrrolidone), polyvinyl alcohol, and copovidone [poly-(1-vinylpyrrolidone-co-vinyl acetate)]. Polymeric methacrylates include polymeric butyl 2-methylprop-2-enoate; polymeric 2-(dimethylamino)ethyl-2-methylprop-2-enoate; and polymeric methyl 2-methylprop-2-enoate (e.g., Evonik's EUDRAGIT™ E portfolio). According to one embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein the solid dispersion; and / or the one or more stabilizing polymers; and / or polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate; and / or polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate; and / or polymeric methacrylate, independently of one another, do not comprise crospovidone (crosslinked polyvinylpyrrolidone, polyvinylpolypyrrolidone, PVPP).

[0015] According to one embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein the solid dispersion; and / or one or more stabilizing polymers; and / or polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate; and / or polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate; and / or polymeric methacrylate do not comprise one or more hyperbranched polymers which may, independently of one another, be selected from the group consisting of dendritic polymers, dendrimers, arborols, cascade, cauliflower, or star polymers, polydisperse hyperbranched polymers and dendrigraft polymers, or other high molecular weight polymers containing a central atom or molecule which may be a monomer or polymer from which three or more chains arise, all having specific branched structures, hyperbranched polyimines, hyperbranched polyurethanes, hyperbranched polyamides, hyperbranched polyesteramines, hyperbranched polyesteramides, hyperbranched polymers comprising hydroxyl, ester, amide, and / or carboxyl groups, and polyesteramide hyperbranched polymers such as one or more hyperbranched polyesteramides having tertiary amine and / or hydroxyl end groups.

[0016] According to another embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein the polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate, and / or the polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate are selected from the group consisting of povidone (polyvinylpyrrolidone), polyvinyl alcohol, and copovidone [poly-(l-vinylpyrrolidone-co-vinyl acetate)], and the polymeric methacrylate is selected from the group consisting of polymeric butyl 2-methylprop-2-enoate, polymeric 2-(dimethylamino)ethyl 2-methylprop-2-enoate, and polymeric methyl 2-methylprop-2-enoate (e.g., Evonik's EUDRAGIT™ E portfolio). In one embodiment, the preferred stabilizing polymer for forming a solid dispersion of amorphous pimobendan is copovidone, which is more hydrophobic than povidone and provides greater protection against crystallization of the drug substance.

[0017] According to yet another embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein the one or more stabilizing polymers is copovidone [poly(1-vinylpyrrolidone-co-vinyl acetate)], preferably the only stabilizing polymer in the solid dispersion. According to yet another embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein pimobendan is present in an amount of 1% to 80% by weight, based on the weight of the solid dispersion, preferably in an amount of 5% to 40% by weight, based on the weight of the solid dispersion, and more preferably in an amount of 10% to 20% by weight, based on the weight of the solid dispersion. According to yet another embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein at least 70%, preferably 75%, more preferably 80%, even more preferably 85%, even more preferably 90%, even more preferably 91%, even more preferably 92%, even more preferably 93%, even more preferably 94%, even more preferably 95%, even more preferably 96%, even more preferably 97%, even more preferably 98%, even more preferably 99%, even more preferably 99.1%, even more preferably 99.2%, even more preferably 99.3%, even more preferably 99.4%, even more preferably 99.5%, even more preferably 99.6%, even more preferably 99.7%, even more preferably 99.8%, even more preferably 99.9%, even more preferably 99.95%, even more preferably 100% of the pimobendan is present in amorphous form.

[0018] The amorphous pimobendan solid dispersion can be prepared using a melt-based process or a solvent evaporation-based process. Preferably, the amorphous pimobendan solid dispersion is prepared by hot melt extrusion. Generally, extrusion is a process in which the physical properties of a material are changed by forcing the material through an orifice or die under controlled conditions. In pharmaceutical manufacturing, hot melt extrusion is a process in which heat and pressure are applied to melt a polymer matrix and disperse a drug substance therein at a molecular level. Hot melt extrusion is a well-known process for preparing solid dispersions to those skilled in the art. The amorphous pimobendan solid dispersion described in the present invention can also be prepared by a solvent evaporation-based process, such as spray drying. Spray drying is also a well-known process for preparing solid dispersions to those skilled in the art. The amorphous pimobendan solid dispersion can be formed by dispersing or dissolving a drug substance and one or more stabilizing polymers in a suitable solvent to form a feed solution, pumping the feed solution through an atomizer into a drying chamber, and removing the solvent to form solid particles in the drying chamber. Examples of suitable solvents include dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water, or mixtures thereof.

[0019] The solid dispersions of the present invention are preferably prepared using conventional hot melt extrusion or spray drying techniques, although it will be appreciated that other conventional techniques known to those skilled in the art, such as other melt-based processes or solvent removal processes, can also be utilized to form suitable solid dispersions. According to one embodiment, there is provided a hot melt extrusion process as disclosed and / or claimed herein, comprising the steps of: (a) processing pimobendan and one or more stabilizing polymers in a pharmaceutical extruder, preferably a screw extruder, more preferably a twin-screw extruder, preferably at a barrel temperature of 120-200°C, more preferably at a barrel temperature of 150-180°C, to obtain an extrudate; (b) grinding the extrudate obtained in step (a) using a granulator or pelletizer to obtain granules; and (c) milling the granules obtained in step (b) to obtain a solid dispersion, preferably a solid dispersion comprising particles with an average particle size of less than 500 μm.

[0020] According to another embodiment, there is provided a spray drying process as disclosed and / or claimed herein, comprising the steps of: (a) dispersing or dissolving pimobendan and one or more stabilizing polymers in one or more solvents, preferably selected from the group consisting of dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water and mixtures thereof, to obtain a feed solution; (b) passing the feed solution obtained in step (a) through an atomizer into a drying chamber; and (c) Removing the solvent(s) in a drying chamber to obtain a solid dispersion, preferably a solid dispersion comprising particles with an average particle size of less than 500 μm. According to one embodiment, there is provided a pharmaceutical composition as disclosed and / or claimed herein, wherein the pharmaceutically acceptable excipients comprise at least one filler, at least one disintegrant, at least one lubricant, and at least one flavoring agent.

[0021] Pharmaceutically acceptable excipients may include one or more fillers, disintegrants, lubricants, glidants, and flavoring agents. Fillers include those known in the art, such as cellulose, lactose, starch derivatives, and mannitol. Preferred fillers are microcrystalline cellulose and lactose. Disintegrants include those known in the art, such as crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose, pregelatinized starch, and sodium starch glycolate, with the latter being preferred. Examples of lubricants include stearic acid, magnesium stearate, and sodium stearate fumarate. Preferred lubricants are magnesium stearate and talc. Examples of glidants include colloidal silicon dioxide and talc. A preferred glidant is talc. Flavoring agents include natural compounds such as dried yeast, meat or liver powder, and synthetic flavoring agents. Preferred flavoring agents include pork liver powder and dried yeast. Optionally, the pharmaceutical compositions of the present invention may also contain a crystalline form of pimobendan, if necessary, to mitigate the excess bioavailability of the amorphous drug substance. Indeed, due to the substantially pH-independent dissolution and transmembrane flux of the amorphous drug substance, the bioavailability of the amorphous drug substance may exceed that of formulations prepared according to prior art.

[0022] The excess bioavailability of formulations containing substantially amorphous drug substance can be reduced by replacing a portion of the amorphous drug substance with a crystalline form, if desired. Another option for mitigating potential excess bioavailability is to reduce the dose of amorphous drug substance administered. The pharmaceutical compositions can be prepared using conventional processes well known to those skilled in the art for preparing solid dosage forms. In certain cases, crystalline pimobendan may be mixed with (substantially) amorphous pimobendan in varying amounts to adjust bioavailability in the subject animal (ensuring bioequivalence). The amorphous pimobendan solid dispersion prepared according to the present invention is processed with pharmaceutically acceptable excipients and, optionally, the crystalline form of the drug substance to obtain a pharmaceutical composition. The preferred dosage form is a chewable tablet. However, other conventional solid dosage forms, such as granules or soft chewable tablets, can also be prepared using standard manufacturing methods known to those skilled in the art.

[0023] According to another embodiment, there is provided a pharmaceutical composition as disclosed and / or claimed herein, further comprising a pharmaceutically effective amount of one or more additional active ingredients, hi one embodiment, the additional active ingredients may be an angiotensin-converting enzyme (ACE) inhibitor, an aldosterone antagonist, and / or a loop diuretic. According to yet another embodiment, there is provided a pharmaceutical composition as disclosed and / or claimed herein, wherein any one or more further active ingredients selected from the group of angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists and / or loop diuretics, independently of each other, are benazepril, spironolactone, furosemide and / or derivatives thereof, in free form or in physiologically acceptable salt form. According to yet another embodiment, there is provided a pharmaceutical composition as disclosed and / or claimed herein, selected from the group consisting of A, B, C, D and E (the crystalline pimobendan shown in the table below preferably refers to the crystalline pimobendan as shown in Figure 1, AGC Pharma Chemicals, Spain):

[0024] [Table 1]

[0025] [Table 2]

[0026] [Table 3]

[0027] [Table 4]

[0028] [Table 5] [Example]

[0029] The following examples are presented to further illustrate the present invention, but should not be construed as limiting the scope of the invention disclosed herein. Example 1: Preparation of solid dispersions containing amorphous pimobendan by hot-melt extrusion Crystalline pimobendan (AGC Pharma Chemicals, Spain) and copovidone (BASF Pharma, Germany) were mixed in a mass ratio of 10:90. The mixture was then processed in a twin-screw extruder. Extrusion was carried out at a maximum barrel temperature of 190°C. The resulting extruded strands were granulated and milled to an average particle size of <500 μm. The substantially amorphous structure of pimobendan in the solid dispersion was characterized by X-ray powder diffraction (see Figure 1). Example 2: Preparation of solid dispersion containing amorphous pimobendan by hot-melt extrusion Crystalline pimobendan (AGC Pharma Chemicals, Spain) and copovidone (BASF Pharma, Germany) were mixed in a mass ratio of 30:70. The mixture was then processed in a twin-screw extruder. Extrusion was carried out at a maximum barrel temperature of 190°C. The resulting extruded strands were granulated and milled to an average particle size of <500 μm. The substantially amorphous structure of pimobendan in the solid dispersion was characterized by X-ray powder diffraction (see Figure 5).

[0030] Example 3: Preparation of solid dispersion containing amorphous pimobendan by hot-melt extrusion Crystalline pimobendan (AGC Pharma Chemicals, Spain) and Eudragit E PO (Evonik, Germany) were mixed in a mass ratio of 5:95. The mixture was processed in a twin-screw extruder. Extrusion was carried out at a maximum barrel temperature of 170°C. The resulting extruded strands were granulated and milled to an average particle size of <500 μm. The substantially amorphous structure of pimobendan in the solid dispersion was characterized by X-ray powder diffraction (see Figure 6). Example 4: Preparation of solid dispersion containing amorphous pimobendan by spray drying Crystalline pimobendan (AGC Pharma Chemicals, Spain) and povidone (BASF Pharma, Germany) were added to a mixed solvent of methanol and dichloromethane (1:1). The mass ratio of pimobendan to povidone was 20:80. The resulting clear feed solution was pumped through an atomizer into a drying chamber at a feed rate of approximately 400 ml / h. The solvent was removed to obtain a solid dispersion with an average particle size of <100 μm. The substantially amorphous structure of pimobendan in the solid dispersion was characterized by X-ray powder diffraction (see Figure 1).

[0031] Example 5: Preparation of a pharmaceutical composition containing the solid dispersion described in Example 1 The solid dispersion of amorphous pimobendan obtained according to Example 1 was mixed with the following excipients in a mixer: The resulting mixture was compressed into tablets using a suitable tablet press and suitable punches. [Table 6]

[0032] Example 6: Preparation of a pharmaceutical composition containing the solid dispersion described in Example 1 The solid dispersion of amorphous pimobendan obtained according to Example 1 was mixed with the following excipients in a mixer: The resulting mixture was compressed into tablets using a suitable tablet press and suitable punches. [Table 7]

[0033] Example 7: Preparation of a pharmaceutical composition containing the solid dispersion described in Example 1 The solid dispersion of amorphous pimobendan obtained according to Example 1 was mixed with the following excipients and crystalline pimobendan (AGC Pharma Chemicals, Spain, see Figure 1) in a suitable mixer. The resulting mixture was compressed into tablets using a suitable tablet press and suitable punches.

[0034] [Table 8]

[0035] Example 8: Preparation of a pharmaceutical composition containing the solid dispersion described in Example 1 The solid dispersion of amorphous pimobendan obtained according to Example 1 was mixed with the following excipients and crystalline pimobendan (AGC Pharma Chemicals, Spain, see Figure 1) in a suitable mixer. The resulting mixture was compressed into tablets using a suitable tablet press and suitable punches.

[0036] [Table 9]

[0037] Example 9: XRPD Diffractograms of Solid Dispersions Prepared According to Examples 1 and 4 The XRPD patterns of Examples 1 and 4 (see Figure 1) were measured using a PANalytical X'pert Pro X-ray MPD diffractometer using CuKα radiation generated at 40 kV and 40 mA. The XRDP patterns clearly show that pimobendan is substantially amorphous, as the diffractogram of the solid dispersion does not show any sharp characteristic peaks.

[0038] (Example 10) Thermodynamic Solubility The thermodynamic solubilities of crystalline pimobendan and the solid dispersion described in Example 1 were measured at two different pH values ​​representative of dog gastric fluid at 37°C by a dynamic dissolution monitoring instrument using UV calibration, preferably consisting of an immersion UV probe connected to a Rainbow instrument (Pion Inc., Billerica MA, USA). The results obtained are as follows: [Table 10] The results clearly show that amorphous pimobendan has a significantly higher thermodynamic solubility than crystalline pimobendan: the difference is about four times in maleic acid buffer at pH 3.0, but more than ten times in phosphate buffer at pH 6.5.

[0039] (Example 11) In vitro dissolution performance The in vitro dissolution profiles of the pharmaceutical composition described in Example 5 and the commercially available pimobendan tablets were determined at pH 3.0 and pH 6.5. Test conditions: equipment similar to USP Apparatus 2, V=1000 ml, rotation speed=50 rpm, chromatographic equipment: Agilent Infinity 1290 UHPLC, RP18, 50×3.0 mm, 1.7 μm column.

[0040] [Table 11] In 1000 mL of dissolution medium, the dissolution rate of the pharmaceutical composition comprising the solid dispersion described in Example 1 was comparable to that of the commercial formulation at both pH values ​​representative of gastric fluid (see Figure 2).

[0041] Example 12: Biorelevant Volume Dissolution and Permeation The dissolution and permeation of biorelevant volumes of the pharmaceutical compositions described in Examples 5 and 7 and the commercially available pimobendan tablet formulation were determined under standard and high pH conditions. Standard pH conditions were: pH 3.0, representative of the stomach, for 30 minutes, followed by pH 6.2, representative of the small intestine, for 120 minutes in the donor chamber, and pH 7.4, characteristic of blood in the acceptor chamber. High pH conditions were: pH 6.5, representative of the stomach, for 30 minutes, followed by pH 7.5, representative of the small intestine, for 120 minutes in the donor chamber, and pH 7.4, characteristic of blood in the acceptor chamber. Pimobendan concentrations were determined by an immersion UV probe, such as using a μFLUX device (Pion Inc., Billerica, MA, USA). In vitro flux was determined from concentration-time profiles recorded in the acceptor chamber at 60- to 120-minute intervals. Permeation rates were calculated from the flux values ​​and the drug substance concentrations in the donor chamber.

[0042] The amount of pimobendan (drug) that dissolved and then permeated the membrane was determined as follows. [Table 12]

[0043] The dissolution amount from the pharmaceutical composition containing the solid dispersion of substantially amorphous pimobendan was higher than that from the commercial formulation under both standard and high pH conditions, and the permeation amount showed an even greater difference (see Figures 3 and 4, respectively). The in vitro transmembrane flux value, which characterizes the total amount of substance passing through a unit area of ​​a biological membrane per unit time and its absorption rate, was calculated as follows:

[0044] [Table 13] The calculated in vitro flux values ​​of pharmaceutical compositions comprising solid dispersions containing substantially amorphous pimobendan are much higher than those of the commercial formulation, and therefore the solid dispersions / pharmaceutical compositions of the present invention are predicted to have improved bioavailability, which is due to the higher solubility, dissolution, supersaturation, and increased permeability of amorphous pimobendan compared to the commercial formulation.

[0045] References (1) CN 112 618 505 (2) EP 0 008 391 (3) EP 0 439 030 (4) EP 2 338 493 (5) Rekis, T. et al., Cryst. Growth Des. 2018, 18(1): 264-273 (6) Vasconcelos T et al., Drug Discovery Today 2012, 12: 1068-1075 (7) WO 2005 / 084647 (8) WO 2008 / 055871 (9) WO 2010 / 010257 (10) WO 2010 / 055119 (11) WO 2011 / 042463 (12) WO 2015 / 082389 (13) WO 2017 / 103054 (14) WO 2021 / 081366

[0046] The following clauses are also part of the present invention and general disclosure: 1. A solid dispersion comprising, preferably consisting of, amorphous pimobendan, preferably substantially amorphous pimobendan, and one or more stabilizing polymers. 2. The solid dispersion of clause 1, wherein the one or more stabilizing polymers are selected from the group consisting of polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate, and polymeric methacrylates. 3. The solid dispersion of clause 2, wherein the polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate are selected from the group consisting of povidone (polyvinylpyrrolidone) and copovidone [poly-(l-vinylpyrrolidone-co-vinyl acetate)], and the polymeric methacrylate is selected from the group consisting of polymeric butyl 2-methylprop-2-enoate, polymeric 2-(dimethylamino)ethyl 2-methylprop-2-enoate, and polymeric methyl 2-methylprop-2-enoate. 4. The solid dispersion of any one of clauses 1 to 3, wherein the one or more stabilizing polymers is copovidone [poly(1-vinylpyrrolidone-co-vinyl acetate)], preferably the only stabilizing polymer in the solid dispersion.

[0047] 5. The solid dispersion according to any one of clauses 1 to 4, wherein pimobendan is present in an amount of 1% to 80% by weight relative to the weight of the solid dispersion, preferably in an amount of 5% to 40% by weight relative to the weight of the solid dispersion, more preferably in an amount of 10% to 20% by weight relative to the weight of the solid dispersion. 6. The solid dispersion according to any one of clauses 1 to 4, wherein at least 70% of the pimobendan is present in amorphous form. 7. Process for preparing a solid dispersion according to any one of clauses 1 to 6, wherein the solid dispersion is prepared by a melt-based process, preferably by hot-melt extrusion, or by a solvent evaporation-based process, preferably by spray drying. 8. The process of clause 7, which is a hot melt extrusion process comprising the steps of: (a) processing pimobendan and one or more stabilizing polymers in a pharmaceutical extruder, preferably a screw extruder, more preferably a twin-screw extruder, preferably at a barrel temperature of 120-200°C, more preferably at a barrel temperature of 150-180°C, to obtain an extrudate; (b) grinding the extrudate obtained in step (a) using a granulator or pelletizer to obtain granules; and (c) milling the granules obtained in step (b) to obtain a solid dispersion, preferably a solid dispersion comprising particles with an average particle size of less than 500 μm.

[0048] 9. The process according to clause 7, wherein the process is a spray drying process comprising the steps of: (a) dispersing or dissolving pimobendan and one or more stabilizing polymers in one or more solvents, preferably selected from the group consisting of dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water or mixtures thereof, to obtain a feed solution; (b) passing the feed solution obtained in step (a) through an atomizer into a drying chamber; and (c) Removing the solvent(s) in a drying chamber to obtain a solid dispersion, preferably a solid dispersion comprising particles with an average particle size of less than 500 μm. 10. A solid dispersion comprising, preferably consisting of, amorphous pimobendan, preferably substantially amorphous pimobendan obtainable by the process according to any one of clauses 7 to 9, and one or more stabilizing polymers. 11. A pharmaceutical composition comprising the solid dispersion according to any one of clauses 1 to 6 and 10 and one or more pharmaceutically acceptable excipients, and optionally further comprising a crystalline form of pimobendan (preferably as depicted in Figure 1), preferably in the form of a tablet, more preferably a chewable tablet.

[0049] 12. The pharmaceutical composition according to clause 11, wherein the pharmaceutically acceptable excipients comprise at least one filler, at least one disintegrant, at least one lubricant, and at least one flavoring agent. 13. The pharmaceutical composition according to any one of clauses 11-12, further comprising a pharmaceutically effective amount of one or more further active ingredients selected from the group of angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists and / or loop diuretics. 14. The pharmaceutical composition according to clause 13, wherein any one or more further active ingredients selected from the group of angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists and / or loop diuretics are, independently of one another, benazepril, spironolactone, furosemide and / or derivatives thereof in free form or in the form of a physiologically acceptable salt. 15. The pharmaceutical composition according to any one of clauses 11 to 14, selected from the group consisting of A, B, C, D:

[0050] [Table 14]

[0051] [Table 15]

[0052] [Table 16]

[0053] [Table 17]

Claims

1. A solid dispersion comprising, preferably consisting of, amorphous pimobendan, preferably substantially amorphous pimobendan, and one or more stabilizing polymers.

2. 2. The solid dispersion of claim 1, wherein the one or more stabilizing polymers are selected from the group consisting of polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate, and polymeric methacrylates.

3. 3. The solid dispersion of claim 2, wherein the polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate, and the polymeric methacrylate are selected from the group consisting of povidone (polyvinylpyrrolidone), polyvinyl alcohol, and copovidone [poly-(1-vinylpyrrolidone-co-vinyl acetate)], and the polymeric methacrylate is selected from the group consisting of polymeric butyl 2-methylprop-2-enoate, polymeric 2-(dimethylamino)ethyl 2-methylprop-2-enoate, and polymeric methyl 2-methylprop-2-enoate.

4. 4. The solid dispersion according to claim 1, wherein the solid dispersion; and / or one or more stabilizing polymers; and / or polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate; and / or polymeric methacrylate, independently of one another, do not comprise crospovidone (crosslinked polyvinylpyrrolidone, polyvinylpolypyrrolidone, PVPP).

5. 5. The solid dispersion according to any one of claims 1 to 4, wherein the solid dispersion; and / or one or more stabilizing polymers; and / or polymerization products of N-vinylpyrrolidone, vinyl acetate, and vinylpyrrolidone mixed with vinyl acetate; and / or polymeric methacrylate do not comprise one or more hyperbranched polymers selected from the group consisting of, independently of one another, dendritic polymers, dendrimers, arborols, cascade, cauliflower, or star polymers, polydisperse hyperbranched polymers, dendrigraft polymers, or other high molecular weight polymers, all having specific branched structures, containing a central atom or molecule which may be a monomer or polymer from which three or more chains arise; hyperbranched polyimines, hyperbranched polyurethanes, hyperbranched polyamides, hyperbranched polyesteramines, hyperbranched polyesteramides, hyperbranched polymers comprising hydroxyl, ester, amide, and / or carboxyl groups, and polyesteramide hyperbranched polymers, such as one or more hyperbranched polyesteramides having tertiary amine end groups and / or hydroxyl end groups.

6. 6. The solid dispersion of any one of claims 1 to 5, wherein the one or more stabilizing polymers is copovidone [poly(1-vinylpyrrolidone-co-vinyl acetate)], preferably the only stabilizing polymer in the solid dispersion.

7. 7. The solid dispersion according to any one of claims 1 to 6, wherein pimobendan is present in an amount of 1% to 80% by weight relative to the weight of the solid dispersion, preferably 5% to 40% by weight relative to the weight of the solid dispersion, more preferably 10% to 20% by weight relative to the weight of the solid dispersion.

8. 8. The solid dispersion according to any one of claims 1 to 7, wherein at least 70% of the pimobendan is present in amorphous form.

9. 9. A process for preparing a solid dispersion according to any one of claims 1 to 8, wherein the solid dispersion is prepared by a melt-based process, preferably by hot-melt extrusion, or by a solvent evaporation-based process, preferably by spray drying.

10. 10. The process of claim 9, which is a hot melt extrusion process comprising the steps of: (a) processing pimobendan and one or more stabilizing polymers in a pharmaceutical extruder, preferably a screw extruder, more preferably a twin screw extruder, preferably at a barrel temperature of 120-200°C, more preferably at a barrel temperature of 150-180°C, to obtain an extrudate; (b) grinding the extrudate obtained in step (a) using a granulator or pelletizer to obtain granules; and (c) milling the granules obtained in step (b) to obtain a solid dispersion, preferably a solid dispersion comprising particles with an average particle size of less than 500 μm.

11. 10. The process of claim 9, which is a spray drying process comprising the steps of: (a) dispersing or dissolving pimobendan and one or more stabilizing polymers in one or more solvents, preferably selected from the group consisting of dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water and mixtures thereof, to obtain a feed solution; (b) pumping the feed solution obtained in step (a) through an atomizer into a drying chamber; and (c) Removing the solvent(s) in a drying chamber to obtain a solid dispersion, preferably a solid dispersion comprising particles with an average particle size of less than 500 μm.

12. A solid dispersion comprising, preferably consisting of, amorphous pimobendan, preferably substantially amorphous pimobendan, obtainable by the process according to any one of claims 9 to 11, and one or more stabilising polymers.

13. 13. A pharmaceutical composition comprising the solid dispersion according to any one of claims 1 to 8 and 12 and one or more pharmaceutically acceptable excipients, and optionally further comprising a crystalline form of pimobendan (preferably as depicted in Figure 1), preferably in the form of a tablet, more preferably a chewable tablet.

14. 14. The pharmaceutical composition of claim 13, wherein the pharmaceutically acceptable excipients comprise at least one filler, at least one disintegrant, at least one lubricant, and at least one flavoring agent.

15. 15. The pharmaceutical composition according to any one of claims 13 to 14, further comprising a pharmaceutically effective amount of one or more further active ingredients selected from the group of angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists and / or loop diuretics.

16. 16. The pharmaceutical composition of claim 15, wherein any one or more further active ingredients selected from the group of angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists and / or loop diuretics are, independently of one another, benazepril, spironolactone, furosemide and / or derivatives thereof in free form or in the form of a physiologically acceptable salt.

17. The pharmaceutical composition according to any one of claims 13 to 16, wherein the crystalline pimobendan is selected from the group consisting of A, B, C, D and E (the crystalline pimobendan shown in the table below preferably refers to the crystalline pimobendan shown in Figure 1): Table 1 Table 2 Table 3 Table 4 Table 5

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