Solid dispersions comprising amorphous pimobendan and one or more stable polymers

Abstract

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

Description

[0001] Incorporation by reference

[0002] All documents cited herein are incorporated herein by reference in their entirety. Technical field

[0003] The present invention relates to the field of medicine, in particular veterinary medicine. Specifically, the present invention relates to novel solid dispersions comprising amorphous pimobendan and one or more stabilizing polymers, methods for their preparation and corresponding pharmaceutical compositions. Prior art

[0004] Pimobendan (4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)-5-methyl-3(2H)-pyridazinone) is a benzimidazolylpyridazinone derivative which is described in EP 0 008 391 as a substance having cardiotonic, hypotensive and antithrombotic activities.

[0005] Pimobendan is known to exhibit polymorphism. More than ten potential polymorphs and solvatomorphs of chiral pimobendan have been described (Rekis et al., 2018).

[0006] EP 0 439 030 discloses the low solubility of pimobendan in aqueous environments, which is characterized by high pH-dependent properties. Depending on the buffer system used, it dissolves in water at about 100 to 300 mg / l when the pH is between 1 and 3, but only about 1 mg / l in water when the pH is 5. In humans, this phenomenon results in strong fluctuations in blood concentration, the levels of which are often too low. These unsatisfactory absorption characteristics can be explained by the high pH-dependence of the solubility of pimobendan in aqueous media and by fluctuations in the pH conditions in the gastrointestinal tract of the tested individuals. According to this patent disclosure, the low solubility and high pH-dependence of the solubility of pimobendan can be overcome by using a homogeneous dry mixture of powdered pimobendan and powdered citric acid, wherein the mixture contains up to one part by weight of pimobendan / at least about five parts by weight of citric acid and a pharmaceutically active carrier, and this mixture is filled into capsules or compressed into tablets for oral administration. It is believed that strong fluctuations in blood concentration can be prevented by acid microspheres which are caused by the dissolution rate of citric acid and form around the pimobendan particles. The microspheres are always acidic and ensure reliable, almost pH-independent dissolution and absorption of pimobendan.

[0007] WO 2005 / 084647 relates to a novel solid preparation containing pimobendan, wherein pimobendan is uniformly dispersed in a polyvalent acid selected from citric acid, acetic acid, maleic acid, tartaric acid or their acid anhydrides and a flavoring substance. According to the disclosure, most animals are not easily receptive to a relatively high amount of citric acid and its sour taste. Therefore, these preparations must be force-fed to animals or mixed with food before administration. According to this patent disclosure, these difficulties can be overcome by using novel preparations, preferably preparations in the form of tablets. The most preferred tablets are characterized in that the tablets contain 1.25 mg, 2.5 mg, 5 mg or 10 mg of pimobendan, and further contain citric acid, artificial beef flavor and pharmaceutically acceptable excipients in a preferably amount of 50 mg / g of the solid preparation.

[0008] WO 2008 / 055871 relates to a liquid preparation containing an etherified cyclodextrin derivative and pimobendan or a pharmaceutically acceptable salt thereof.

[0009] WO 2010 / 010257 relates to the use of a coating composition for applying to a solid veterinary pharmaceutical composition prepared from pimobendan, and the coating composition is applied by a film coating method comprising a powdered appetizing material, a binder and a solvent.

[0010] WO 2010 / 055119 discloses a novel preparation containing pimobendan and an organic carboxylic acid, wherein the only organic carboxylic acid is succinic acid, and the weight ratio of succinic acid to pimobendan is at least 11:1.

[0011] EP 2 338 493 provides a new crystalline form of pimobendan, and its solubility characteristics enable it to ensure satisfactory resorption of the substance without adding an organic acid or its acid anhydride.

[0012] WO 2015 / 082389 relates to a composition containing pimobendan granules with an integral coating having a carrier matrix, the carrier matrix being used to ensure rapid dissolution of the active substance under each pH condition representing the gastrointestinal tract and thus ensure reliable absorption; and a method of microencapsulating pimobendan using a spray condensation technique and incorporating the coated granules into an oral preparation (such as incorporating them into tablets).

[0013] WO 2017 / 103054 discloses a solid preparation containing pimobendan or a pharmaceutically acceptable salt thereof dispersed in malic acid and a flavoring agent suitable for small animals. It also relates to a wet granulation process for preparing the preparation.

[0014] WO 2021 / 081366 relates to a chewable oral preparation containing pimobendan in particulate form, which is prepared by mixing particulate pimobendan with lactose and / or dicalcium phosphate, granulating, and coating the mixture with a polyvinyl alcohol-polyethylene glycol graft copolymer.

[0015] The following are other references:

[0016] CN 112 618 505A describes a compound pharmaceutical composition for pets containing benazepril and pimobendan and a preparation method thereof.

[0017] WO 2011 / 042463 describes a pharmaceutical composition containing at least one hyperbranched polymer and at least one pharmaceutically active ingredient and a preparation method of the pharmaceutical composition, wherein these polymers are present in a specific weight ratio with the pharmaceutically active ingredient.

[0018] Vasconcelos T et al., Drug Discovery Today 2012, 12: 1068-1075 describe a solid dispersion as a strategy for improving the oral bioavailability of drugs with poor water solubility.

[0019] The object of the present invention is to provide an improved pimobendan preparation that overcomes the problems of the prior art. Summary of the Invention

[0021] Surprisingly, the inventors of the present invention have successfully overcome the low solubility and high pH-dependent solubility of pimobendan and ensured very satisfactory dissolution and transmembrane flux of pimobendan under different biologically relevant conditions by forming a solid dispersion of amorphous pimobendan in one or more stable polymers. In the solid dispersion, pimobendan exists in a substantially amorphous form.

[0022] In one aspect, the object of the present invention has thus been surprisingly solved by providing a solid dispersion containing amorphous pimobendan (preferably substantially amorphous pimobendan) and one or more stable polymers, preferably consisting of amorphous pimobendan (preferably substantially amorphous pimobendan) and one or more stable polymers.

[0023] In another aspect, the object of the present invention has thus been surprisingly solved by providing a solid dispersion containing amorphous pimobendan and one or more stable polymers.

[0024] In another aspect, the object of the present invention has thus been surprisingly solved by providing a solid dispersion consisting of amorphous pimobendan and one or more stable polymers.

[0025] In another aspect, the object of the present invention has thus been surprisingly solved by providing a solid dispersion comprising substantially amorphous pimobendan and one or more stabilizing polymers.

[0026] In another aspect, the object of the present invention has thus been surprisingly solved by providing a solid dispersion consisting of substantially amorphous pimobendan and one or more stabilizing polymers.

[0027] In another aspect, the object of the present invention has been surprisingly solved by providing a method for preparing the solid dispersions as disclosed and / or claimed herein, wherein the solid dispersions are prepared by a melt-based method (preferably by hot melt extrusion) or a solvent evaporation-based method (preferably by spray drying).

[0028] In another aspect, the object of the present invention has thus been surprisingly solved by providing a solid dispersion comprising amorphous pimobendan (preferably substantially amorphous pimobendan) and one or more stabilizing polymers, preferably consisting of amorphous pimobendan (preferably substantially amorphous pimobendan) and one or more stabilizing polymers, which solid dispersion can be obtained by the methods as disclosed and / or claimed herein.

[0029] In another aspect, the object of the present invention has been surprisingly solved by providing a solid dispersion comprising amorphous pimobendan and one or more stabilizing polymers, which solid dispersion can be obtained by the methods as disclosed and / or claimed herein.

[0030] In another aspect, the object of the present invention has been surprisingly solved by providing a solid dispersion comprising substantially amorphous pimobendan and one or more stabilizing polymers, which solid dispersion can be obtained by the methods as disclosed and / or claimed herein.

[0031] In another aspect, the object of the present invention has been surprisingly solved by providing a solid dispersion consisting of amorphous pimobendan and one or more stabilizing polymers, which solid dispersion can be obtained by the methods as disclosed and / or claimed herein.

[0032] In another aspect, the object of the present invention has been surprisingly solved by providing a solid dispersion consisting of substantially amorphous pimobendan and one or more stabilizing polymers, which solid dispersion can be obtained by the methods as disclosed and / or claimed herein.

[0033] In another aspect, the object of the present invention has been surprisingly solved by providing a pharmaceutical composition comprising a solid dispersion as disclosed and / or claimed herein and one or more pharmaceutically acceptable excipients, said composition optionally further comprising one or more crystalline forms of pimobendan (preferably according to Figure 1 ), wherein preferably, said pharmaceutical composition is a tablet, more preferably a chewable tablet.

[0034] In the solid dispersion, the amorphous state of pimobendan is crucial for increasing its solubility. When the drug substance exists in amorphous form, no energy is required to break the drug lattice. For this reason, the amorphous form of pimobendan has been found to achieve substantially higher apparent solubility and significantly faster and higher dissolution under different biorelevant conditions characterizing the dog gastrointestinal tract, as compared to the crystalline form. The solid dispersion of amorphous pimobendan of the present invention generates a higher transmembrane flux due to higher supersaturation, which can improve the bioavailability of the drug substance. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 : XRPD diffraction patterns of crystalline pimobendan (AGC Pharma Chemicals, Spain) and solid dispersions comprising substantially amorphous pimobendan prepared according to Examples 1 and 4.

[0036] Figure 2 : In vitro dissolution curves of the pharmaceutical composition according to Example 5 and a commercially available pimobendan tablet formulation at pH 3.0 and pH 6.5, respectively. Test conditions: apparatus similar to USP Apparatus 2, V = 1000 ml, rotation speed = 50 rpm, chromatographic instrument: Agilent Infinity 1290UHPLC, RP18, 50x3.0 mm, 1.7 μm column.

[0037] Figure 3 : In vitro biorelevant volume dissolution and permeation of the pharmaceutical composition according to Example 5 and a commercially available pimobendan tablet formulation under the default pH conditions characterizing the stomach (pH 3.0) and small intestine (pH 6.2) by using simulated gastric and intestinal fluids of fasted dogs (Biorelevant, London, United Kingdom). The concentration of the drug substance was determined by an immersed UV probe.

[0038] Figure 4: In vitro biorelevant volume dissolution and permeation of the pharmaceutical composition according to Example 5 and a commercially available pimobendan tablet formulation under high pH conditions representative of the stomach (pH 6.5) and small intestine (pH 7.5) by using simulated gastric and intestinal fluids of fasted dogs (Biorelevant, London, United Kingdom). The concentration of the drug substance was determined by an immersed UV probe.

[0039] Figure 5 : XRPD diffraction pattern of a solid dispersion comprising substantially amorphous pimobendan prepared according to Example 2.

[0040] Figure 6 : XRPD diffraction pattern of a solid dispersion comprising substantially amorphous pimobendan prepared according to Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0042] Before further elaborating on the embodiments of the present invention, it should be noted that as used herein and as used in the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural referents.

[0043] 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. Unless otherwise stated or otherwise known to one of ordinary skill in the art, all given ranges and values can vary by 1% to 5%, and thus the term "about" is typically omitted in the specification and claims. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the currently described are the preferred methods, devices, and materials. All publications mentioned herein are incorporated by reference herein to illustrate and disclose substances, excipients, carriers, and methods reported in the publications that can be used in conjunction with the present invention. Nothing herein shall be construed as an admission that the present invention is not entitled to antedate such disclosure based on a prior invention.

[0044] As used herein, the term "drug" or "drug substance" refers to pimobendan (4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)-5-methyl-3(2H)-pyridazinone).

[0045] The term "solid dispersion" refers to a solid state system comprising at least two components, wherein one component is dispersed in one or more other components.

[0046] 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.

[0047] The term "amorphous pimobendan" means a solid dispersion containing pimobendan in a substantially amorphous solid form.

[0048] A solid in an "amorphous" solid form means that it is in a non-crystalline state. The solid form of the 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.

[0049] The term "substantially amorphous pimobendan" or "pimobendan in a substantially amorphous solid form" means that the crystalline form of pimobendan cannot be detected in the material / solid dispersion by XRPD and / or DSC, for example and preferably using the conditions set forth in the examples herein.

[0050] The term "stable polymer" as disclosed and / or claimed herein refers to any of the hydrophilic polymers known to those skilled in the art, preferably the polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate, especially the polymerization products of N-vinylpyrrolidone, vinyl acetate, and mixtures of vinylpyrrolidone and vinyl acetate; and polymeric methacrylates, more preferably vinylpyrrolidone-vinyl acetate copolymers. It should also be understood that the term can mean a mixture of any two or more of the above polymers.

[0051] The term "pharmaceutically acceptable excipient" includes all excipients that have been approved for human and / or veterinary medical products.

[0052] According to one embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein the one or more stable polymers are selected from: the polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate; and / or the polymerization products of N-vinylpyrrolidone, vinyl acetate, and mixtures of vinylpyrrolidone and vinyl acetate; and polymeric methacrylates.

[0053] Polymerization products of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate; and / or polymerization products of N-vinylpyrrolidone, vinyl acetate, and mixtures of vinylpyrrolidone and vinyl acetate mainly include povidone (polyvinylpyrrolidone), polyvinyl alcohol, and copovidone [poly-(1-vinylpyrrolidone-co-vinyl acetate)]. Polymerized methacrylates include polymerized butyl 2-methylprop-2-enoate; polymerized 2-(dimethylamino)ethyl 2-methylprop-2-enoate; and polymerized methyl 2-methylprop-2-enoate (e.g., from Evonik's E portfolio).

[0054] 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 mixtures of vinylpyrrolidone and vinyl acetate; and / or polymerized methacrylates independently of each other do not include crospovidone (crosslinked polyvinylpyrrolidone, polyvinylpoly-pyrrolidone (PVPP)).

[0055] 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 the polymerization product of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate; and / or the polymerization product of N-vinylpyrrolidone, vinyl acetate, and a mixture of vinylpyrrolidone and vinyl acetate; and / or the polymerized methacrylates independently of one another do not include one or more hyperbranched polymers, which are optionally selected from: dendritic polymer, dendrimer, arborol, cascade, cauliflower polymer or star polymer, polydisperse hyperbranched polymer, dendrigraft polymer or other high molecular weight polymers having a specific branched structure containing a central atom or molecule, the specific branched structure containing a central atom or molecule may be monomeric or polymeric and three or more chains extend therefrom; hyperbranched polyimine, hyperbranched polyurethane, hyperbranched polyamide, hyperbranched polyesteramine, hyperbranched polyesteramide, hyperbranched polymers containing 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 having hydroxyl end groups.

[0056] According to another embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein the polymerization product of N-vinylpyrrolidone and vinylpyrrolidone-vinyl acetate; and / or the polymerization product of N-vinylpyrrolidone, vinyl acetate, and a mixture of vinylpyrrolidone and vinyl acetate are selected from: povidone (polyvinylpyrrolidone), polyvinyl alcohol and copovidone [poly-(1-vinylpyrrolidone-co-vinyl acetate)]; and the polymerized methacrylates are selected from: polybutyl 2-methylprop-2-enoate; poly-2-(dimethylamino)ethyl 2-methylprop-2-enoate; and polymethyl 2-methylprop-2-enoate (e.g., from Evonik's E portfolio).

[0057] In one embodiment, the preferred stabilizing polymer used to form the solid dispersion of amorphous pimobendan is copovidone, which is more hydrophobic than povidone and provides higher protection against crystallization of the drug substance.

[0058] According to a further 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)], which is preferably the only stabilizing polymer in the solid dispersion.

[0059] According to a further embodiment, there is provided a solid dispersion as disclosed and / or claimed herein, wherein pimobendan is present in an amount of from 1% to 80% by weight, preferably from 5% to 40% by weight, and more preferably from 10% to 20% by weight, based on the weight of the solid dispersion.

[0060] According to a further 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 pimobendan is present in amorphous form.

[0061] Solid dispersions of amorphous pimobendan can be prepared by using melt-based methods or solvent evaporation-based methods. Preferably, solid dispersions of amorphous pimobendan are prepared by hot melt extrusion. Generally, extrusion is a process of changing the physical properties of a substance by forcing it through an orifice or die under controlled conditions. In pharmaceutical manufacturing, hot melt extrusion is a process of applying heat and pressure to melt a polymer matrix and disperse a drug substance therein at the molecular level. Hot melt extrusion is a method well known to those skilled in the art for preparing solid dispersions. According to the present invention, solid dispersions of amorphous pimobendan can also be prepared by solvent evaporation-based methods, such as spray drying. Spray drying is also a method well known to those skilled in the art for preparing solid dispersions. Solid dispersions of amorphous pimobendan can be formed by dispersing or dissolving the 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 in the drying chamber to form solid particles. Examples of suitable solvents include dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water, or mixtures thereof.

[0062] Although the solid dispersions of the present invention are preferably prepared using conventional hot melt extrusion or spray drying techniques, it is to be understood that suitable solid dispersions can be formed using other conventional techniques known to those skilled in the art, such as other melt-based methods or solvent removal methods.

[0063] According to one embodiment, there is provided a hot melt extrusion method as disclosed and / or claimed herein, which comprises the following steps:

[0064] (a) Processing pimobendan and one or more stabilizing polymers, preferably at a barrel temperature of 120 - 200 °C, more preferably at a barrel temperature of 150 - 180 °C, by means of a pharmaceutical extruder (preferably a screw extruder, more preferably a twin-screw extruder), to obtain an extrudate,

[0065] (b) Using a granulator or pelletizer to comminute the extrudate obtained in step (a) to obtain granules, and

[0066] (c) Grinding the granules obtained in step (b) to obtain a solid dispersion, which preferably comprises granules having an average diameter of less than 500 μm.

[0067] According to another embodiment, there is provided a spray drying method as disclosed and / or claimed herein, which comprises the following steps:

[0068] (a) Dispersing or dissolving pimobendan and one or more stabilizing polymers in one or more solvents to obtain a feed solution, the one or more solvents being preferably selected from: dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water, and mixtures thereof,

[0069] (b) Pumping the feed solution obtained in step (a) via an atomizer into a drying chamber, and

[0070] (c) Removing one or more solvents in the drying chamber to obtain a solid dispersion, which preferably comprises granules having an average diameter of less than 500 μm.

[0071] According to one embodiment, there is provided a pharmaceutical composition as disclosed and / or claimed herein, wherein the pharmaceutically acceptable excipients include at least one filler, at least one disintegrant, at least one lubricant, and at least one flavoring agent.

[0072] Pharmaceutically acceptable excipients may include one or more fillers, disintegrants, lubricants, glidants, and flavoring agents. Fillers include fillers known in the art, such as cellulose, lactose, starch derivatives, and mannitol. Preferred fillers are microcrystalline cellulose and lactose. Disintegrants include disintegrants known in the art, which include crospovidone (crosslinked polyvinylpyrrolidone), croscarmellose, pregelatinized starch, and sodium starch glycolate, with the latter being preferred. Examples of lubricants are stearic acid, magnesium stearate, and sodium stearyl fumarate. Preferred lubricants are magnesium stearate and talc. Examples of glidants are colloidal silicon dioxide and talc. Preferred glidant is talc. Flavoring agents may include natural compounds, such as dry yeast, meat or liver powder, and synthetic flavoring agents. Preferred flavoring agents are pork liver powder and dry yeast.

[0073] Optionally, if desired, the pharmaceutical composition of the present invention may also contain pimobendan in crystalline form to reduce the supra-bioavailability of the amorphous drug substance. Due to the substantially and practically pH-independent dissolution and transmembrane flux of the amorphous drug substance, its bioavailability may exceed that of the formulations prepared according to the prior art.

[0074] If desired, the supra-bioavailability of a formulation containing a drug substance substantially in amorphous form can be reduced by replacing part of the amorphous drug substance with the crystalline form. Another way to reduce the potential supra-bioavailability is to reduce the dose of the amorphous drug substance.

[0075] The pharmaceutical composition can be prepared using conventional methods for preparing solid dosage forms known to those skilled in the art.

[0076] In certain cases, different amounts of crystalline pimobendan can be mixed with (substantially) amorphous pimobendan to adjust its bioavailability (ensuring bioequivalence) in the target animal.

[0077] The solid dispersion of amorphous pimobendan prepared according to the present invention is treated with pharmaceutically acceptable excipients and optionally the crystalline form of the drug substance to obtain the pharmaceutical composition. The preferred dosage form is chewable tablets. However, other conventional solid dosage forms (such as granules or soft chewable tablets) can also be prepared by using standard preparation methods known to those skilled in the art.

[0078] According to another embodiment, there is provided a pharmaceutical composition as disclosed and / or claimed herein, which further comprises a pharmaceutically effective amount of one or more other active ingredients. In one embodiment, the other active ingredients may be an angiotensin-converting enzyme (ACE) inhibitor, an aldosterone antagonist, and / or a loop diuretic.

[0079] According to yet another embodiment, there is provided a pharmaceutical composition as disclosed and / or claimed herein, wherein any one or more other active ingredients selected from an angiotensin-converting enzyme (ACE) inhibitor, an aldosterone antagonist, and / or a loop diuretic are, independently of each other, benazepril, spironolactone, furosemide, and / or a derivative thereof in free form or in a physiologically acceptable salt form.

[0080] According to yet another embodiment, there is provided a pharmaceutical composition as disclosed and / or claimed herein, which is selected from: A, B, C, D, and E (the crystalline pimobendan described in the following table preferably refers to the crystalline pimobendan according to Figure 1 , AGC PharmaChemicals, Spain):

[0081] A:

[0082]

[0083]

[0084] B:

[0085]

[0086] C:

[0087]

[0088]

[0089] D:

[0090]

[0091] E:

[0092] Examples

[0093] The following examples are used to further illustrate the present invention; however, they should not be construed as limiting the scope of the present invention disclosed herein.

[0094] Example 1 - Preparation of a solid dispersion containing amorphous pimobendan by hot melt extrusion

[0095] Mix crystalline pimobendan (AGC Pharma Chemicals, Spain) and copovidone (BASF Pharma, Germany) at a weight ratio of 10:90. Subsequently, process the blend in a twin-screw extruder. Extrude at a maximum barrel temperature of 190 °C. Granulate the resulting extruded strands and grind to an average particle size of <500 μm. Characterize the substantially amorphous structure of pimobendan in the solid dispersion by X-ray powder diffraction (see Figure 1 ).

[0096] Example 2 - Preparation of a solid dispersion containing amorphous pimobendan by hot melt extrusion

[0097] Mix crystalline pimobendan (AGC Pharma Chemicals, Spain) and copovidone (BASF Pharma, Germany) at a weight ratio of 30:70. Subsequently, process the blend in a twin-screw extruder. Extrude at a maximum barrel temperature of 190 °C. Granulate the resulting extruded strands and grind to an average particle size of <500 μm. Characterize the substantially amorphous structure of pimobendan in the solid dispersion by X-ray powder diffraction (see Figure 5 ).

[0098] Example 3 - Preparation of a solid dispersion containing amorphous pimobendan by hot melt extrusion

[0099] Mix crystalline pimobendan (AGC Pharma Chemicals, Spain) and Eudragit E PO (Evonik, Germany) at a weight ratio of 5:95. Subsequently, process the blend in a twin-screw extruder. Extrude at a maximum barrel temperature of 170 °C. Granulate the resulting extruded strands and grind to an average particle size of <500 μm. Characterize the substantially amorphous structure of pimobendan in the solid dispersion by X-ray powder diffraction (see Figure 6 ).

[0100] Example 4 - Preparation of a solid dispersion containing amorphous pimobendan by spray drying

[0101] Add crystalline pimobendan (AGC Pharma Chemicals, Spain) and polyvinylpyrrolidone (BASF Pharma, Germany) to a solvent mixture of methanol and dichloromethane (1:1). The weight ratio of pimobendan to polyvinylpyrrolidone is 20:80. Pump the resulting clear feed solution through an atomizer into a drying chamber at a feed rate of approximately 400 ml / h. Remove the solvent to provide a solid dispersion with an average particle size of <100 μm. Characterize the substantially amorphous structure of pimobendan in the solid dispersion by X-ray powder diffraction (see Figure 1 ).

[0102] Example 5 - Preparation of a pharmaceutical composition comprising the solid dispersion according to Example 1

[0103] The solid dispersion of amorphous pimobendan obtained according to Example 1 was blended with the excipients listed below in a blender. The resulting mixture was compressed into tablets using a suitable tableting machine and suitable punches.

[0104]

[0105]

[0106] Example 6 - Preparation of a pharmaceutical composition comprising the solid dispersion according to Example 1

[0107] The solid dispersion of amorphous pimobendan obtained according to Example 1 was blended with the excipients listed below in a blender. The resulting mixture was compressed into tablets using a suitable tableting machine and suitable punches.

[0108]

[0109] Example 7 - Preparation of a pharmaceutical composition comprising the solid dispersion according to Example 1

[0110] The solid dispersion of amorphous pimobendan obtained according to Example 1 was blended with the excipients listed below and crystalline pimobendan (AGC Pharma Chemicals, Spain, according to Figure 1 ) in a suitable blender. The resulting mixture was compressed into tablets using a suitable tableting machine and suitable punches.

[0111]

[0112]

[0113] Example 8 - Preparation of a pharmaceutical composition comprising the solid dispersion according to Example 1

[0114] The solid dispersion of amorphous pimobendan obtained according to Example 1 was blended with the excipients listed below and crystalline pimobendan (AGC Pharma Chemicals, Spain, according to Figure 1 ) in a suitable blender. The resulting mixture was compressed into tablets using a suitable tableting machine and suitable punches.

[0115]

[0116] Example 9 - XRPD diffraction pattern of the solid dispersions prepared according to Examples 1 and 4

[0117] XRPD patterns of Examples 1 and 4 (see Figure 1 ) were obtained using a PANalytical X’pert Pro X-ray MPD diffractometer with copper K-α radiation generated at 40 kV and 40 mA. The XRDP patterns clearly indicate that pimobendan is substantially in an amorphous form as no sharp characteristic peaks are present in the diffraction pattern of the solid dispersion.

[0118] Example 10 - Thermodynamic Solubility

[0119] The thermodynamic solubilities of crystalline pimobendan and the solid dispersion according to Example 1 were determined at two different pH values representative of dog gastric juice at 37 °C using a UV-calibrated dynamic dissolution monitoring instrument, which preferably consists of an immersion UV probe connected to a Rainbow instrument (Pion Inc., Billerica MA, USA).

[0120] The results obtained were as follows:

[0121]

[0122] The results clearly show that amorphous pimobendan exhibits significantly higher thermodynamic solubility than crystalline pimobendan. In maleic acid buffer at pH 3.0, the difference is about 4-fold, while in phosphate buffer at pH 6.5, the difference is greater than 10-fold.

[0123] Example 11 - In Vitro Dissolution Performance

[0124] The in vitro dissolution profiles of the pharmaceutical composition according to Example 5 and a commercially available pimobendan tablet formulation were determined at pH 3.0 and pH 6.5. Test conditions: an instrument similar to USP apparatus 2, V = 1000 ml, rotation speed = 50 rpm, chromatographic instrument: Agilent Infinity 1290UHPLC, RP18, 50 x 3.0 mm, 1.7 μm column.

[0125]

[0126] In 1000 mL of dissolution medium, the dissolution rate of the pharmaceutical composition containing the solid dispersion of Example 1 is comparable to that of the commercially available formulation at two pH values representative of gastric juice (see Figure 2 ).

[0127] Example 12 - Biorelevant Volumetric Dissolution and Permeation

[0128] The biorelevant volume dissolution and permeation of the pharmaceutical compositions of Examples 5 and 7 and a commercially available pimobendan tablet formulation were determined under default pH conditions and high pH conditions. Default conditions: maintained in the donor chamber at pH 3.0 representative of the stomach for 30 minutes, then at pH 6.2 representative of the small intestine for up to 120 minutes, and in the receptor chamber at pH 7.4 representative of blood. High pH conditions: maintained in the donor chamber at pH 6.5 representative of the stomach for 30 minutes, then at pH 7.5 representative of the small intestine for up to 120 minutes, and in the receptor chamber at pH 7.4 representative of blood. The pimobendan concentration was determined by immersing a UV probe, for example, by using a μFLUX device (Pion Inc., Billerica MA, USA). The in vitro flux was determined from the concentration-time curves recorded at 60 - 120 minute intervals in the receptor chamber. Permeability was calculated from the flux values and the drug substance concentration in the donor chamber.

[0129] The amount of pimobendan (drug) dissolved and then permeated through the membrane was determined as follows:

[0130]

[0131] Under default pH conditions and high pH conditions, the amount of drug dissolved from the pharmaceutical compositions containing a solid dispersion comprising substantially amorphous pimobendan was higher than that from the commercially available formulation. The amount of permeation showed an even greater difference (see respectively Figure 3 and 4 ).

[0132] The in vitro transmembrane flux value characterizing the total amount of substance across the biological membrane per unit area per unit time and thus the absorption rate were calculated as follows:

[0133]

[0134]

[0135] The calculated in vitro flux value of the pharmaceutical composition containing a solid dispersion comprising substantially amorphous pimobendan was much higher than that of the commercially available formulation. Therefore, it is expected that the solid dispersion / drug composition of the present invention has improved bioavailability. The improved bioavailability is due to the higher solubility, dissolution, supersaturation, and permeation of amorphous pimobendan compared to the commercially available formulation.

[0136] References

[0137] CN 112 618 505

[0138] EP 0 008 391

[0139] EP 0 439 030

[0140] EP 2 338 493

[0141] Rekis, T et al., Cryst. Growth Des. 2018, 18(1):264 - 273

[0142] Vasconcelos T et al., Drug Discovery Today 2012, 12:1068 - 1075

[0143] WO 2005 / 084647

[0144] WO 2008 / 055871

[0145] WO 2010 / 010257

[0146] WO 2010 / 055119

[0147] WO 2011 / 042463

[0148] WO 2015 / 082389

[0149] WO 2017 / 103054

[0150] WO 2021 / 081366

[0151] The following clauses are also part of the present invention and the general disclosure:

[0152] 1. A solid dispersion comprising amorphous pimobendan and one or more stabilizing polymers, preferably consisting of amorphous pimobendan and one or more stabilizing polymers, and the amorphous pimobendan is preferably substantially amorphous pimobendan.

[0153] 2. The solid dispersion according to clause 1, wherein the one or more stabilizing polymers are selected from: the polymerization products of N - vinylpyrrolidone and vinylpyrrolidone - vinyl acetate, and polymethacrylates.

[0154] 3. The solid dispersion according to clause 2, wherein the polymerization products of N - vinylpyrrolidone and vinylpyrrolidone - vinyl acetate are selected from: povidone (polyvinylpyrrolidone) and copovidone [poly-(1 - vinylpyrrolidone - co - vinyl acetate)]; and the polymethacrylates are selected from: poly(butyl 2 - methylprop - 2 - enoate); poly[2-(dimethylamino)ethyl 2 - methylprop - 2 - enoate]; and poly(methyl 2 - methylprop - 2 - enoate).

[0155] 4. The solid dispersion according to any one of clauses 1 to 3, wherein the one or more stabilizing polymers is copovidone [poly-(1-vinylpyrrolidone-co-vinyl acetate)], which is preferably the only stabilizing polymer in the solid dispersion.

[0156] 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, preferably 5% to 40% by weight, and more preferably 10% to 20% by weight based on the weight of the solid dispersion.

[0157] 6. The solid dispersion according to any one of clauses 1 to 4, wherein at least 70% of pimobendan is present in an amorphous form.

[0158] 7. A method for preparing the solid dispersion according to any one of clauses 1 to 6, wherein the solid dispersion is prepared by a melt-based method (preferably by hot melt extrusion) or a solvent evaporation-based method (preferably by spray drying).

[0159] 8. The method according to clause 7, which is a hot melt extrusion method and comprises the following steps:

[0160] (a) Treating pimobendan and the one or more stabilizing polymers, preferably at a barrel temperature of 120 - 200°C, more preferably at a barrel temperature of 150 - 180°C, with the aid of a pharmaceutical extruder (preferably a screw extruder, more preferably a twin-screw extruder) to obtain an extrudate.

[0161] (b) Using a granulator or pelletizer to crush the extrudate obtained in step (a) to obtain pellets, and

[0162] (c) Grinding the pellets obtained in step (b) to obtain the solid dispersion, which preferably comprises particles with an average diameter of less than 500 μm.

[0163] 9. The method according to clause 7, which is a spray drying method and comprises the following steps:

[0164] (a) Dispersing or dissolving pimobendan and the one or more stabilizing polymers in one or more solvents to obtain a feed solution, and the one or more solvents are preferably selected from: dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water or mixtures thereof.

[0165] (b) Pumping the feed solution obtained in step (a) to a drying chamber via an atomizer.

[0166] (c) Removing the one or more solvents in the drying chamber to obtain a solid dispersion, which preferably comprises particles with an average diameter of less than 500 μm.

[0167] 10. A solid dispersion obtainable by a method according to any one of clauses 7 to 9, which comprises amorphous pimobendan and one or more stabilizing polymers, preferably consisting of amorphous pimobendan and one or more stabilizing polymers, and the amorphous pimobendan is preferably substantially amorphous pimobendan.

[0168] 11. A pharmaceutical composition which comprises a solid dispersion according to any one of clauses 1 to 6 and 10 and one or more pharmaceutically acceptable excipients, and optionally further comprises one or more crystalline forms of pimobendan (preferably according to Figure 1 ), wherein preferably, the pharmaceutical composition is a tablet, more preferably a chewable tablet.

[0169] 12. The pharmaceutical composition according to clause 11, wherein the pharmaceutically acceptable excipients include at least one filler, at least one disintegrant, at least one lubricant and at least one flavoring agent.

[0170] 13. The pharmaceutical composition according to any one of clauses 11 to 12, which further comprises a pharmaceutically effective amount of one or more other active ingredients selected from angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists and / or loop diuretics.

[0171] 14. The pharmaceutical composition according to clause 13, wherein the optionally present one or more other active ingredients selected from angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists and / or loop diuretics are independently benazepril, spironolactone, furosemide and / or their derivatives in free form or in a physiologically acceptable salt form.

[0172] 15. The pharmaceutical composition according to any one of clauses 11 to 14, which is selected from: A, B, C, D:

[0173] A:

[0174]

[0175]

[0176] B:

[0177]

[0178] C:

[0179]

[0180] D:

[0181]

[0182]

Claims

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

2. The solid dispersion according to claim 1, wherein the one or more stabilizing polymers are selected from: the polymerization products of N-vinylpyrrolidone, vinyl acetate, and mixtures of vinylpyrrolidone and vinyl acetate; and polymerized methacrylates.

3. The solid dispersion according to claim 2, wherein the polymerization products of N-vinylpyrrolidone, vinyl acetate, and mixtures of vinylpyrrolidone and vinyl acetate and the polymerized methacrylates are selected from: povidone (polyvinylpyrrolidone), polyvinyl alcohol, and copovidone [poly-(1-vinylpyrrolidone-co-vinyl acetate)]; and the polymerized methacrylates are selected from: polybutyl 2-methylprop-2-enoate; poly[2-(dimethylamino)ethyl 2-methylprop-2-enoate]; and polymethyl 2-methylprop-2-enoate.

4. The solid dispersion according to any one of claims 1 to 3, wherein the solid dispersion; and / or the one or more stabilizing polymers; and / or the polymerization products of N-vinylpyrrolidone, vinyl acetate, and mixtures of vinylpyrrolidone and vinyl acetate; and / or the polymerized methacrylates independently of one another do not include crosslinked povidone (crosslinked polyvinylpyrrolidone, polyvinylpolypyrrolidone, PVPP).

5. The solid dispersion according to any one of claims 1 to 4, wherein the solid dispersion; and / or the one or more stabilizing polymers; and / or the polymerization products of N-vinylpyrrolidone, vinyl acetate, and mixtures of vinylpyrrolidone and vinyl acetate; and / or the polymerized methacrylates independently of one another do not include one or more hyperbranched polymers, which are optionally selected from: dendritic polymers, dendrimers, arborols, cascades, cauliflower-shaped polymers or star polymers, polydisperse hyperbranched polymers, dendrigraft polymers, or other high molecular weight polymers having a specific branched structure containing a central atom or molecule, the specific branched structure containing a central atom or molecule being monomeric or polymeric and having three or more chains extending therefrom; hyperbranched polyimines, hyperbranched polyurethanes, hyperbranched polyamides, hyperbranched polyesteramines, hyperbranched polyestersamides, hyperbranched polymers containing 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 having hydroxyl end groups.

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

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, preferably 5% to 40% by weight, and more preferably 10% to 20% by weight based on the weight of the solid dispersion.

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

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

10. The method according to claim 9, which is a hot melt extrusion method and comprises the following steps: (a) Processing pimobendan and the one or more stabilizing polymers by means of a pharmaceutical extruder, preferably a screw extruder, more preferably a twin-screw extruder, at a barrel temperature of preferably 120 - 200 °C, more preferably 150 - 180 °C, to obtain an extrudate; (b) Crushing the extrudate obtained in step (a) using a granulator or pelletizer to obtain granules; and (c) Grinding the granules obtained in step (b) to obtain a solid dispersion, which preferably comprises granules with an average diameter of less than 500 μm.

11. The method according to claim 9, which is a spray drying method and comprises the following steps: (a) Dispersing or dissolving pimobendan and the one or more stabilizing polymers in one or more solvents to obtain a feed solution, wherein the one or more solvents are preferably selected from: dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water, and mixtures thereof; (b) Pumping the feed solution obtained in step (a) into a drying chamber via an atomizer; and (c) Removing the one or more solvents in the drying chamber to obtain a solid dispersion, which preferably comprises granules with an average diameter of less than 500 μm.

12. A solid dispersion obtainable by the method according to any one of claims 9 to 11, which comprises amorphous pimobendan and one or more stabilizing polymers, preferably consisting of amorphous pimobendan and one or more stabilizing polymers, and the amorphous pimobendan is preferably substantially amorphous pimobendan.

13. A pharmaceutical composition, which comprises the solid dispersion according to any one of claims 1 to 8 and 12 and one or more pharmaceutically acceptable excipients, and optionally further comprises one or more crystalline forms of pimobendan (preferably according to Figure 1), wherein preferably, the pharmaceutical composition is a tablet, more preferably a chewable tablet.

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutically acceptable excipient comprises at least one filler, at least one disintegrant, at least one lubricant, and at least one flavoring agent.

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

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

17. The pharmaceutical composition according to any one of claims 13 to 16, selected from: A, B, C, D, and E (the crystalline pimobendan described in the following table preferably refers to the crystalline pimobendan according to Figure 1): A： B： C： D： E：

Images