EA041471B1 - PHARMACEUTICAL COMPOSITIONS OF PIMOBENDAN - Google Patents

Description

The field of technology to which the invention belongs

The invention relates to the field of medicine, in particular to the field of veterinary medicine. The invention relates to improvements in formulations for oral administration of the phosphodiesterase inhibitor pimobendan for the treatment of congestive heart failure that occurs due to heart valve insufficiency or dilated cardiomyopathy, and methods for preparing the formulations.

Background Information

Pimobendan (4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)-5-methyl-3(2H)-pyridazinone) is a benzimidazolepyridazone derivative which has been described in EP 0008391 as a substance having cardiotonic, hypotensive and antithrombotic activity.

EP 0439030 reports the low solubility of pimobendan in an aqueous medium, which is highly dependent on pH. Depending on the buffer system used, about 100 to 300 mg/l dissolves at pH between 1 and 3, but at pH 5 only about 1 mg/l dissolves in water. In humans, this phenomenon leads to large fluctuations in blood concentrations, which are usually too low. These unsatisfactory absorption characteristics were explained by the high dependence of pimobendan solubility on pH in the aquatic environment and by the variable pH conditions in the gastrointestinal tract of the study subjects. In accordance with this patent, the low solubility and high solubility-dependence of pimobendan on pH can be overcome by using a homogeneous dry mixture of powdered pimobendan and powdered citric acid, where the above mixture consists of no more than about one part by weight of pimobendan for at least about five parts by weight of citric acid and pharmaceutically active carriers. Said mixture is enclosed in capsules or compressed into tablets for oral use. It is believed that highly fluctuating blood concentrations can be prevented by the acidic microsphere that results from the dissolution of citric acid and is formed around the pimobendan particles. This microsphere is always acidic and ensures reliable, practically pH-independent dissolution and absorption of pimobendan.

WO 2005/084647 relates to a novel solid composition which comprises pimobendan which is homogeneously dispersed in a polyvalent acid selected from the group consisting of citric acid, acetic acid, maleic acid, tartaric acid or its anhydride, and a flavoring agent. According to the above publication, a large amount of citric acid and its sour taste is not easily tolerated by most animals. Thus, these formulations must be force-fed to the animal or mixed with food prior to use. According to WO 2005/084647 these difficulties can be overcome by using this new composition, preferably in the form of tablets. Most preferred is a tablet, characterized in that such a tablet contains 1.25, 2.5, 5 or 10 mg of pimobendan, and additionally includes citric acid, preferably in an amount of 50 mg/g of the solid composition, an artificial beef-flavored flavor and a pharmaceutical acceptable fillers.

WO 2010/055119 discloses a novel composition that includes pimobendan and organic carboxylic acids, where the only carboxylic acid is succinic acid and the weight ratio of succinic acid to pimobendan is at least 11:1.

WO 2010/010257 relates to the use of a coating composition for applying a solid veterinary pharmaceutical composition containing pimobendan using a spray application method, which consists of a powder of an appetite enhancer, a binder and a solvent.

EP 2338493 provides new crystalline forms of pimobendan whose dissolution characteristics are such that the addition of an organic acid or anhydride is thus not necessary to ensure sufficient dissolution of the substance.

Based on its biopharmaceutical properties, pimobendan can be assigned to class IV in the Biopharmaceutical Classification System (BCS). This means that it exhibits problematic molecular characteristics such as low solubility and low absorbability; both properties are considered as such that limit the absorption rate. Despite this, the underabsorption characteristics of pimobendan can be explained primarily by the high dependence of solubility on pH in the aquatic environment and by the varying pH conditions in the gastrointestinal tract of treated animals. It is known that even the pH of the gastric juice can fluctuate over a relatively wide range, namely between 1 and 5, depending on the presence of food. It has been found that during fasting, the stomach pH in dogs ranges from 0.9 to 2.5, while the stomach pH can show a pH increase of 2-3 units in the first hour after a meal. Also, intestinal juices are characterized by varying pH conditions, which range from 3 to 7.5.

In accordance with this prior art, insufficient absorption of pimobendan due to

- 1 041471 juice dependence of its dissolution on pH is prevented by the simultaneous use of a large amount of organic acid in the composition or by using another crystalline form (polymorphic form) of this substance.

The aim of the present invention is thus to provide an improved pimobendan formulation that overcomes the limitations of the prior art.

Brief summary of the invention

Surprisingly, the inventor has succeeded in overcoming the high pH dependence of pimobendan dissolution and in obtaining a very satisfactory level of dissolution under any pH conditions that are encountered in the gastrointestinal tract, and thus in sufficient absorption even with significant fluctuations in the pH value in the gastrointestinal tract. tract without the use of an organic carboxylic acid or by modifying the crystalline form of the substance, but using the method of embedding in lipids (lipid coating). Lipid-embedded pimobendan particles are produced by spray crystallization technology, for example as described in US 4,865,851. Spray crystallization (also known as spray cooling) is one method that is used to produce microparticles or, in particular, microspheres. They are solid spherical particles, having an approximate size within a micrometer, in which the drug is evenly distributed throughout the volume of the particles. The lipid-embedded particles exhibit rapid and substantial dissolution of pimobendan from an oral formulation at any pH that occurs in the gastrointestinal tract of treated animals, providing sufficient drug absorption regardless of highly variable pH conditions. The spray crystallization technology developed to produce lipid-embedded particles is fast, inexpensive, and can be easily scaled up. It is environmentally friendly because it does not require the use of a solvent in the composition or in the manufacturing process. By using lipid-embedded particles, it has become possible to create palatable oral formulations of pimobendan that dissolve rapidly and substantially under all pH conditions that represent the microenvironment(s) of the gastrointestinal tract, without the inclusion of any acidic compounds.

The object of the present invention has been unexpectedly solved by providing a pharmaceutical composition which comprises pimobendan in the form of particles embedded in carrier matrix lipids, wherein the carrier matrix comprises polyethylene glycols (PEGs) which are selected from the group consisting of polyethylene glycols having an average molecular weight of 4000 to 6000 g/mol.

In another aspect, the object of the present invention has been surprisingly solved by providing a composition wherein incorporation of pimobendan into carrier matrix lipids serves to ensure rapid and substantial dissolution of pimobendan regardless of pH conditions.

In yet another aspect, the object of this invention has been unexpectedly solved by providing a process for obtaining a composition, as disclosed in this document, which includes:

(a) dispersing pimobendan particles in a molten carrier matrix, wherein the carrier matrix comprises polyethylene glycols (PEGs) which are selected from the group consisting of polyethylene glycols having an average molecular weight of 4000 to 6000 g/mol, (b) spraying the dispersion obtained in step (a), and (c) cooling and collecting coated particles.

In yet another aspect, the object of this invention has been unexpectedly solved by providing a composition that includes pimobendan in the form of particles embedded in the lipids of a carrier matrix obtained using the methods to obtain a composition as disclosed herein.

In yet another aspect, the object of the present invention has been unexpectedly solved by providing a pharmaceutical composition for oral administration to warm-blooded animals, preferably domestic animals, in particular dogs, comprising a veterinarily effective amount of the composition, as disclosed herein, one or more physiologically acceptable excipients, and optionally a veterinarily effective amount of one or more additional active ingredients selected from the group of angiotensin converting enzyme (ACE) inhibitors, aldosterone antagonists and/or loop diuretics.

By using the pharmaceutical composition according to the invention, the low solubility and high pH dependence of pimobendan solubility can be overcome without the co-administration of a large amount of organic acid or the use of another crystalline form (polymorph) of the substance, as demonstrated by the rapid and substantial dissolution of the active substance at any pH value that represents the microenvironment(s) of the gastrointestinal tract. The substantially pH-independent dissolution ensures sufficient uptake even under varying pH conditions in subjects being treated.

- 2 041471

Detailed Description of the Invention

Before embodiments of the present invention are described in detail, it should be noted that the singular form as used herein and in the appended claims includes reference to the plural form unless the context clearly indicates otherwise.

Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as is conventionally known to one of ordinary skill in the art to which this invention pertains. All ranges and values given may vary from 1% to 5% unless otherwise indicated or otherwise known to one of ordinary skill in the art, thus the term approximately is usually omitted from the description and claims. While any methods and materials similar or equivalent to those described herein may be used in the practice or testing of this invention, preferred methods, devices and materials will be described below. All of these publications in this document are incorporated herein by reference for the purpose of describing and disclosing substances, excipients, carriers and methods, as indicated in the publications, which can be used in connection with this invention. Nothing in this document should be construed as an admission that this invention does not provide a right to precede such disclosure by virtue of an earlier invention.

In one aspect, the object of the present invention has been surprisingly solved by a method for preparing a composition as disclosed herein, which includes:

(a) dispersing particulate pimobendan, preferably with an average particle size of less than 20 µm, in a molten carrier matrix comprising polyethylene glycols with an average molecular weight of 4000 to 6000 g/mol, most preferably PEG 6000, where the carrier matrix preferably has a dot melting from 40 to 80°C, more preferably from 50 to 70°C, by using conventional dispersion techniques, such as using a high shear mixer, to obtain a dispersion, preferably a homogeneous dispersion;

(b) atomizing the dispersion obtained in step (a) by using conventional atomizers such as centrifugal atomizers, high pressure nozzles or pneumatic nozzles and/or sonic nozzles, preferably installed in standard spray curing/cooling equipment, more preferably when using spray systems based on a dual fluid pressure nozzle or pneumatic nozzle mounted on standard spray curing/cooling equipment at a propellant pressure of 1 to 10 bar, preferably 2 to 8 bar, and more preferably 3 to 6 bar; and (c) cooling and collecting the coated particles using conventional cooling and collecting techniques, such as using a stream of cold air or an inert gas such as dry nitrogen, preferably at a temperature of 0 to 30°C, more preferably at a temperature of 3 to 15 °C, even more preferably at a temperature of 5 to 15°C, most preferably at a temperature of 4 to 8°C, to the equipment for spraying and collecting particles, preferably in a cyclone separator or a bag filter.

According to a further aspect, the object of the present invention has been unexpectedly solved by providing a composition which comprises pimobendan particles with a solid shell carrier matrix, wherein the carrier matrix comprises polyethylene glycols (PEGs) which are selected from the group consisting of polyethylene glycols having an average molecular weight of 4000 to 6000 g/mol, and where pimobendan in the composition or similar drugs exhibit rapid and complete (rapid and substantial) dissolution under all pH conditions that represent the microenvironment(s) of the gastrointestinal tract of the animals being treated.

According to a further aspect, the present invention provides pharmaceutical compositions for oral administration to pets, in particular dogs, which comprise pimobendan particles embedded in lipids in a suitable carrier material.

In accordance with yet another additional aspect, the present invention provides a method for providing reliable, rapid and substantial dissolution of pimobendan under all pH conditions that represent the microenvironment(s) of the gastrointestinal tract of animals being treated, which includes coating pimobendan with an acceptable carrier and including placed in particulate lipids into an oral composition, eg tablets.

To effectively overcome the high pH dependence of pimobendan dissolution and provide coated particles that exhibit rapid and substantial dissolution under all pH conditions that are present in the gastrointestinal tract of dogs, with an average diameter of coated pimobendan particles preferably less than 50 µm.

The melting point of the carrier must be high enough to prevent melting of the coated particles in the oral cavity, but not too high so that the pimobendan itself does not melt and/or undergo chemical degradation during the coating process. Thus, the carrier or carrier mixture used as carrier matrix in the present invention will have a melting point of 40 to 80°C and preferably 50 to 70°C.

- 3 041471

In a further embodiment of this invention, the carrier matrix comprises polyethylene glycol, in particular PEG 6000.

In a further embodiment of the present invention, polyethylene glycol 6000 is present in an amount of 10 to 100% by weight of the carrier matrix component of the composition, preferably 20 to 75% by weight of the carrier matrix component of the composition, more preferably 20 to 50% by weight of the carrier matrix component of the composition. .

In a further embodiment of the present invention, the coated particles according to the present invention, i. e. particulate pimobendan embedded in a carrier matrix lipids have a median value (D50) for particle size distribution that is less than 500 µm, preferably less than 300 µm, more preferably less than 250 µm, and even more preferably less than 200 µm. Particle size control is essential to ensure that the dissolution of pimobendan from the subsequent formulated product will be rapid and substantial under all pH conditions that are present in the gastrointestinal tract of the treated animals. Coated particles having a D50 value of less than 200 µm are preferred in this regard. The D50 value is the median for the particle size for a given particle size distribution, i.e. particle size value, compared to which 50% of all particles are smaller. For example, a D50 value of 200 µm means that 50% of all particles are smaller than 200 µm.

In a further embodiment of the present invention, the content of pimobendan in the coated particles ranges from 1 to 80% by weight, preferably from 5 to 30% by weight, more preferably from 10 to 20% by weight.

In addition, acceptable pimobendan coating carriers may also include additional polyglycosylated glycerides.

Polyglycosylated glycerides are mixtures of fatty acid glycerides and polyoxyethylene fatty acid esters. In these mixtures, the fatty acids are saturated or unsaturated and the glycerides are mono-, di-, or triglycerides, or mixtures thereof in any ratio. Examples of suitable polyglycosylated glycerides include, but are not limited to, lauroyl macrogol glycerides or stearoyl macrogol glycerides.

Polyglycosylated glycerides have a hydrophilic-lipophilic balance (HLB) value greater than 10 and are water-dispersible. Preferably, the polyglycosylated glycerides are stearoyl macrogol glycerides. Particularly preferred polyglycosylated glycerides are stearoyl macrogol-32 glycerides (eg Gelucire 50/13). Stearoyl macrogol-32 glycerides are semi-solid/solid at room temperature, having a melting point of 50°C.

USP polyethylene glycols (PEGs), also known as macrogols, are hydrophilic polymers of oxyethylene. PEGs having a molecular weight average greater than 900 g/mol are generally semi-solid or solid at ambient temperature. A suitable average molecular weight range for PEGs is from 1500 to 20000 g/mol. Suitable commercially available products include, but are not limited to, PEG 1500, PEG 4000, and PEG 6000. In accordance with this invention, the PEG(s) present in the carrier matrix has(have) an average molecular weight range of 4000 to 6000 g/mol. In an additional special group of compositions of this embodiment, this PEG has an average molecular weight of approximately 6000 g/mol.

The carrier matrix may also contain a mixture of at least one polyglycosylated glyceride and at least one polyethylene glycol. Preferred polyglycosylated glycerides, which are stearoyl macrogol-32 glycerides, are present in an amount that is 10-100% by weight of the carrier matrix component of the composition, and particularly preferably 20-50% by weight of the carrier matrix component of the composition. Preferred polyethylene glycols have an average molecular weight of 4000 to 6000 g/mol and suitable PEG is present in an amount that is 10-100% by weight of the carrier matrix component of the composition, and preferably 30-80% by weight of the carrier matrix component of the composition. Only one polyglycosylated glyceride and one polyethylene glycol may be present in such a case.

Particles according to the present invention can be prepared by spraying a dispersion of pimobendan into a molten carrier matrix and cooling the particles obtained according to the present invention, and such a process constitutes a further aspect of the present invention. The dispersion can be prepared by adding particulate pimobendan to a molten carrier or mixture of carriers, or alternatively by mixing the ingredients of the dispersion together in solid form and melting the carrier matrix. The particulate pimobendan can be dispersed in the molten carrier matrix using conventional techniques, such as using a high shear mixer. In general, the temperature of the molten carrier matrix should be 20-40° C. higher than its melting point. In general, the carrier or carrier mixture that is used to coat the pimobendan particles should have a melting point in the range of 40 to 80°C, preferably 50 to 70°C, and the temperature of the molten matrix

- 4 041471 tsy carrier will be 20-40°C higher than its melting point. Atomization techniques that can be applied include the use of conventional atomizers such as centrifugal atomizers, high pressure nozzles and sonic nozzles. The use of a spray system based on a dual fluid pressure nozzle mounted on standard spray curing/cooling equipment is particularly suitable.

During the atomization process, the molten dispersion will generally be delivered to the atomizer nozzle at a temperature in the range of 70 to 100°C, preferably 75 to 95°C, more preferably 75 to 90°C, the exact temperature depending on the specific carrier matrix used. The propellant supplied to the nozzle may be air or an inert gas such as nitrogen. The propellant pressure is 1 to 10 bar, preferably 2 to 8 bar, and more preferably 3 to 6 bar. The spray pressure is desirably controlled in order to obtain particles of the preferred size.

The coated particles can be crystallized and collected using conventional techniques. The coated particles can be suitably crystallized by applying a stream of cold air or dry nitrogen to the spray chamber at 0 to 30°C, preferably 3 to 15°C, more preferably 5 to 15°C, most preferably 4 to 8 °C. The coated particles are collected as a free flowing powder using either a cyclone separator or a baghouse. The coated particles are spherical and have a D50 value of less than 500 µm, preferably less than 300 µm, more preferably less than 250 µm, and even more preferably less than 200 µm.

Coated particles according to the invention may be incorporated into an oral pharmaceutical composition using additional pharmacologically active ingredients and/or physiologically acceptable carriers and/or excipients.

Compositions according to the invention may, for example, include tablets, granules, powders, suspensions, oral ointments and gels. Tablets, including chewable tablets, in particular, are the preferred dosage form.

Accordingly, the invention also relates to an oral composition of pimobendan, preferably a tablet, which comprises a veterinarily effective amount of pimobendan as the active substance in the form of particles embedded in the lipids of a carrier matrix and physiologically acceptable excipients.

The amount of pimobendan in the oral composition is preferably in the range of 0.01 to 10% by weight, more preferably 0.5 to 1.0% by weight of the total composition.

Pimobendan oral compositions of the present invention may also include veterinarily effective amounts of additional active ingredients which may be selected from angiotensin converting enzyme (ACE) inhibitors, aldosterone antagonists and/or loop diuretics. Non-limiting examples of active substances that can be used in combination with pimobendan coated particles in accordance with this invention are: benazepril (XPC no. 86541-75-5), spirolactone (XPC no. 52-01-7) and/or furosemide ( XPC No. 54-31-9), all independently of each other in free form or in the form of a physiologically acceptable salt, which is preferably placed in the carrier matrix lipids. These additional actives may also be added to the oral composition of pimobendan in the form of lipid-embedded particles obtained using a spray crystallization technique. Preferably, oral compositions of pimobendan according to this invention also consist of veterinarily effective amounts of benazepril in free form or in the form of a physiologically acceptable salt, which is preferably placed in a carrier matrix. Additional active substances may be present in the oral composition of this invention in an amount of from 0.01 to 50% by weight, preferably from 0.1 to 20% by weight, based on the total weight of the total composition(s).

Oral formulations of pimobendan can be formulated using conventional pharmaceutically acceptable excipients. Thus, for example, tablets can be prepared using binders (for example, pregelatinized starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (for example, magnesium stearate, talc or colloidal silicon oxide ), disintegrants (eg starch or sodium carboxymethyl starch) or wetting agents (eg sodium lauryl sulfate). The tablet composition according to the present invention, in addition, contains one or more attractive, physiologically acceptable, natural or synthetic flavors. Preferred flavors are artificial beef flavor, liver powder, and brewer's yeast. Flavoring agents are preferably present in the tablet composition of the present invention in the range of 1.0 to 60% by weight, more preferably 5.0 to 30% by weight, based on the total weight of the entire composition(s).

- 5 041471

An oral ointment or gel composition according to the invention may contain pharmacologically acceptable excipients, for example thickeners (e.g. xanthan gum, polyvinylpyrrolidone, polyacrylates such as carbopols, corn starch, microcrystalline cellulose, hydroxyethyl cellulose, silicon dioxide, or combinations thereof), humectants substances (e.g. glycerol), preservatives (e.g. benzyl alcohol, benzoic acid, benzoic acid esters or p-hydroxybenzoates, pH adjusting agents (bases or acids), binders, fillers, surfactants or dispersing agents. The above pharmacologically acceptable excipients are known to those of ordinary skill in the art of veterinary formulations.The oral ointment or gel composition of the present invention also contains veterinarily acceptable flavoring agents. Bretenia are, for example, beef-flavoured artificial flavor, food extracts such as dried liver or malt extract, and honey-flavoured flavors.

The pharmaceutical compositions of the present invention may be prepared according to conventional methods well known in the pharmaceutical industry. Thus, for example, tablets can be obtained by direct compression of a dry mixture of lipid-embedded particles of pimobendan together with excipients and optionally together with additional active substances or by wet granulation. An oral ointment or gel composition can be prepared by dispersing lipid-embedded pimobendan particles and optionally additional active ingredients in a suitable carrier.

Compositions for use in accordance with this invention may, if necessary, be present in a package or dispenser device, which may contain one or more unit doses. The packaging may, for example, consist of a metal or plastic film, such as a blister pack.

The compositions of the present invention are useful in the treatment of congestive heart failure which occurs due to heart valve insufficiency or dilated cardiomyopathy in companion animals, particularly dogs.

Efficiency is due to sufficient dissolution and subsequent absorption of the active substance. The dissolution profiles obtained for the tablet composition according to the invention and for the commercially available tablets in which both tablets contain 5 mg of pimobendan were compared in pH 1.2, 4.5 and 7.5 buffers, i.e. under pH conditions that represent different parts/microenvironments of the gastrointestinal tract of pets. Dissolved concentrations of pimobendan were determined using an approved Ultra High Performance Liquid Chromatography (UHPLC) method.

Oral compositions according to the invention exhibit high palatability, which means voluntary acceptance or consumption of the composition by warm-blooded animals, eg pets, in particular dogs. Administration of an oral composition containing lipid-embedded pimobendan particles and suitable additional ingredients according to the present invention was tested in dogs.

Brief description of the figures

Fig. 1: Relative dissolution profiles of tablet formulations that contain 5 mg of pimobendan prepared according to Example 3 of the present invention and are commercially available in the form of chewable tablets, respectively, under highly acidic pH conditions (pH 1.2). Test conditions: V=1000 ml, rotation speed=100 rpm, chromatography conditions: Agilent Infinity 1290 UHPLC, RP18, 50x3.0 mm, 1.7 µm column, 27:73 v/v% acetonitrile: phosphate buffer as mobile phase, volumetric flow rate 0.4 ml/min., detection at a wavelength of 290 nm.

Fig. 2: Relative dissolution profiles of tablet formulations which contain 5 mg of pimobendan prepared according to Example 3 of the present invention and are commercially available in the form of chewable tablets, respectively, under moderately acidic pH (pH 4.5) conditions. The test conditions are identical to those for FIG. 1.

Fig. 3: Relative dissolution profiles of tablet formulations that contain 5 mg of pimobendan prepared according to Example 3 of the present invention and are commercially available in the form of chewable tablets, respectively, at neutral pH (pH 7.5). The test conditions are identical to those for FIG. 1.

Examples

The following examples serve to further illustrate the present invention; but this should not be construed as limiting the scope of the present invention disclosed in this application.

Example 1 Pimobendan embedded in Gelucire 50/13 carrier matrix lipids (18.0 kg) was melted in a stainless steel vessel and brought to a temperature of 85°C. Pimobendan (2.0 kg) with an average particle size <20 µm was added to the molten liquid. The molten dispersion was subjected to high shear mixing to obtain a homogeneous suspension and

- 6 041471 was pumped into the spray crystallization device. The mixture was sprayed using a spray system based on a two-fluid pressure nozzle with a propellant gas pressure of 3 to 6 bar. The atomized droplets were cooled by air entering the atomization chamber at a temperature of 5 to 10° C., and the solid particles were collected in a cyclone separator. The lipid-embedded pimobendan was a spherical particle with an average particle size of 90 µm.

Example 2 Pimobendan embedded in the carrier matrix lipids Gelucire 50/13 (4.5 kg) and PEG 6000 (13.5 kg) was melted in a stainless steel vessel and brought to a temperature of 90°C. Added pimobendan (2 kg) with a particle size <20 μm. The molten dispersion was subjected to high shear mixing to obtain a homogeneous suspension, and this mixture was subjected to spray crystallization as described in Example 1 to obtain a product coated with lipids, which has the same particle size and shape. For example, three different batches were made with a D50 value of 118 µm, 136 µm, and 166 µm, respectively.

Example 3 Tablet formulation.

Pimobendan placed in a carrier matrix that consists of Gelucire 50/13 and PEG 6000 was mixed with pig liver flavor, dry yeast and additional excipients in a rotary mixer. The resulting mixture was compressed into tablets using a suitable tablet press and suitable punches.

Direct Compression Tablets Quantity (v/v%) Pimobendan embedded in carrier matrix lipids 6.3 Lactose 20.5 Pig liver powder 20.0 Microcrystalline cellulose 19.0 pregelatinized starch AND 2 Sodium carboxymethyl starch 10.0 Dry yeast 10.0 Talc 2.0 magnesium stearate 1.0

Example 4 Tablet formulation.

Pimobendan embedded in Gelucire 50/13 carrier lipid matrix, furosemide and excipients were mixed in a rotary mixer and the mixture was then compressed into tablets using a suitable tablet press and suitable punches.

oral tablet Quantity (v/v%) Pimobendan embedded in carrier matrix lipids 3.1 Furosemide 5.0 Lactose 25.0 Microcrystalline cellulose 21.9 Flavored beef flavor 20.0 pregelatinized starch 14.0 Sodium carboxymethyl starch 8.0 Talc 2.0 magnesium stearate 1.0

Example 5 Tablet formulation.

Lipid-embedded pimobendan particles, prepared according to Example 2, were mixed with lipid-coated benazepril, the particles of which were placed in a carrier matrix, which consists of glycerol distearate, dry yeast, liver-flavoured artificial flavor and additional excipients, in a rotary mixer, and then the resulting mixture was compressed into tablets using a suitable tablet press.

- 7 041471

Direct Compression Tablets Quantity (v/v%) Pimobendan embedded in carrier matrix lipids 6.3 Lipid coated benazepril 12.5 Dry yeast 25.0 Sodium carboxymethyl starch 15.0 Microcrystalline cellulose 13.2 Lactose monohydrate 12.5 pregelatinized starch 10.0 Liver Flavored Artificial Flavor 3.5 Talc 2.0

Example 6 Dissolution in vitro.

The absorption of pimobendan is highly dependent on the level of dissolution of the active substance under the variable pH conditions that are present in the gastrointestinal tract. The dissolution profiles of pimobendan from tablets prepared in accordance with example 3 of the present invention and commercially available chewable tablets, which both contain 5 mg of the active substance, were compared under various pH conditions that are present in the gastrointestinal tract. The results are shown in FIG. 1-3. As can be seen from these data, the dissolution rate of pimobendan from the tablet formulation prepared in accordance with this invention was high and significant at each of the pH values tested. At pH 1.2, the rate and level of dissolution from the composition of the present invention and commercially available chewable tablets were substantially identical. Despite this, at pH 4.5 and 7.5, the dissolution of the active substance was much more rapid and complete from the tablet composition in accordance with this invention than for the reference preparation. These results clearly demonstrate that the tablet composition obtained in accordance with this invention provides a very satisfactory dissolution of pimobendan under all conditions that are present in the gastrointestinal tract, even if there are significant pH fluctuations, without the addition of any organic carboxylic acids. , which are present in abundant amounts in commercially available preparations.

Dissolution rate (%) - pH 1.2 Time (min.) 0 10 15 20 thirty 45 Composition according to Example 3 Commercial composition 0 0 86.8 74.9 91.0 90.0 Level] 92.7 93.7 open 94.1 93.8 ia (%) - p 96.2 94.5 H4.5 Time (min) 0 10 15 20 thirty 45 Composition according to Example 3 0 88.2 92.3 93.2 93.8 93.8 a commercial composition 0 62.0 77.8 85.7 88.7 88.4

Dissolution rate (%) - pH7.5 Time (min) 0 10 15 20 thirty 45 Composition according to Example 3 0 85.0 89.6 89.8 90.4 90.7 a commercial composition 0 58.6 71.9 78.4 81D 81.8

Example 7 In vitro dissolution.

The dissolution profiles of pimobendan and benazepril from tablets prepared according to Example 5 containing 2.5 mg of pimobendan and 5 mg of benazepril were compared with formulations of commercially available chewable tablets in pH 1.2, 4.5 and 7.5 buffers. The results obtained from this study demonstrate that the dissolution of pimobendan and benazepril from the composition, which

- 8 041471 keeps both active substances, placed in a lipid shell, is slower than in the corresponding commercial composition, which contains only one active substance, i.e. either pimobendan or benazepril, the dissolution rate of both actives after 45 minutes of dissolution is higher for the combination than for the commercial mono-composition under all pH conditions that are present in the gastrointestinal tract of dogs.

Dissolution rate (%) - pH 1.2 Time (min.) 0 10 15 20 thirty 45 Pimo Ben Pimo Ben Pimo Ben Pimo Ben Pimo Ben Composition according to Example 5 0 32 33 48 47 62 59 82 78 89 88 Commercial composition of pimobendan 0 63 - 75 - 83 - 87 - 87 - Commercial composition of benazepril 0 - 56 - 71 - 76 - 80 - 84

Pimo=pimobendan; Bena = benazepril.

Dissolution rate (%) - pH 4.5 Time (min.) 0 10 15 20 thirty 45 Pimo Ben Pimo Ben Pimo Ben Pimo Ben Pimo Ben Composition according to Example 5 0 38 24 55 37 67 48 82 63 82 69 Commercial composition of pimobendan 0 58 - 68 - 72 - 74 - 73 - Commercial composition of benazepril 0 - 34 - 45 - 53 - 58 - 63

Pimo=pimobendan; Bena = benazepril.

Dissolution rate (%) - pH 7.5 Time (min.) 0 10 15 20 thirty 45 Pimo Ben Pimo Ben Pimo Ben Pimo Ben Pimo Ben Composition according to Example 5 0 43 33 59 48 70 60 80 73 81 78 Commercial composition of rpimobendan 0 51 - 60 - 64 - 67 - 67 - Commercial composition of benazepril 0 - 54 - 61 - 63 - 62 - 60

Pimo=pimobendan; Bena = benazepril.

Example 8 - Test for palatability (degree of acceptability) 30 male and female dogs of different breeds and ages were tested indoors. The investigator offered each dog a single daily dose of the tablet formulation prepared according to Example 3 of the present invention, which was adapted to the weight of the animal, for three days. In the case of the tablet composition according to the present invention, the tablet was first offered by hand for 30 seconds. If the dog did not accept the composition, it was offered to the dog in its empty bowl. The dog again had 30 seconds to accept the composition. If one of the above suggestions resulted in the dog voluntarily taking the pill, this was considered acceptable or voluntary taking the pill. If the dog spat out the tablet, this was reported as a rejection. Voluntary intake was observed in 82 out of 90 possible cases (ie when the tablet was offered to 30 animals for 3 days). This corresponds to an acceptance level of 91.1%.

Bibliography

1. EP 0008391.

2. EP 0439030.

3. EP 2338493.

4. WO 2005/084647.

5. WO 2010/010257.

6. WO 2010/055119.

-

Claims (10)

CLAIM 1. A pharmaceutical composition that includes pimobendan in the form of particles placed in the carrier matrix lipids, where the carrier matrix includes polyethylene glycols (PEGs), which are selected from the group consisting of polyethylene glycols having an average molecular weight of from 4000 to 6000 g/mol. 2. The pharmaceutical composition of claim 1, wherein the incorporation into the matrix lipids of the carrier serves to ensure rapid and substantial dissolution of the pimobendan regardless of pH conditions. 3. Pharmaceutical composition according to any one of claims 1, 2, wherein the carrier matrix comprises polyethylene glycol 6000. 4. The pharmaceutical composition of claim 3, wherein polyethylene glycol 6000 is present in an amount of 10 to 100% by weight of the carrier matrix component of the composition, preferably 20 to 75% by weight of the carrier matrix component of the composition, more preferably 20 to 50% by weight. the weight of the carrier matrix component of the composition. 5. Pharmaceutical composition according to any one of claims 1-4, where the composition consists of: Quantity (v/v%) Pimobendan embedded in carrier matrix lipids 6.3 Lactose 20.5 Pig liver powder 20.0 Microcrystalline cellulose 19.0 pregelatinized starch AND 2 Sodium carboxymethyl starch 10.0 Dry yeast 10.0 Talc 2.0 magnesium stearate 1.0 6. Pharmaceutical composition according to any one of claims 1 to 5, wherein the distribution of the average size value (D50 value) of the coated particles, i.e. particulate pimobendan embedded in carrier matrix lipids is less than 500 µm, preferably less than 300 µm, more preferably less than 250 µm, and even more preferably less than 200 µm; and where preferably the coated particles are spherical. 7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the content of pimobendan in the coated particles ranges from 1 to 80% by weight, preferably from 5 to 30% by weight, more preferably from 10 to 20% by weight. 8. A method for producing a pharmaceutical composition according to any one of claims 1 to 7, which includes: (a) dispersing pimobendan particles in a molten carrier matrix, wherein the carrier matrix comprises polyethylene glycols (PEGs) which are selected from the group consisting of polyethylene glycols having an average molecular weight of 4000 to 6000 g/mol, (b) spraying the dispersion obtained in step (a), and (c) cooling and collecting coated particles. 9. The method of obtaining according to claim 8, which includes: (a) dispersing pimobendan in the form of particles, preferably with an average particle size of less than 20 μm, in a molten carrier matrix comprising polyethylene glycols with an average molecular weight of from 4000 to 6000 g/mol, most preferably PEG 6000, where the carrier matrix preferably has a melting point of 40 to 80° C., more preferably 50 to 70° C., by using conventional dispersion techniques such as using a high shear mixer to obtain a dispersion, preferably a homogeneous dispersion; (b) atomizing the dispersion obtained in step (a) by using conventional atomizers such as centrifugal atomizers, high pressure nozzles or pneumatic nozzles and/or sonic nozzles, preferably installed in standard spray curing/cooling equipment, more preferably when using spray systems based on a dual fluid pressure nozzle or pneumatic nozzle mounted on standard spray curing/cooling equipment at a propellant pressure of 1 to 10 bar, preferably 2 to 8 bar, and more preferably 3 to 6 bar; and (c) cooling and collecting the coated particles using conventional cooling and collecting techniques, such as using a stream of cold air or an inert gas such as dry nitrogen, preferably at a temperature of 0 to 30°C, more preferably at a temperature of 3 to 15 °C, even more preferably at a temperature of 5 to 15°C, most preferably at a temperature of 4 to 8°C, to the equipment for spraying and collecting particles, preferably in a cyclone separator or a bag filter. 10. A pharmaceutical composition that includes pimobendan in the form of particles embedded in carrier matrix lipids, which are obtained using the method according to any one of claims 8, 9, where the carrier matrix includes polyethylene glycols (PEGs), which are selected from the group consisting of polyethylene glycols - -