Pharmaceutical composition comprising pimobendan

专利摘要:
The invention relates to novel solid formulations comprising as pharmaceutically active compound pimobendan and to processes for producing such solid formulations. 5 The invention furthermore relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, wherein the solid formulations according to the invention are used. -1/7 Fig. 1 . .- 5
公开号:AU2013204087A1
申请号:U2013204087
申请日:2013-04-08
公开日:2013-05-02
发明作者:Martin A. Folger；Bernhard Hassel；Stefan Henke；Jens Schmalz
申请人:Boehringer Ingelheim Vetmedica GmbH；Boehringer Ingelheim Vetmedica Inc；
IPC主号:A61K9-20

专利说明:
Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Pharmaceutical composition comprising pimobendan" The following statement is a full description of this invention, including the best method of performing it known to me/us: H:rbrInterwovenNRPortblDCCRBR5054839_1.DOC - 8/4/13 Pharmaceutical composition comprising pimobendan This application is a divisional application of Australian Application No. 2005218912 the specification and drawings of which as originally filed are incorporated herein in 5 their entirety by reference. 1. BACKGROUND OF THE INVENTION TECHNICAL FIELD The invention relates to the field of animal health. In particular, the invention relates to 10 novel oral pharmaceutical compositions comprising as pharmaceutical active compounds pimobendan. BACKGROUND INFORMATION Pimobendan (4,5-dihydro-6-[2-(4-methoxyphenyl)-1 H-benzimidazol-5-yl]-5-methyl 15 3(2H)-pyridazone) is disclosed in EP 008 391 B1, herein incorporated by reference in its entirety. Pimobendan is a cardiotonic, hypotensive and anti-thrombotic. Said substance is the standard in the indication congestive heart failure. Pimobendan only hardly dissolves in water. The resorption of pimobendan when 20 administered orally is prone to considerable inter-and intra-individual fluctuations if the active substance is incorporated in known or conventional pharmaceutical forms for oral administration. The reason for this is that pimobendan is characterized by a low solubility in aqueous media and a very highly pH-dependent solubility. To overcome this, hard gelatine capsules were used containing pimobendan formulated with citric 25 acid, in particular at a weight ratio of pimobendan to citric acid of between 1:10 and 1:20 (EP 439 030 B1, herein incorporated by reference in its entirety). However, the high quantity of citric acid and the acidic taste of citric acid is not voluntarily accepted by most animals-thus, such capsules have to be force-fed to the animals or mixed with food prior to application. 30 The problem underlying tl-e present invention was to provide a pimobendan solid formulation voluntarily acceptable by mammalian subjects, especially small animals.
H:WtJ~incrovereRPtblDCCRBW96143_l M~ANe-LUlo -2 2. BRIEF SUMMARY OF THE INVENTION The invention relates to novel solid formulations comprising as pharmaceutical active compound pimobendan or a pharmaceutical acceptable salt thereof which is homogenously dispersed in a polyvalent acid and a flavor acceptable to small 5 animals. Preferably, such solid formulations are granules or tablets. Most preferred is a tablet characterized in that the tablet comprises, preferably consists of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further consists of lactose, corn starch, croscarmellose-sodium, citric acid, preferably at an amount of 50 mg/g of the solid formulation, artificial beef flavor, polyvidone, colloidal anhydrous silica and 10 magnesium stearate. The invention further relates to fluid-bed granulation processes for production of the solid formulations comprising or consisting of the steps: a) an aqueous solution of pimobendan and a binder as defined above is 15 sprayed onto a solid carrier bed comprising one or several carriers and/or excipients, flavor and citric acid or its anhydride and b) the mixture of a) is dried and c) the mixture of b) is sieved and de-agglomerated and d) a flow regulator is added to the mixture of c) and 20 e) a lubricant is added to the mixture of d) and f) the mixture of e) is blended for uniformity of granules to obtain final granules and/or g) the final granules of f) are compressed to solid formulations. 25 Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out. Furthermore, the invention relates to a method of prevention and/or treatment of diseases wherein cardiotonic, hypotensive and anti-thrombotic substances have a 30 therapeutic benefit, comprising administering to a mammal in need of such -3 treatment a therapeutically effective amount of a solid formulation according to the invention as disclosed above. Preferred is a method of prevention and/or treatment of congestive heart failure, 5 comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation according to the invention as disclosed above. Most preferably, the method comprises administering a tablet according to the invention , as defined above. io Furthermore, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterised in that a solid formulation according to the invention is used. Preferably, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterised in that a tablet comprising, 15 preferably consisting of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan and further consisting of lactose, corn starch, croscarmellose-sodium, 50 mg / g citric acid, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate is used. 20 3. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Illustration of the basic top spray fluid bed process Reference signs: 1 Exhaust air ventilator; 2 Filter; 3 Pump; 4 Stirrer; 5 Aqueous Suspension of micronised pimobendan and binder solution (PVP, HPMC, starch, gelatine); 6 Heating device for inlet air; 7 Sieve; 8 Nozzle, aqueous suspension is 25 sprayed onto powder bed (citric acid, lactose, starch, flavour); 9 Powder bed Figure 2: Flow Chart of Manufacturing Process Figure 3: Dissolution Profiles, Pimobendan 1.25 mg tablets, showing 95% so confidence intervals of the mean; USP apparatus 2 (Paddle), Rotation Speed 75 -4 rpm, Buffer pH 4.0. Comparison of dissolution profiles of tablets which were stored 1 and 6 months at 400/75 % in HDPE bottles; batch no. PB020049 Figure 4: Dissolution Profiles, Pimobendan 1.25 mg tablets, showing 95% 5 confidence intervals of the mean; USP apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Comparison of dissolution profiles of tablets which were stored 12 days at 25*C/60 % in open glass bottles; batch no. PBO10080 Figure 5: Dissolution Profiles, Pimobendan 2.5 mg tablets, showing 95% 1o confidence intervals of the mean; USP apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Comparison of dissolution profiles of tablets which were stored 3 and 6 months at 40*C/75 % in Alu-Alu Blister; batch no. PB010076 Figure 6: Dissolution Profiles, Pimobendan 5.0 mg tablets, showing 95% 15 confidence intervals of the mean; USP apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Comparison of dissolution profiles of tablets which were stored 6 months at 400C/75 % in HDPE bottles; batch no. PB020059 Figure 7: Dissolution Profiles, Pimobendan 5.0 mg tablets, showing 95% 20 confidence intervals of the mean; USP apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Manufacturing variable: Different compression forces; batch no. PB020205 4. DETAILED DESCRIPTION OF THE INVENTION 25 Before the embodiments of the present invention it must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "a tablet" includes a plurality of such tablets, reference to the "carrier" is a reference to one or more carriers and equivalents thereof known to those so skilled in the art, and so forth. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of -5 ordinary skill in the art to which this invention belongs. All given ranges and values may vary by 1 to 5% unless indicated otherwise or known otherwise by the person skilled in the art, therefore, the term "about" was omitted from the description. Although any methods and materials similar or equivalent to those described 5 herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications which might be used in connection with the invention. Nothing 1o herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. The solution to the above technical problem is achieved by the description and the embodiments characterized in the claims. 15 To overcome the difficulties in the art, a process was invented. Only the invention of this novel fluid-bed granulation process allowed the formulation of voluntarily acceptable solid formulations according to the invention. With the process according to the invention, it was possible to formulate a voluntarily accepted, 20 long-term stable, large scale producable, homogenously dispersed, fast-releasing solid formulation. Despite the large size, pimobendan was homogenously dispersed. Such solid formulations comprising a flavor suitable for small animals, which surprisingly still allows a formulation comprising a polyvalent acid and yet have a palatibility rate of more than 70%- in many cases more than 90%. Thus, 25 the solid formulations according to the invention are a major step forward in therapeutic application as they do not have to be force-fed to the animal. In a first important embodiment, the invention relates to a solid formulation, comprising pirnobendan or a pharmaceutically acceptable salt thereof, see e.g. 3o EP 008 391 B1 or EP 439 030 81 (both herein incorporated by reference in its entirety), which is homogenously dispersed in a polyvalent acid selected from the -6 group of citric acid, acetic acid, maleic acid, tartaric acid or the anhydride of any of said polyvalent acids, and a flavor acceptable to small animals. Such flavors according to the Invention preferably are selected from artificial beef flavours, artificical chicken flavours, pork liver extract, artificial meat flavour, honey flavour 5 and the like. Said flavors not only disguise the taste of the polyvalent acid, but also of pimobendan. Preferably, the solid formulation according to the invention is a tablet or granule formulation. The granule formulation according to the invention is explained in io more detail below. More preferably, the solid formulation is chewable. The invention preferably also relates to a solid formulation according to the invention, further comprising one or several pharmaceutically acceptable excipients. Excipients according to the invention are preferably selected from the 15 group consisting of diluents, disintegrants, carriers, binders, flow regulators, lubricants and solvents. Any other excipients known to the skilled person and found suitable for the solid formulation according to the invention may also be comprised in the solid formulation according to the invention. See also Remington, J.P. The science and Practice of Pharmacy (2000). 20th ed. Lippincott Williams & 20 Wilkins Publishers, Philiadelphia, US. More preferably, said excipients are carriers / disintegrants selected from the group lactose, starch, cellulose, microcrystalline cellulose and cellulose derivatives, e.g. methylcellulose, and the like. Any other carrier known to the skilled person and found suitable for the solid formulation according to the invention may also be comprised in the solid formulation 25 according to the invention. See also Remington, J.P. The science and Practice of Pharmacy (2000). 20th ed. Lippincott Williams & Wilkins Publishers, Philiadelphia, US. One or several binders according to the invention are preferably selected from the so group consisting of polyvidone (used synonymously for povidone), methylcell u lose, hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose, -7 starch, gelatine, and the like. Any other binder known to the skilled person and found suitable for the solid formulation according to the invention may also be comprised in the solid formulation according to the Invention. See also Remington, J.P. The science and Practice of Pharmacy (loc. cit.). 5 The solid formulation according to the invention may also comprise one or several flow regulators selected from the group consisting of silica, preferably colloidal anhydrous silica, calcium silicate, magnesium silicate, talc, and the like, Any other flow regulator known to the skilled person and found suitable for the solid lo formulation according to the invention may also be comprised in the solid formulation according to the invention. See also Remington, J.P. The science and Practice of Pharmacy (loc. cit.). The solid formulation according to the invention may also comprise one or several 15 disintegrants selected from the group consisting of croscarmellose sodium, sodium starch glycolate, pregelatinised starch, cross-linked polyvinylpyrrolidone and the like. Any other disintegrant known to the skilled person and found suitable for the solid formulation according to the invention may also be comprised in the solid formulation according to the invention. See also Remington, J.P. The science and 20 Practice of Pharmacy (loc. cit.). The solid formulation according to the invention may also comprise one or several lubricants selected from the group consisting of magnesium stearate, calcium stearate, glyceryl behenate, polyethylene glycol, stearic acid, talc and the like. Any 25 other lubricant known to the skilled person and found suitable for the solid formulation according to the invention may also be comprised in the solid formulation according to the invention. See also Remington, J.P. The science and Practice of Pharmacy (loc. cit.). The invention preferably also relates to a solid formulation according to the so invention, characterized in that the carriers are starch and lactose. The invention preferably also relates to a solid formulation according to the invention, -8 characterized in that the lactose consists of coarse particles greater than 200 pm in size. The person skilled in the art knows other types of lactose which are suitable as well as carrier according to the invention, e.g. fine lactose equal or smaller than 200 pm in size or spray-dried lactose. Preferred is lactose consisting of coarse particles 5 greater than 200 pm in size. The invention preferably also relates to a solid formulation according to the invention, characterized in that the starch or various starches are selected from the group consisting of native starch, gelatinized starch, partly gelatinized starch, starch powder, 10 starch granules, chemically modified starch and swellable physically modified starch. The invention preferably also relates to a solid formulation according to the invention, characterized in that the starch is corn starch. 15 The invention preferably also relates to a solid formulation according to the invention, comprising 0,5 to 20 mg of pimobendan. The more preferred solid formulation contains 1 to 10 mg of pimobendan. The even more preferred solid formulation contains 1.25 to 5 mg of pimobendan. Most preferred solid formulations contain 1.25 mg, 2.5 mg, 5 mg or 10 mg of pimobendan. 20 The invention preferably also relates to a solid formulation according to the invention, comprising a content of 1: 10-1: 40 of pimobendan in relation to citric acid or its anhydride, preferably 1:20. 25 The invention preferably also relates to a solid formulation according to the invention, characterized in that the weight of the whole solid formulation is in the range of 250 to 3000 mg, with a more preferred weight range of 500 mg to 2000 mg, and most preferred weight of 500 mg, 1000 mg or 2000 mg. 30 The invention preferably also relates to a solid formulation according to the invention, characterized in that the solid formulation is produced by a fluid-bed granulation process comprising or consisting of the steps: a) an aqueous solution of pimobendan and a binder as defined above is ........ ~~ 9.. --- -9 sprayed onto a solid carrier bed comprising one or several carriers and/or excipients as defined above, flavor and citric acid or its anhydride and b) the mixture of a) is dried and c) the mixture of b) is sieved and de-agglomerated and 5 d) a flow regulator is added to the mixture of c) and e) a lubricant is added to the mixture of d) and f) the mixture of e) is blended for uniformity of granules to obtain final granules and/or g) the final granules of f) are compressed to solid formulations. 10 Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out. The invention preferably also relates to a solid formulation according to the invention, 15 characterized in that the solid formulation is produced by a fluid-bed granulation process comprising or consisting of the steps: a) an aqueous solution of pimobendan and povidone is sprayed onto a solid carrier bed comprising lactose, starch, flavor and citric acid or its anhydride and 20 b) the mixture of a) is dried and c) the mixture of b) is sieved and de-agglomerated and d) a flow regulator is added to the mixture of c) and e) a lubricant is added to the mixture of d) and f) the mixture of e) is blended for uniformity of granules to obtain final 25 granules and/or g) the final granules of f) are compressed to solid formulations.
-10 Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out. The invention preferably relates to a granule formulation as obtained by the 5 process above that can either be administered in the granular form or as tablets after compressing the final granules to tablets. Therefore, the solid formulation according to the invention preferably is a granule (or a plurality of such granules) or a tablet. The administration of the granules can take place by mixing with food or by offering the granules directly to the animal, e.g. in a bowl. The application of io the granular form will allow an individual dosing of pimobendan according to the body weight of the animal. The tablets according to the invention have surprising advantages. The dissolution profile is ensuring immediate release of pimobendan. Surprisingly, it could be 15 demonstrated that while compressing the final granules as mentioned above, a decrease in the dissolution characteristics is not observed. By ensuring an immediate release profile of pimobendan, the amount of drug to be administered can be kept as low as possible, thereby improving the safety profile especially for long-term treatment. 20 Furthermore, the dosing accuracy of the tablet is excellent. This is due to the fact that in accordance with the manufacturing process according to this invention, an excellent uniformity of pimobendan content is achieved. Furthermore, the tablets can be broken into two halves so that half the dose per tablet can be administered. 25 Compared with the existing gelatine capsule, the dosing accuracy and compliance of both the animal and the animal owner are assured. This is even more important since the drug is administered for a life-long treatment. Also, the palatability of the tablet is excellent. More than 90 % of the dogs to whom 3o the tablet according to this invention is given, accept the tablet voluntarily with only the tablet offered in a bowl. Compared with the existing gelatine capsule, the - 11 compliance of both the animal and the animal owner are significantly improved. This is even more important since the drug is administered for a life-long treatment. 5 The invention preferably also relates to a tablet according to the invention, characterized in that the tablet is stable for at least 18 months at 25 0 C and 60% relative humidity. In the examples, testing parameter assays are disclosed for degradation of pimobendan, dissolution, loss on drying, hardness and disintegration of the tablet. The tablets according to the invention are within the 10 specification limits regarding degradation of pimobendan, dissolution, loss on drying, hardness and disintegration. Suitable packaging materials for tablets according to the invention are selected from, but not limited to: aluminum/aluminum blisters, PVC/PVDC blisters, and 15 HDPE (high density polyethylene bottles). The invention preferably also relates to a tablet according to the invention, characterized in that the tablet is oblong in shape, For such a tablet, characteristics like crushing strength, disintegration, uniformity of weight and 20 content uniformity fulfill the requirements of the European Pharmacopoeia (ISBN/ISSN 92-871-5106-7 of 4 th Edition 2004, Vol. 4.8, European Directorate for the Quality of Medicines (EDQM), European Pharmacopoeia, 226 avenue de Colmar, F-67029 Strasbourg, France, http://www.pheur.org) and the United States Pharmacopoeia (http://www.usp.orc; in print: USP-NF, catalog No. 2270001). 25 The invention preferably relates to a solid formulation, and most preferred a tablet according to the invention, characterized in that the solid formulation or tablet comprising 0,5 - 20 mg pimobendan, preferably of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further comprises, preferably consists of lactose (35 - 50 % 3o by weight relative to the dry mass of the solid formulation/tablet = (w/w)), corn starch (25 - 50 % w/w), croscarmellose-sodium (1 - 5 %), citric acid (2,5 - 10 % -12 w/w), artificial beef flavor (5 - 30 % w/w), polyvidone (1 - 5 % w/w), colloidal anhydrous silica (0.1 - 1, preferably 0.1 - 0.5 % w/w) and magnesium stearate (0,25 - 1,5 % w/w), wherein the percentage by weight of pimobendan contains preferably about 0,25% (w/w) and the sum of the percentages by weight of all 5 ingredients of the solid formulation including pimobendan is 100 % (w/w). A skilled man is in a position to prepare such solid formulations, preferably a tablet. Thus, the skilled man knows that he can add to 0,25 % (w/w) pimobendan at most 32,625 % (w/w) corn starch, 4 % (w/w) croscarmellose-sodium 5 % (w/w) citric acid, 20 % (w/w) artificial beef flavor, 4% (w/w) polyvidone, colloidal, 0,5 % (w/w) 1o anhydrous silica, 1 % (w/w) magnesium stearate if the amount of lactose to be 32,625 % (w/w). Moreover, the skilled man also knows, that if he decided to reduce the amount of the artificial beef flavor, for example, to the minimum of 5 % (w/w), he can increase the amount of lactose, for example, to 47,625 % (w/w). The invention also relates to a solid formulation, preferably a tablet, comprising about 15 0,25% (w/w) pimobendan and any of the above other ingredients of the solid formulation, preferably the tablet, in the range given above so that the sum of the amounts by weight of the individual formulation ingredients is 100%. The present invention is also directed to a solid formulation, preferably to a tablet, 20 which comprises, preferably consists of 1 mg pimobendan, 100 - 200 mg lactose, 100 - 200 mg corn starch, 4 - 20 mg croscarmellose-sodium, 10 - 40 mg citric acid anhydrous, 20 - 120 mg artificial beef flavor, 4 - 20 mg polyvidone, 0.4 - 4 mg colloidal anhydrous silica, and 1 - 6 mg magnesium stearate for each 400 mg of total weight of the solid formulation, preferably a tablet. According to a further 25 embodiment of the present invention, the solid formulation, preferably the tablet, comprises, preferably consists of 1 mg pimobendan, 120 - 180 mg lactose, 120 180 mg corn starch, 8 - 18 mg croscarmellose-sodiurn, 15 - 30 mg citric acid anhydrous, 40 - 100 mg artificial beef flavor, 8 - 18 mg polyvidone, 0.5 - 2 mg colloidal anhydrous silica, and 2 - 5 mg magnesium stearate for each 400 mg of 3o total weight of the solid formulation / tablet. For example, the present invention relates to a solid formulation comprising for each 400 mg of total weight: 1 mg - 13 pimobendan, 20 mg citric acid anhydrous, 130,5 mg lactose, 130,5 mg corn starch, 16 mg polyvidone, 16 mg croscarmellose-sodium, 80 mg artificial beef flavor, 4 mg magnesium stearate, and 2 mg colloidal anhydrous silica. A skilled man is in a position to prepare such solid formulation/tablet. The skilled man also 5 knows that he can varied the amount of each ingredient of the solid formulation / tablet within the ranges given above in that the total weight of the solid formulation / tablet for each 1 mg pimobendan is 400 mg. For example, the amount of lactose may be 100, 101, 102, ... 108, 109, 110 etc.; 111, 112, ... 118, 119, 120 etc; 121, 122, ... 128, 129, 120 etc; 131, 132, ... 138, 139, 140 etc; 141, 142, ... 148, 149, lo 150 etc; 151, 152, ... 158, 159, 160 etc; 161, 162, ... 168, 169, 170 etc; 171, 172, ... 178, 179, 180 etc; 108, 182, ... 188, 189, 190 etc; 191, 192, ... 198, 199, 200 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. In the same manner the amount of corn starch may be 100, 101, 102, ... 108, 109, 110 etc.; 111, 112, ... 118, 119, 120 15 etc; 121, 122, ... 128, 129, 120 etc; 131, 132, ... 138, 139, 140 etc; 141, 142, 148, 149, 150 etc; 151, 152, ... 158, 159, 160 etc; 161, 162, ... 168, 169, 170 etc; 171, 172, ... 178, 179, 180 etc; 108, 182, ... 188, 189, 190 etc; 191, 192, ... 198, 199, 200 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. Furthermore, the amount of citric acid 2o anhydrous may be 10, 11, 12, ... 18, 19, 20 etc.; 21, 22, ... 28, 29, 30 etc; 31, 32, ... 38, 39, 40 mg for each 400 mg of total weight of the solid formulation, preferably a tablet comprising about 1 mg pimobendan. Furthermore, the amount of artificial beef flavor may be 20, 21, 22, ... 28, 29, 30 etc.; 31, 32, ... 38, 39, 40 etc; 41, 42, ... 48, 49, 50 etc; 50, 51, 52, ... 58, 59, 60 etc.; 61, 62, ... 68, 69, 70 25 etc; 71, 72, ... 78, 79, 80 etc, 81, 82, 83,... 88, 89, 90 etc.; 91, 92, ... 98, 99, 100 etc; 101, 102, ... 108, 109, 110 etc; 111, 112, ... 118, 119, 120 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. Furthermore, the amount of polyvidone may be 4, 5, 6, ... 8, 9, 10 etc.; 11, 12, ... 18, 19, 20 mg for each 400 mg of total weight of the solid 3o formulation, preferably a tablet, comprising about 1 mg pimobendan. Furthermore, the amount of croscarmellose-sodium may be 4, 5, 6, ... 8, 9, 10 etc.; 11, 12, H:b rwvmcenW1RoblDCCRBRW%1I 943_1.doc4/(Uzui3 - 14 18, 19, 20 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising 1 mg pimobendan. Furthermore, the amount of magnesium stearate may be 1.0, 1.1, 1.2, ... 1.8, 1.9, 2.0 etc.; 2.1, 2.2, ... 2.8, 2.9, 3.0 etc; 3.1, 3. 2, ... 3.8, 3.9, 40 etc; 4.0, 4.1, 4. 2, ... 4. 8, 4.9, 5.0 etc.; 5.1, 5. 2, ... 5.8, 5.9, 6.0 mg 5 for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. Furthermore, the amount of colloidal anhydrous silica may be 0.4, 0.5, 0.6, 0,7, 0.8, 0. 9, 1.0, 1.1, 1.2, ... 1.8, 1.9, 2.0 etc.; 2. 1, 2.2, ... 2.8, 2.9, 3. 0 etc; 3.1, 3.2, ... 3.8, 3.9, 4.0 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. A skilled man is 10 in a position to prepare any of such inventive solid formulation, preferably as a tablet. In another important embodiment, the invention relates to a fluid-bed granulation process comprising, preferably consisting of the steps: a) an aqueous solution of pimobendan and a binder as defined above is 15 sprayed onto a solid carrier bed comprising one or several carriers and/or excipients as defined above, flavor and citric acid or its anhydride and b) the mixture of a) is dried and c) the mixture of b) is sieved and de-agglomerated and 20 d) a flow regulator is added to the mixture of c) and e) a lubricant is added to the mixture of d) and f) the mixture of e) is blended for uniformity of granules to obtain final granules and/or g) the final granules of f) are compressed to solid formulations. 25 Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out. The invention preferably relates to a fluid-bed granulation process comprising, 30 preferably consisting of the steps: a) an aqueous solution of pimobendan and polyvidone is sprayed onto a solid support comprising lactose, starch, flavor and citric acid or its anhydride and - 15 b) the mixture of a) is dried and c) the mixture of b) is sieved and de-agglomerated and d) a flow regulator is added to the mixture of c) and e) a lubricant is added to the mixture of d) and 5 f the mixture of e) is blended for uniformity of granules to obtain final granules and/or g) the final granules of f) are tabletted. Step g) is omitted if the solid formulation is a granule. If the solid formulation is a 10 tablet, step g) is carried out. Another embodiment is a method of prevention and/or treatment of diseases wherein cardiotonic, hypotensive and anti-thrombotic substances have a therapeutic benefit, comprising administering to a mammal in need of such treatment a therapeutically 15 effective amount of a solid formulation according to the invention as disclosed above. Preferred is a method of prevention and/or treatment of congestive heart failure, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation according to the invention as disclosed above. Most preferably, the method comprises administering a tablet according to the 20 invention, characterized in that the tablet comprises, preferably consists of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further comprises, preferably consists of lactose, corn starch, croscarmellose-sodium, citric acid preferably at an amount of 50 mg/g, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate. Preferably also, such treatment is by orally applying the solid formulation 25 according to the invention. The mammal according to the invention is preferably a mammal selected from the group consisting of dogs, cats and rodents such as rabbits. 30 - 16 Furthermore, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterised in that a solid formulation according to the invention is used. Preferably, the invention 5 relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterlsed in that a tablet consisting of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan and further consisting of lactose, corn starch, croscarmellose-sodium, 50 mg / g citric acid, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate is used. 10 The present invention furthermore relates to a kit, comprises a solid formulation, preferably a tablet according to the present invention described herein, and a package leaflet or user instruction including the information that the solid formulation, preferably the tablet is to used, preferably via the oral route for the 15 prevention and/or treatment of congestive heart failure in a mammal in need of such prevention or treatment, preferably in a dog, cat or rodent. 5. EXAMPLES The following examples serve to further illustrate the present invention; but the 2o same should not be construed as limiting the scope of the invention disclosed herein. EXAMPLE 1: Compositions 25 Composition A Ingredients mg/tablet mg/tablet mg/tablet Volatile kg/batch 1.25 mg 2.5 mg 5.0 mg ingre chewable chewable chewable dient (01) Pimobendan 1.250 2.500 5.000 0.175 (02) Citric acid anhydrous 25.000 50.000 100.000 3.500 < 200 pm I I (03) Starch 163.125 326.250 652.500 22.8375 - 17 (04) Lactose, coarse 163.125 326.250 652.500 22.8375 (05) Polyvidon 20.000 40.000 80.000 2.800 (06) Croscarmellose Sodium 20.000 40.000 80.000 2.800 (07) Artificial Powdered 100.000 200.000 400.000 14.000 Beef Flavour I (08) Silica, colloidal 2.500 5.000 10.000 0.350 anhydrous (09) Magnesium stearate 5.000 10.000 20.000 0.700 (10) Purified water+ 500.000 1000.000 2000.000 - 70.000 Composition B s Ingredients mg/tablet mg/tablet mg/tablet Volatile kg/batch 1.25 mg 2.5 mg 5.0 mg ingre chewable chewable chewable dient Pimobendan 1.250 2.500 5.000 0.175 Citric acid anhydrous 25.000 50.000 100.000 3.500 <200 pm Starch 163.125 326.250 652.500 22.8375 Lactose, coarse 238.125 476.250 952.500 22.8375 Polyvidon 20.000 40.000 80.000 2.800 Croscarmellose Sodium 20.000 40.000 80.000 2.800 Meat Flavour 25.000 50.000 100.000 14.000 Silica, colloidal anhydrous 2.500 5.000 10.000 0.350 Magnesium stearate 5.000 10.000 20.000 0.700 Purified water + 500.000 1000.000 2000.000 - 70.000 -18 EXAMPLE 2: Raw Materials (01) Pimobendan Function: Active ingredient 5 (02) Citric acid anhydrous < 200 pm Function: Diluent ,Disintegrant (03) Starch 10 Function: Carrier,Disintegrant (04) Lactose coarse Function: Carrier, Disintegrant 15 (05) Povidone Function: Binder (06) Croscarmellose Sodium Function: Disintegrant 20 (07) Artificial Powdered Beef Flavour Function: Flavour (08) Silica, colloidal anhydrous 25 Function: Flow regulator; Disintegrant (09) Magnesium stearate Function: Lubricant 3o (10) Purified water Function: Solvent 35 EXAMPLE 3: Product description Appearance: brownish, oblong tablets, with breakline. Tablet Tablet Tablet Weight 500 mg 1000 mg 2000 mg Length About 19.0 un About 24.0 mm About 25.0 mm Width About 7.0 mm About 7.5 mm About 15.0 mm Thickness About 4.2 mm About 5.6 mm About 6.0 mm - 19- EXAMPLE 4: Manufacturing Process 1 batch = 140000 tablets (1.25 mg Dosage) 1 batch = 70000 tablets (2.50 mg Dosage) 5 1 batch = 35000 tablets (5.00 mg Dosage) 1. Granulating Transfer in a suitable Granulator after prescreening: (01) Starch (e.g. 18 mesh sieve) 22.8375 k (02) Lactose (e.g. 18 mesh sieve) 22.8375 k (03) Citric acid anhydrous (e.g. 18 mesh sieve) 3.500 k (04) Croscarmellose sodium (e.g. 18 mesh sieve) 2.800 k (05) Artificial Beef Flavour (e.g. 45 mesh sieve) 14.000 k (05) Povidone (Spray solution) 2.800 k (06) UDCG 115 BS (Spray liquid) 0.175 k, Premix in the granulator and granulate 68.950k Purified water (e.g. 16.8 kg, range: 12.0 - 18.0 kg) is used as a solvent for the spray solution of povidone and dispersion of pimobendan. 2. Screening Screen the premixture 1. 68.950 ki 68.950 ki 3. Final mixing Add (07) Sillica, colloidal anhydrous (e.g. 25 mesh sieve) 0.350 kj (08) Magnesium stearate (e.g. 25 mesh sieve) 0.700 kj In a tumbling mixer, mix the screened premixture (2.) and the two ingredients 70.000 kc 70.000 kg 4. Compression Using a rotary press, compress the final mixture (3.) 70.000 kg into tablets of 500 mg, 1000mg, 2000 mg. 70.000 kg 5. Packaging -20 Transfer the tablets in a suitable container. The tablets can be packed e.g. by blistering of the tablets in a suitable machine. EXAMPLE 5: In process controls 5 1. Granules 1.1 Appearance: Brownish, white-speckled granules 10 1.2 Loss on Drying: Determine the loss on drying e.g.: HR73; 3 g /105 *C /5 min Target: approx. 3.0 % Tolerance limits: below 5.0 % 15 2. Tablets 2.1 Appearance: Brownish, white-speckled, oblong tablets with breakline 20 2.2 Weight uniformity: 1) 1.25 mg chewable Average weight: 475 - 525 mg 2) 2.5 mg chewable Average weight: 950 - 1050 mg 25 3) 5 mg chewable Average weight: 1900 -2100 mg 2.3 Hardness: Determine the hardness 1) 1.25 mg Target: 140 N 30 Tolerance: 60 - 250 N 2) 2.5 mg Target: 160 N Tolerance: 60 - 250 N 35 3) 5.0 mg Target 190 N Tolerance: 60 - 300 N 2.4 Disintegration time: Determine the disintegration time according to USP/EP Tolerance limits: < 15 minutes with water at 37 0 C, with 40 disks -21 EXAMPLE 6: Palatability study A study to Investigate the palatability of pimobendan-containing tablets was carried out. For a period of four days, two products were given to twenty or ten dogs, respectively, for voluntary uptake. For example, the following formulations with a 5 content of 5 mg / 500 mg active ingredient were examined: Ch. 010122 (tablets with 10 % content of Ch. 010123 (tablets with 10 % content of artificial beef flavor) artificial beef flavor) Pimobendan (UTD-CG 5 mg Pinobendan (UD-CG 5 mg 115BS) 115 BS) Lactose 85,5 mg Lactose 55,5 mg Corn starch 199,5 mg Corn starch 129,5 mg Croscarmellose- 20 mg Croscarmellose- 20 mg Sodium Sodium Citric acid 100 mg Citric acid 100 mg Artificial Beef Flavor 50 mg Artificial Beef Flavor 150 mg Polyvidone 25 mg Polyvidone 25 mg Macrogol 6000 15 mg Macrogol 6000 15 mg Total: 500 mg Total: 500 mg In case of Ch. 010123 in competition with the identical formulation in granulated format, a voluntary uptake was observed in 36 out of 40 possible opportunities (i.e. i when offered to 10 dogs for 10 days),. This compares to an acceptance rate of 90,0%. In case of Ch. 010222 in competition with a formulation in granulated format of equal quantity with 30% flavor, a voluntary uptake was observed in 31 out of 40 possible opportunities. This compares to an acceptance rate of 77,5%. 15 - 22 EXAMPLE : Dissolution profiles Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in Fig. 3. 5 DISSOLUTION PROFILES, PIMOBENDAN 1.25 MG TABLETS SHOWING 95 9b CONFIDENCE INTERVALS OF THE MEAN USP APPARATUS 2 (PADDLE), ROTATION SPEED 75 RPM, BUFFER pH 4.0 COMPARISON OF DISSOLUTION PROFILES OF TABLETS WHICH WERE STORED 10 1 AND 6 MONTHS AT 40"C/75 % IN HDPE BOTTLES BATCH NO. PB020049 15 Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in Fig. 4. 20 DISSOLUTION PROFILES, PIMOBENDAN 1.25 MG TABLETS SHOWING 95 % CONFIDENCE INTERVALS OF THE MEAN USP APPARATUS 2 (PADDLE), ROTATION SPEED 75 RPM, BUFFER pH 4.0 25 COMPARISON OF DISSOLUTION PROFILES OF TABLETS WHICH WERE STORED 12 DAYS AT 25 0 C/60% IN OPEN GLASS BOTTLES BATCH NO. PBO10080 30 DISSOLUTION PROFILES, PIMOBENDAN 1.25 MG TABLETS 35 MANUFACTURING VARIABLE: DIFFERENT COMPRESSION FORCES 020102 10 82 82 81 84 20 98 97 97 98 30 101 99 100 100 45 101 101 102 102 -23 Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in Fig. 5. 5 DISSOLUTION PROFILES, PIMOBENDAN 2.5 MG TABLETS SHOWING 95 % CONFIDENCE INTERVALS OF THE MEAN USP APPARATUS 2 (PADDLE), ROTATION SPEED 75 RPM, BUFFER pH 4.0 COMPARISON OF DISSOLUTION PROFILES OF TABLETS WHICH WERE STORED 10 3 AND 6 MONTHS AT 40*C/75 % IN ALU-ALU BLISTER BATCH NO. PB010076 15 Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in Fig. 6. DISSOLUTION PROFILES, PIMOBENDAN 5.0 MG TABLETS 20 SHOWING 95 % CONFIDENCE INTERVALS OF THE MEAN USP APPARATUS 2 (PADDLE), ROTATION SPEED 75 RPM, BUFFER pH 4.0 COMPARISON OF DISSOLUTION PROFILES OF TABLETS WHICH WERE STORED 6 MONTHS AT 40*C/75 % IN HDPE BOTTLES 25 BATCH NO. PB020059 Examples for representative dissolution profiles of the tablet according to this 30 invention are as disclosed in Fig. 7. DISSOLUTION PROFILES, PIMOBENDAN 5.0 MG TABLETS SHOWING 95 % CONFIDENCE INTERVALS OF THE MEAN 35 USP APPARATUS 2 (PADDLE), ROTATION SPEED 75 RPM, BUFFER pH 4.0 MANUFACTURING VARIABLE: DIFFERENT COMPRESSION FORCES BATCH NO. 020205 * watch Time (min) % Disolyed, meau (n =6) Tablet hardness Nl. .. 150N 186 N 222 N 020205 10 56 56 56 56 20 76 75 76 76 30 79 79 80 80 45 80 80 81 81 -24 Analytical Results for Pimobendan Chewable Tablet Batches Used In Stability Study 1.25 mg PB020049 HDPE bottle 97 95 94 93 PB020049 Alu-Alu blister 095 93 94 ______ PB020049 PVC/PVDC blister _____ 94 93 93 ______ PB020050 HDPE bottle 94 92 93 91 _______ PB020050 Alu-Alu blister _____ 92 92 91 ______ PB020050 PVC/PVDC blister _____ 93 93 92 PB02005 1 HDPE bottle 94 93 92 92 PB 020051 Alu-Alu blister 94 93 92 _______ PB 020051 PVC/P VDC blister 93 93 91 2.5 mg PB020052 HDPE bottle 98 n.d. d. 93 PB020052 Alu-Alu blister n.d. n.d. 94 PB020052 PVC/PVDC blister n.d. n.d. 92 PB020053 HDPE bottle 97 n.d. n.d. 91 PB020053 Alu-Alu blister n.d. n.d. 91 PB020053 PVC/PVDC blister n.d. n.d. 91 PB020054 HDPE bottle 97 n.d. nd. 91 PB020054 Alu-Alu blister n.d. a.d. 92 PB020054 PVC/PVDC blister n.d. n.d. 91 5.0 mg PB020059 HDPE bottle 95 93 92 92 PB020059 Alu-Alu blister 93 92 92 PB020059 PVC/PVDC blister ____ 92 92 91 PB020060 HDPE bottle 92 91 90 89 PB020060 Alu-Alu blister ____ 91 91 90 PB020060 PVC/PVDC blister 91 91 89 5.0_mg_ PB020061 HDPE bottle 94 91 91 89 PB020061 Alu-Alu blister 92 92 90 PB020061 PVC/PVDC blister 91 91 89 n.d. = not determined -25 EXAMPLE 8: Content uniformity Samples were taken from both the final blend before tabletting and from the tabletting process. The following results demonstrate the uniformityof 5 pimobendan content. Blend Uniformity Batch Assay[mg/g] % Target 0007LP - A 2,37 94,8 0007LP - B 2,48 992 0007LP - C 2,43 972 00O7LP - D 2,44 97,6 0007LP - E 2,47 988 0007LP- F 2,50 100,0 0007LP - G 2,49 99,6 0007LP - H 2,49 99,6 0007LP - 1 2,50 100,0 0007LP - J 2,43 972 Average 2,46 98,4 OOO8LP - A 2,41 96,4 0008LP - B 2,48 992 OOO8LP - C 2,45 98,0 0008LP - D 2,45 980 0008LP- E 2,46 98,4 008LP - F 2,43 97,2 0008LP - G 2,46 98,4 0008LP - H 2,44 97,6 0008LP - 1 2,47 98,8 0008LP - J 2,50 100,0 Average 2,46 98,2 Uniformity of Process Batch Assay [mg/gl % Target PM020080 - 1 2,48 99,2 PM020080 - 2 2,52 100,8 PM020080 - 3 2,50 1000 PM020080 - 4 2,52 100,8 PM020080 - 5 2,49 996 PM020080 - 6 2,52 100,8 Average 2,51 100,2 PM020081 - 1 2,45 98,0 PM020081 - 2 2,51 100,4 PM020081 - 3 2,48 99,2 - 26 PM020081 - 4 2,45 98,0 PM020081 - 5 2,47 98,8 PM020081 - 6 2,45 98,0 Average 2,47 98,7 EXAMPLE 9: Accuracy of broken tablets The tablets according to this invention were part of an content uniformity test for the broken tablets. 10 tablets were taken from the beginning, middle and end of 5 the tabletting process and broken into two halves. The pimobendan content was determined. Pimobendan 5 mg tablet, batch no. 0000251607 Specification Start Middle End CU min. (mg) > 2,13 2,44 2,43 2,41 CU max. (mg) 2,87 2,61 2,57 2,57 CU average 2,25 - 2,62 2,52 2,51 2,50 (mg RSD (6,0 2,3 1,9 2,0 Pimobendan 1,25 mg tablet, batch no. 0000251604 Specification Start Middle End CU min. (mg) 0,532 0,577 0,590 0,582 CUJ max. (mg) 5 0,718 0,664 0,650 0,645 CU average 0,563 - 0,656 0,621 0,621 0,616 (mg RSD(%) 6,0 5,4 3,4 3,6 10 - 27 EXAMPLE 10: Stability data after 24 months (dissolution/ assay of pimobendan/ degradation of pimobendan) Product: Pimobendan chewable tablets 1.25 mg Batch No.: PB020049 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 95(min)- 0 months 95(min)- 0 months 95(min) 102(max)/97(avg); 24 102(max)/97(avg); 24 102(max)/97(avg); 24 Dissolution 25 0 C/60*C months 96-99/97 months 96-99/97 months 92-96/94 0 months 95(min)- 0 months 95(min)- 0 months 95(min) 102(max)/97(avg); 24 102(max)/97(avg); 24 102(max)/97(avg); 24 30*C/70*C months 96-97/97 months 96-98/97 months 95-99/97 0 months 95(min)- 0 months 95(min)- 0 months 95(min) 102(max)/97(avg); 6 102(max)/97(avg); 6 102(max)/97(avg); 6 40*C/75*C months 92-94/93 months 91-94/93 months 92-95/94 Batch No.:PB020049 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) Assay of 0 months 1.251; 24 0 months 1.251; 24 0 months 1.251; 24 Pimobendan 25*C/60*C months 1.233 months 1.236 months 1.237 0 months 1.251; 24 0 months 1.251;24 0 months 1.251; 24 30*C/70"C months 1.229 months 1.242 months 1.236 0 months 1.251; 6 0 months 1.251; 6 months 0 months 1.251; 6 40*C/75 0 C months 1.221 1.214 months 1.231 Batch No. :PB020049 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 1)<0. 10(K 2006a);2)<0.10(DU- 0 months 1)<0.10(K CG 134 0 months 1)<0.10(K 2006a);2)<0.10(DU-CG BS);3)<0.10(any 2006a);2)<0.10(DU-CG 134 BS);3)<0.10(any unspecified);4)<0. 10(to 134 BS);3)<O. I 0(any unspecified);4)<0. 10(tot tal); 24 months unspecified);4)<0.10(total al); 24 months 1)<0.10; Degradation of 1)<0.10;2)<0.10; ); 24 months 1)<0.10; 2)<0.10; 3)<0.10; Pimobendan 25*C/60*C 3)<0.10; 4)<O.10 2)<0.10; 3)<0.10; 4)<0.10 4)<0.10 O months 1)<O.10(K 2006a);2)<0.10(DU- 0 months 1)<0.10(K CG 134 0 months 1)<0.10(K 2006a);2)<0.10(DU-CG BS);3)<0.10(any 2006a);2)<0.10(DU-CG 134 BS);3)<0.10(any unspecified);4)<0. I 0(to 134 BS);3)<0.10(any unspecified);4)<0. 10(tot tal); 24 months unspecified);4)<0.10(total al); 24 months 1)<0.10; 1)<0.10;2)0.10; ); 24 months 1)0.35; 2)<0.10; 3)<0.10; 30"C/7 0 C 3)<0.10; 4)0.10 2)<0.10; 3)<O.10; 4)0.35 4)<0.10 0 months 1)<0.10(K 0 months 1)<0.10(K 2006a);2)<0.10(DU- 0 months 1)<0.10(K 2006a);2)<0.10(DU-CG CG 134 2006a);2)<0.10(DU-CG 134 BS);3)<0.10(any BS);3)<0.10(any 134 BS);3)<0.10(any unspecified);4)<0.10(tot unspecified);4)<0. 10(to unspecified);4)<0.10(total al); 6 months 1)<0. 10; tal); 6 months .1)0.10; );6 months 1)0.55; 2)<0.10; 3)<0.10; 40'C/75*C 2)0.11; 3)<0.10; 4)0.21 2)<0.10; 3)<O.10; 4)0.55 4)<0.10 - 28 Product: Pimobendan chewable tablets 1.25 mg Batch No.:PB020050 HDPE bottle (m) PVC/PVCD () Aluminium blister (m) 0 months 91(min)- 0 months 91(min)- 0 months 91(min) 96(max)/94(avg); 24 96(max)/94(avg); 24 96(max)/94(avg); 24 Dissolution 25*C/60 0 C months 96-104/99 months 84-101/95 months 92-96/94 0 months 91(min)- 0 months 91(min)- 0 months 91(min) 96(max)/94(avg); 24 96(max)/94(avg); 24 96(max)/94(avg); 24 30*C/70 0 C months 94-102/97 months 93-102/97 months 97-105/99 0 months 91(min)- 0 months 91(min)- 0 months 91(min) 96(max)/94(avg); 6 96(max)/94(avg); 6 96(max)/94(avg); 6 40*C/75 0 C months 91-92/91 months 91-93/92 months 91-92/91 Batch No.: PB020050 HDPE bottle (m) PVC/PVCD (m) Aluminium blister (m) Assay of 0 months 1.231; 24 0 months 1.231; 24 0 months 1.231; 24 Pimobendan 25*C/60 0 C months 1.224 months 1.201 months 1.228 0 months 1.231; 24 0 months 1.231; 24 0 months 1.231; 24 30*C/70 0 C months 1.213 months 1.217 months 1.230 0 months 1.231; 6 0 months 1.231; 6 months 0 months 1.231; 6 40OC/75*C months 1.205 1.202 months 1.215 Batch No.:PB020050 HDPE bottle (m) PVC/PVCD (m) Aluminium blister (m) 0 months 1)<0.10(K 2006a);2)<0.10(DU- 0 months 1)<0. 10(K CG 134 0 months 1)<0.10(K 2006a);2)<0.10(DU-CG BS);3)<0.10(any 2006a);2)<0.10(DU-CG 134 BS);3)<0.10(any unspecified);4)<0. 10(to 134 BS);3)<0.10(any unspecified);4)<0.10(tot tal); 24 months unspecified);4)<0.10(total al); 24 months 1)<0.10; Degradation of 1)<O. 10; 2)<0.10; ); 24 months 1)<0.10; 2)<0.10; 3)<0.10; Pimobendan 25*C/60 0 C 3)<0.10; 4)<0.10 2)<0.10; 3)<0.10; 4)<0.10 4)<0.10 0 months 1)<0.10(K 2006a);2)<0.10(DU- 0 months 1)<0.10(K CG 134 0 months 1)<0.10(K 2006a);2)<0.10(DU-CG BS);3)<0.10(any 2006a);2)<0.10(DU-CG 134 BS);3)<0.10(any unspecified);4)<0.10(to 134 BS);3)<0.10(any unspecified);4)<0.10(tot tal); 24 monthsl)<0.10; unspecified);4)<0.10(total al); 24 months 1)<0.10; 2)<0.10; 3)<0.10; ); 24 months 1)0.37; 2)<0.10; 3)<0.10; 30*C/7 0 C 4)<0.10 2)<0.10;3)<0.10; 4)0.37 4)<0.10 0 months 1)<0.10(K 2006a);2)<0.10(DU- 0 months 1)<0.10(K CG 134 0 months 1)<0.10(K 2006a);2)<0.10(DU-CG BS);3)<0.10(any 2006a);2)<0.10(DU-CG 134 BS);3)<0.10(any unspecified);4)<0.10(to 134 BS);3)<0.10(any unspecified);4)<0.10(tot tal); 6 months 1)<0.10; unspecified);4)<0.10(total al); 6 months 1)<0.10; 2)<0.10; 3)<0.10; ); 6 months 1)0.58; 2)<0.10; 3)<0.10; 40*C/75*C 4)<0.10 2)<0.10; 3)<0.10; 4)0.58 4)<0.10 -29 Product: Pimobeudan chewable tablets 1.25 mg Batch No.: PB020051 HDPE bottle () PVC/PVDC (m) Aluminium blister (m) 0 months 92(min)- 0 months 92(min)- 0 months 92(min) 95(max)/94(avg); 24 95(max)/94(avg); 24 95(max)/94(avg); 24 Dissolution 25*C/60*C months 92-100/96 months 94-101/97 months 91-100/95 0 months 92(min)- 0 months 92(min)- 0 months 92(min) 95(max)/94(avg); 24 95(max)/94(avg); 24 95(max)/94(avg); 24 30*C/70*C months 92-99/96 months 95-98/97 months 92-100/97 0 months 92(min)- 0 months 92(min)- 0 months 92(min) 95(max)/94(avg); 6 95(max)/94(avg); 6 95(max)/94(avg); 6 40*C/75 0 C months 91-93/92 months 90-92/91 months 91-94/92 Batch No.: PB020051 HDPE bottle (m) PVC/PVDC (W) Aluminium blister (m) Assay of 0 months 1.230; 24 0 months 1.230; 24 0 months 1.230; 24 Pimobendan 25*C/60 0 C months 1.222 months 1.225 months 1.228 0 months 1.230;24 0 months 1.230; 24 0 months 1.230; 24 30*C/70*C months 1.214 months 1.221 months 1.230 0 months 1.230;6 0 months 1.230; 6 months 0 months 1.230; 6 40*C/75*C months 1.210 1.202 months 1.218 Batch No.PB020051 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 1)<0. 10(K 2006a);2)<0.10(DU CG 134 0 months 1)<0.10(K BS);3)<0.10(any 2006a);2)<0.10(DU-CG 0 months 1)<0.10(K unspecified);40. 10(to 134 BS);3)<0.10(any 2006a);2)<0.10(DU-CG tal); 24 months unspecified);4)<0.10(total 134 BS);3)<0.10(any Degradation of 1)<0.10; 2)<0.10; ); 24 months1)<0.10; unspecified);4)<0.10(tot Pimobendan 25 0 C/60 0 C 3)<0.10; 4)<0.10 2)<0.10; 3)<0.10; 4)<0.10 al); 0 months 1)<0.10(K 2006a);2)<0.10(DU CO 134 0 months 1)<0.10(K BS);3)<0.10(any 2006a);2)<0.10(DU-CG 0 months 1)<0.10(K unspecified);4)<0. 10(to 134 BS);3)<0.10(any 2006a);2)<0.10(DU-CG tal); 24 months unspecified);4)<0. 10(total 134 BS);3)<0.10(any 1)<0.10; 2)<0.10; ); 24 months 1)<0.33; unspecified);4)<0.10(tot 30*C/7*C 3)<0.10; 4)<0.10 2)<0.10; 3)<0.10; 4)0.33 al); 0 months 1)<0.10(K 2006a);2)<0.10(DU- 0 months 1)<0.10(K CG 134 2006a);2)<0.10(DU-CG 0 months 1)<0.10(K BS);3)<0.10(any 134 BS);3)<0.10(any 2006a);2)<0.10(DU-CG unspecified);4)<0. 10(to unspecified);4)<0. 1 0(total 134 BS);3)<0. 10(any tal); 6 months 1)<0.10; ); 6 months 1)<0.54; unspecified);4)<0.10(tot 40*C/75*C 2)0.10; 3)<0.10; 4)0.10 2)<0.10; 3)<D.10; 4)<0.54 al); -30 Product: Pimobendan chewable tablets 2.5 mg Batch No.: PB020052 HDPE bottle (W) PVC/PVDC (m) Aluminium blister (m) 0 months 97(min)- 0 months 97(min)- 0 months 97(min) 99(max)/98(avg); 12 99(max)/98(avg); 12 99(max)/98(avg); 12 Dissolution 30*C/70"C Months 93-95/94 months 93-94/94 months 94-97/96 0 months 97(min)- 0 months 97(min)- 0 months 97(min) 99(max)/98(avg); 6 99(max)/98(avg); 6 99(max)/98(avg); 6 40*C/75*C months 93-94/93 months 91-93/92 months 93-95/94 Batch No.:PB020052 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) Assay of 0 months 2.49; 12 0 months 2.49; 12 months 0 months 2.49; 12 Pimobendan 30*C/70*C months 2.49 2.47 months 2.50 0 months 2.49; 6 0 months 2.49; 6 months 0 months 2.49; 6 months 40"C/75 0 C months 2.41 2.41 2.45 Batch No.:PB020052 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 0 months 1)<0. 10(K2006a); 0 months 1)<0.10(K2006a); 2)<0.10(UDCG 134 1)<0.10(K2006a); 2)<0.10(UDCG 134 BS); 3)<0.10 (any 2)<0.10(UDCG 134 BS); BS); 3)<0.10 (any unspecified); 3)<0.10 (any unspecified); 4)<0.10(total); 12 unspecified); 4)<0.10(total); 12 months 1)<0.10; 4)<0.10(total); 12 months months 1)<0.10; Degradation of 2)<0.10; 3)<0.10; 1)<0.10; 2)<0.10; 2)<0.10; 3)<0.10; Pimobendan 30"C/7"C 4)<0.10 3)<0.10; 4)<0.10 4)<0.10 0 months 1)<0. 10(K2006a); 0 months 0 months 2)<0.10(UDCG 134 1)<0.10(K2006a); 1)<0.10(K2006a); BS); 3)<0.10 (any 2)<0.10(UDCG 134 BS); 2)<0.10(UDCG 134 unspecified); 3)<0.10 (any BS); 3)<0.10 (any 4)<0.10(total); 6 unspecified); unspecified); months 1)<0.10; 4)<0.10(total); 6 months 4)<0.10(total); 6 months 2)<0.10; 3)<0.10; 1)0.43; 2)<0.10; 3)<0.10; 1)<0.10; 2)<0.10; 40"C/75*C 4)<0.10 4)0.43 3)<0.10; 4)<0.10 -31 Product: Pimeobendan chewable tablets 2.5 mg Batch No.:PB020053 HDPE bottle (W) PVC/PVCD (m) Aluminium blister (m) 0 months 96(min)- 0 months 96(min)- 0 months 96(min) 98(max)/97(avg); 12 98(max)/97(avg); 12 98(max)/97(avg);12 Dissolution 30*C/70 0 C months 92-94/93 months 90-93/92 months 91-95/93 0 months 96(min)- 0 months 96(min)- 0 months 96(min) 98(max)/97(avg); 6 98(max)/97(avg); 6 98(max)/97(avg); 6 40*C/75*C months 89-93/91 months 91-91/91 months 90-92/91 Batch No.: PB020053 HDPE bottle (m) PVC/PVCD (m) Aluminium blister (m) Assay of 0 months 2.44;12 0 months 2.44; 12 months O months 2.44; 12 Pinobendan 30*C/70*C months 2.44 2.41 months 2.46 0 months 2.44; 6 0 months 2.44; 6 months 0 months 2.44; 6 months 40*C/75*C months 2.41 2.40 2.40 Batch No.:PB020053 HDPE bottle (m) PVC/PVCD (m) Aluminium blister (m) 0 months 0 months 1)<0.10(K2006a); 0 months 1)<0. 10(K2006a); 2)<0.10(UDCG 134 1)<0.10(K2006a); 2)<0.10(UDCG 134 BS); 3)<0.10 (any 2)<0.10(UDCG 134 BS); BS); 3)<0.10 (any unspecified); 3)<0.10 (any unspecified); 4)<0.10(total); 12 unspecified); 4)<0. 10(total); 12 months 1)<0.10; 4)<0.10(total); 12 months months 1)<0.10; Degradation of 2)<0.10; 3)<0.10; 1)<0.10; 2)<O.10; 2)<0.10; 3)<0.10; Pimobendan 30*C/7*C 4)<0.10 3)<0.10; 4)<0.10 4)<0.10 0 months 1)<0.10(K2006a); 0 months 0 months 2)<0.10(UDCG 134 1)<0.10(K2006a); 1)<0.10(K2006a); BS); 3)<0.10 (any 2)<0.10(UDCG 134 BS); 2)<0.10(UDCG 134 unspecified); 3)<0.10 (any BS); 3)<0.10 (any 4)<0.10(total); 6 unspecified); unspecified); months 1)<0.10; 4)<0.10(total); 6 months 4)<0.10(total); 6 months 2)<0.10; 3)<0.10; 1)0.39; 2)<0.10; 3)<0.10; 1)<0.10; 2)<0.10; 40*C/75*C 4)<0.10 4)0.39 3)<0.10; 4)<0.10 - 32 Product: Pimobendan chewable tablets 2.5 mg Batch No.: PB020054 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 96(min)- 0 months 96(min)- 0 months 96(min) 98(max)/97(avg); 12 98(max)/97(avg); 12 98(max)/97(avg); 12 Dissolution 30 0 C/70 0 C months 93-95/94 months 90-93/91 months 93-94/94 0 months 96(min)- 0 months 96(min)- 0 months 96(min) 98(max)/97(avg); 6 98(max)/97(avg); 6 98(max)/97(avg); 6 40*C/75*C months 90-92/91 months 90-92/91 months 91-93/92 Batch No.: PB020054 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) Assay of 0 months 2.45; 12 0 months 2.45; 12 months 0 months 2.45; 12 Pimobendan 3 0 *C/7oC months 2.47 2.45 months 2.44 0 months 2.45; 6 0 months 2.45; 6 months 40*C/75*C months 2.40 0 months; 6 months 2.39 2.41 Batch No.PB020054 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 0 months 1)<0.10(K2006a); 0 months 1)<0.10(K2006a); 2)<0.10(UDCG 134 1)<0.10(K2006a); 2)<0.10(UDCG 134 BS); 3)<0.10 (any 2)<0.10(UDCG 134 BS); BS); 3)<0.10 (any unspecified); 3)<0. 10 (any unspecified); 4)<0.10(total); 12 unspecified); 4)<0.10(total); 12 months 1)<0.10; 4)<0.10(total); 12 months months 1)<0.10; Degradation of 2)<0.10; 3)<0.10; 1)<0.10; 2)<0.10; 2)<0.10; 3)<0.10; Pimobendan 30*C/7*C 4)<0.10 3)<0. 10; 4)<0. 10 4)<0. 10 0 months 1)<0.10(K2006a); 0 months 0 months 2)<0.10(UDCG 134 1)<O.1D(K2006a); 1)<0.10(K2006a); BS); 3)<0.10 (any 2)<0.10(UDCG 134 BS); 2)<0.10(UDCG 134 unspecified); 3)<0.10 (any BS); 3)<0.10 (any 4)<0.10(total); 6 unspecified); unspecified); months 1)<0.10; 4)<0.10(total); 6 months 4)<0.10(total); 6 months 2)<0.10; 3)<0.10; 1)0.36; 2)<0.10; 3)<0.10; 1)<0.10; 2)<0.10; 40*C/75"C 4)<0.10 4)0.36 3)<0.10; 4)<0.10 - 33 Product: Pimobendan chewable tablets 5 mg Batch No.: PB020059 HDPE bottle (m) PVC/PVDC m) Auminium blister m 0 months 94 (min)- 0 months 94 (min)-96 0 months 94 (min)-96 96 (max)/95 (avg); (max)/95 (avg); 24 (max)/95 (avg); 24 Dissolution 25*C/60% 24 months 83-90188 months 83-92/88 months 85-89/87 0 months 94 (min)- 0 months 94 (min)-96 0 months 94 (min)-96 96 (max)/95 (avg); (max)/95 (avg); 24 (max)/95 (avg); 24 30*C/70*C 24 months 83-95/89 months 82-97/88 months 83-91187 0 months 94 (min)- 0 months 94 (min)-96 0 months 94 (min)-96 96 (max)/95 (avg); 6 (max)/95 (avg); 6 months (max)/95 (avg); 6 40*C/75 0 C months 91-92/91 90-92/91 months 81-93/92 Batch No.: PB020059 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) Assay of 0 month 4.95; 24 0 month 4.95; 24 month 0 month 4.95; 24 month Pimobendan 25"C/60% month 4.94 4.92 4.92 0 month 4.95; 24 0 month 4.95; 24 month 0 month 4.95; 24 month 30*C/70"C month 4.90 4.92 4.96 0 month 4.95; 6 0 month 4.95; 6 month 0 month 4.95; 6 month 40*C/75*C month 4.88 4.91 4.95 Batch No.:PB020059 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 1)<0.10 (K 2006a); 2) <0.10 (UD-CG 134 BS); 3) 0 months 1)<0.10 (K 0 months 1)<0.10 (K <0.10 (any 2006a); 2) <0.10 (UD-CG 2006a); 2) <0.10 (UD unspecified); 4) 134 BS); 3) <0.10 (any CG 134 BS); 3) <0.10 <0.10 (total); 24 unspecified); 4) <0.10 (any unspecified); 4) months 1) <0.10; 2) (total); 24 months 1) <0.10 (total); 24 months Degradation of <0.10; 3) <0.10; 4) <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) Pimobendan 25*C/60% <0.10 4) <0.10 <0.10; 4) <0.10 0 months 1)<0.10 (K 2006a); 2) <0.10 (UD-CG 134 BS); 3) 0 months 1)<0.10 (K 0 months 1)<0.10 (K <0.10 (any 2006a); 2) <0.10 (UD-CG 2006a); 2) <0.10 (UD unspecified); 4) 134 BS); 3) <0.10 (any CG 134 BS); 3) <0.10 <0.10 (total); 24 unspecified); 4) <0.10 (any unspecified); 4) months 1) <0.10; 2) (total); 24 months 1) <0.10 (total); 24 months <0.10; 3) <0.10; 4) <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) 30*C/7 0 C <0.10 4) <0.10 <0.10; 4) <0.10 0 months 1)<0.10 (K 2006a); 2) <0.10 (UD-CG 134 BS); 3) 0 months 1)<0. 10 (K 0 months 1)<0.10 (K <0.10 (any 2006a); 2) <0.10 (UD-CG 2006a); 2) <0.1.0 (UD unspecified); 4) 134 BS); 3) <0.10 (any CG 134 BS); 3) <0.10 <0.10 (total); 6 unspecified); 4) <0.10 (any unspecified); 4) months 1) <0.10; 2) (total); 6 months 1) 0.23; <0.10 (total); 6 months <0.10; 3) <0.10; 4) < 2) <0.10; 3) <0.10; 4) 1) <0.10; 2) <0.10; 3) 40*C/75*C 0.10 0.23 <0.10; 4) <0.10 - 34 Product: Pimobendan chewable tablets 5 mg Batch No.:PB020060 HDPE bottle (m) PVC/PVCD (m) Aluminium blister (m) 0 months 91 (min)- 0 months 91 (min)-94 0 months 91 (min)-94 94 (max)/92 (avg); (max)/92 (avg); 24 (max)/92 (avg); 24 Dissolution 25"C/60% 24 months 85-90/87 months 84-90/86 months 82-88/86 0 months 91 (min)- 0 months 91 (min)-94 0 months 91 (min)-94 94 (maxy92 (avg); (max)/92 (avg); 24 (max)/92 (avg); 24 30*C/70*C 24 months 85-90/87 months 82-90/87 months 86-90/88 0 months 94 (min)- 0 months 91 (min)-94 0 months 91 (min)-94 96 (max)/95 (avg); 6 (max)/92 (avg); 6 months (max)/92 (avg); 6 40"C/75 0 C months 88-89/89 88-90/89 months 89-92/90 Batch No.: PB020060 HDPE bottle (m) PVCIPVDC (m) Aluminium blister (m) Assay of 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.87; 24 month Pimobendan 25*C/60% month 4.88 4.86 4.90 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.84; 24 month 30"C/70*C month 4.83 4.86 4.89 0 month 4.87; 6 0 month 4.87; 6 month 0 month 4.87; 6 month 40*Cf75*C month 4.86 4.87 4.86 Batch No.:PB020060 HDPE bottle (m) PVC/PVCD (m) Aluminium blister (m) 0 months 1)<0.10 (K 2006a); 2) <0.10 (UD-CG 134 BS); 3) 0 months 1)<0.10 (K 0 months 1)<0.10 (K <0.10 (any 2006a); 2) <0.10 (UD-CG 2006a); 2) <0.10 (UD unspecified); 4) 134 BS); 3) <0.10 (any CG 134 BS); 3) <0.10 <0.10 (total); 24 unspecified); 4) <0.10 (any unspecified); 4) months 1) <0.10; 2) (total); 24 months 1) <0.10 (total); 24 months Degradation of <0.10; 3) <0.10; 4) <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) Pimobendan 25*C60% <0.10; 4) <0.10; <0.10; 4) <0.10; 0 months 1)<0.10 (K 2006a); 2) <0.10 (JD-CG 134 BS); 3) 0 months 1)<0.10 (K 0 months 1)<0. 10 (K <0.10 (any 2006a); 2) <0.10 (UD-CG 2006a); 2) <0.10 (UD unspecified); 4) 134 BS); 3) <0.10 (any CG 134 BS); 3) <0.10 <0.10 (total); 24 unspecified); 4) <0.10 (any unspecified); 4) months 1) <0.10; 2) (total); 24 months 1) <0.10 (total); 24 months <0.10; 3) <0.10; 4) <0.10; 2) <0:10; 3) <0.10; 1) <0.10; 2) <0.10; 3) 30*C/7*C <0.10; 4)<0.10; <0.10; 4) <0.10; 0 months 1)<0.10 (K 0 months 1)<0.10 (K 2006a); 2) <0.10 2006a); 2) <0.10 (UD-CG (UD-CG 134 BS); 3) 134 BS); 3) <0.10 (any 0 months 1)<0.10 (K <0.10 (any unspecified); 4) <0.10 2006a); 2) <0.10 (UD unspecified); 4) (total); 24 months 1) CO 134 BS); 3) <0.10 <0.10 (total); 6 <0.10; 2) <0.10; 3) <0.10; (any unspecified); 4) months 1) <0.10; 2) 4) <0.10; 6 months 1) <0.10 (total); 6 months <0.10; 3) <0.10; 4) 0.22; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) 40*C/75*C <0.10 4)0.22 <0.10; 4) <0.10 - 35 Product: Pimobendan chewable tablets 5 mg Batch No.: PB020061 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 92 (min)- 0 months 92 (min)-95 0 months 92 (min)-95 95 (max)/94 (avg); (max)/94 (avg); 24 (max)/94 (avg); 24 Dissolution 25 0 C/60% 24 months 83-90/87 months 86-91/88 months 65-92/84 0 months 92 (min)- 0 months 92 (min)-95 0 months 92 (min)-95 95 (max)/94 (avg); (max)/94 (avg); 24 (max)/94 (avg); 24 30*C/70*C 24 months 84-88/87 months 81-87/85 months 88-91/90 0 months 92 (min)- 0 months 92 (min)-95 0 months 92 (min)-95 95 (max)/94 (avg); 6 (max)/94 (avg); 6 months (max)/94 (avg); 6 40*C/75 0 C months 88-90/89 88-90/89 months 88-91/90 Batch No.:PB020061 HDPE bottle (m) PVCIPVCD (m) Aluminium blister (m) Assay of 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.87; 24 month Pimobendan 25*C/60% month 4.83 4.85 4.88 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.87; 24 month 30*C/70*C month 4.82 4.80 4.90 0 month 4.87; 6 0 month 4.87; 6 month 0 month 4.87; 6 month 40*C/75 0 C month 4.83 4.82 4.88 Batch No.PB020061 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) 0 months 1)<O.10 (K 2006a); 2) <0.10 (UD-CG 134 BS); 3) 0 months 1)<0.10 (K 0 months 1)<0.10 (K <0.10 (any 2006a); 2) <0.10 (UD-CG 2006a); 2) <0.10 (UD unspecified); 4) 134 BS); 3) <0.10 (any CG 134 BS); 3) <0.10 <0.10 (total); 24 unspecified); 4) <0.10 (any unspecified); 4) months 1) <0.10; 2) (total); 24 months 1) <0.10 (total); 24 months Degradation of <0.10; 3) <0.10; 4) <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) Pimobendan 25 0 C/60% <0.10; 4) <0.10; <0.10; 4) <0.10 0 months 1)<0.10 (K 2006a); 2) <0.10 (UD-CG 134 BS); 3) 0 months 1)<0.10 (K 0 months 1)<0.10 (K <0.10 (any 2006a); 2) <0.10 (UD-CG 2006a); 2) <0.10 (UD unspecified); 4) 134 BS); 3) <0.10 (any CG 134 BS); 3) <0.10 <0.10 (total); 24 unspecified); 4) <0.10 (any unspecified); 4) months 1) <0.10; 2) (total); 24 months 1) <0.10 (total); 24 months <0.10; 3) <0.10; 4) <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) 30*C/7*C <0.10; 4) <0.10; <0.10; 4) <0.10 0 months 1)<0.10 (K 2006a); 2) <0.10 (UD-CG 134 BS); 3) 0 months 1)<0.10 (K 0 months 1)<O.10 (K <0.10 (any 2006a); 2) <0.10 (UD-CO 2006a); 2) <0.10 (UD unspecified); 4) 134 BS); 3) <0.10 (any CG 134 BS); 3).<0.10 <0.10 (total); 6 unspecified); 4) <0.10 (any unspecified); 4) months 1) <0.10; 2) (total); 6 months 1) 0.22; <0.10 (total); 6 months <0.10; 3) <0.10; 4) 2) <0.10; 3) <0.10; 4) 1) <0.10; 2) <0.10; 3) 40*C/75 0 C <0.10 0.22 <0.10; 4) <0.10 - 36 EXAMPLE 11 1. SUMMARY 1.1 Conduct of study Test items a) Test tablet 1 b) Vetmedin@ 1.25 mg (chewable tablets for dogs) Batch nos. a) 111201 b) 3652051 Test species Dog / Beagle Breeder Marshall BioResources 5800 Lake Bluff Rd. North Rose, Ny 14516 USA Number of animals 10 male animals (5 animals per group) Dose levels Group 1: Tablet formulation combination of Vetmedin@ 'I.25 ng + Test tablet 1 Group 2: Tablet formulation combination of Vetmedin® 1.25 mg + Test tablet 1 Route of administration Oral Frequency of administration Twice daily for 5 days at a 6-hour interval. Duration of study - 4 acclimatisation weeks - Two (2) administration parts with 5 administration days each.
-37 1.2 Findings Mortality None of the animals died prematurely. Clinical signs No test item-related clinical signs were observed for any of the animals in both cycles after oral treatment with Vetmedin@ 1.25 mg + Test tablet I/animallday. Preference and acceptance of the test item The results of preference and acceptance of the test items are presented in the table below. High palatability corresponds with a high preference value and a small acceptance value. In conclusion, Vetmedin 1.25 mg chewable tablet was more palatable then test tablet 1 according to the results of preference and acceptance. Table 1: Vetmedin@ 1.25 mg Test tablet 1 Group I and 2 (animal nos. 1 m - 10 m) 1 . 2. 1 . 2. Administration Administration Administration Administration (Morning, (Afternoon, (Morning, (Afternoon, fed) fasted) fed) fasted) Preference Mean number of 3.1 2.6 1.0 1.3 animals with first I intake 2.9 1.2 Acceptance Mean score 3.1 3.1 3.4 3.5 3.1 3.5 - 38 Body weight No test item-related changes were noted. Food and drinking water consumption No test item-related influence was noted on the food consumption. The visual appraisal of the drinking water consumption did not reveal any test item-related influence. 2. GENERAL INFORMATION 2.1 Alm of experiment To investigate the palatability of different chewable tablet formulations containing Pimobendan when given to dogs. 2.2 Duration of study - 4 acclimatisation weeks . Two (2) administration parts with 5 administration days each. 2.3 Test items 2.3.1 Test item 1 Designation Test tablet 1 Batch no. 111201 Receipt no. 49659 Date of receipt December 06, 2011 Characteristics Brownish, round tablet Storage conditions At room temperature Stability / Expiry date No data available to LPT Content 1.25 mg Pimobendan per tablet Retention sample of the test item No retention sample was taken.
- 39 2.3.2 Test item 2 Designation Vetmedin@ 1.25 mg (chewable tablets for dogs) Batch no. 3652051 Receipt no. 49658 Date of receipt December 06, 2011 Characteristics Brownish, oblong oval tablet Storage conditions At room temperature Stability / Expiry date August 2012 Content 1.25 mg Pimobendan per tablet Retention sample of the test item No retention sample was taken. 3. METHODS 3.1 Administration Route of administration Voluntary oral intake. Frequency of administration Twice daily for 5 days per group. Formulations 2 different tablet formulations: Test tablet 1 Vetmedin@ 1.25 mg (chewable tablets for dogs) Dose levels See Section 3.4 Selection of route of administration According to veterinary use. The oral route is the intended route. The test items were provided ready-to-use by the Sponsor. The tablet combination was offered to the animals simultaneously in the morning and in the afternoon always at the same time of the day according to a randomisation scheme. * As a first step, both tablets were placed on the floor/feeding bowl. * In a second step, both tablets were offered by hand (with or without dry dog -40 food). e The animals were not forced to take the tablet. The test item administrations in the morning were carried out approximately 5 hours before start of feeding. The 2nd daily administration took place in the afternoon approximately 1 h after feeding. The interval between both administrations was at least 6 hours. The time of feeding and dosing were documented in the raw data. 4. OBSERVATIONS 4.1 Preference and acceptance of the test Item For testing preference and acceptance, the two tablets were offered first by placing them on the floor in close proximity. The position of the two test tablets (right or left position) altered during the offering in the morning and in the afternoon according to the randomisation list. The two tablets were offered by a lab assistant placing them on the floor in close proximity. If the tablets were not taken from the floor after one minute, they were placed in a feeding bowl and offered for one minute again, as some dogs take the food from the floor only when it is in a feeding bowl. If the tablets were not taken from the feeding bowl after one minute. they were offered by hand at the same time, one in each hand, allowing free choice by the dog. If neither of the two tables was taken from hand after one minute, the tablets were covered with feed in order to facilitate intake. The manner in which the administration of the test item was accepted and any preference for one of the tablets occurred was documented as follows: Preference: Which of the two offered tablets was taken first Acceptance score, i.e. the following scores were applied: Score 1 = Immediate intake from floor Score 2 = Hesitating intake from floor > 10 sec or from a feeding bowl Score 3 = Immediate intake from hand Score 4 = Hesitating intake from hand > 10 sec or from hand after covering with feed Score 5 = No intake -41 5. RESULTS 5.1 Preference and acceptance of the test item The results of the preference and acceptance of the test items by group are presented in the table on the next page. High palatability corresponds with a high preference value and a small acceptance value. See Table 2 (next Daae): H:brnteroven Kof- o n - w_- .....- '"''-" - 42 Vetmedin@ 1.25 mg Test tablet I Group 1 (animal nos. 1 m - 5 m) 1. 2. 1. 2. Administration Administration Administration Administration (Morning, (Afternoon. fed) (Morning, (Afternoon. fed) fasted) fasted) Preference Mean number of 3.0 2.8 1.0 1.0 animals with first intake 2.9 1.0 Acceptance 2.8 2.6 3.0 3.2 Mean score 2.7 3.1 Group 2 (animal nos. 6 m - 10 m) 1. 2. 1. 2. Administration Administration Administration Administration (Morning, (Afternoon, fed) (Morning, (Afternoon, fed) fasted) fasted) Preference Mean number of 3.2 2.4 1.0 1.6 animals with first intake 2.8 1.3 Acceptance 3.5 3.5 3.8 3.8 Mean score 3.5 3.8 Group I and 2 (animal nos. 1 m - 10 m) 1. 2. 1. 2. Administration Administration Administration Administration (Morning, (Afternoon, fed) (Morning. (Afternoon, fed) fasted) fasted) Preference Mean number of 3.1 2.6 1.0 1.3 animals with first intake 2.9 1.2 Acceptance 3.1 3.1 3.4 3.5 Mean score I 3.1 3.5 - 43 EXAMPLE 12 1. SUMMARY 1.1 Conduct of study Test items a) Test tablet 2 b) Vetmedin@ 1.25 mg (chewable tablets for dogs) Batch nos. a) 111202 b) 3652051 Test species Dog / Beagle Breeder Marshall BioResources 5800 Lake Bluff Rd. North Rose, Ny 14516 USA Number of animals 10 male animals (5 animals per group) Dose levels Group 1: Tablet formulation combination of Vetmedin@ 1.25 mg + Test tablet 2 Group 2: Tablet formulation combination of Vetmedin@ 1.25 mg + Test tablet 2 Route of administration Oral Frequency of administration Twice daily for 5 days in a 6-hour interval. Duration of study - 4 acclimatisation weeks - Two (2) administration parts with 5 administration days each.
-44 1.2 Findings Mortality None of the animals died prematurely. Clinical signs No test item-related clinical signs were observed for the animals after oral treatment with Vetmedin@ 1.25 mg + Test tablet 2/animal/day. Preference and acceptance of the test item The results of preference and acceptance of the test items are presented in the table below. High palatability corresponds with a high preference value and a small acceptance value. In conclusion, Vetmedin 1.25 mg chewable tablet was more palatable then test tablet 2 according to the results of preference and acceptance. Table 3: Vetmedin@ 1.25 mg Test tablet 2 Group 1 and 2 (animal nos. I m - 10 m) 1. 2. 1. 2. Administration Administration Administration Administration (Morning, (Afternoon, (Morning, (Afternoon, fed) fasted) fed) fasted) Preference Mean number of 2.8 3.0 1.0 0.8 animals with first I intake 2.9 0.9 Acceptance 3.0 2.9 3.4 3.5 Mean score 1 3.0 3.5 -45 Body weight No test item-related changes were noted. Food and drinking water consumption No test item-related influence was noted on the food consumption. The visual appraisal of the drinking water consumption did not reveal any test item-related influence. 2. GENERAL INFORMATION 2.1 Aim of experiment To investigate the palatability of different chewable tablet formulations containing Pimobendan when given to dogs. 2.2 Duration of study - 4 acclimatisation weeks - Two (2) administration parts with 5 administration days each. 2.3 Test items 2.3.1 Test item I Designation Test tablet 2 Batch no. 111202 Receipt no. 49660 Date of receipt December 06, 2011 Characteristics Brownish, round tablet Storage conditions At room temperature Stability / Expiry date No data available to LPT Content 1.25 mg Pimobendan per tablet Retention sample of the test item No retention sample was taken.
- 46 2.3.2 Test item 2 Designation Vetmedin@ 1.25 mg (chewable tablets for dogs) Batch no. 3652051 Receipt no. 49658 Date of receipt December 06, 2011 Characteristics Brownish, oblong oval tablet Storage conditions At room temperature Stability / Expiry date August 2012 Content 1.25 mg Pimobendan per tablet Retention sample of the test item No retention sample was taken. 3. METHODS 3.1 Administration Route of administration Voluntary oral intake. Frequency of administration Twice daily for 5 days per group. Formulations 2 different tablet formulations. Test tablet 2 Vetmedine 1.25 mg (chewable tablets for dogs) Dose levels See Section 3.4 Selection of route of administration According to veterinary use. The oral route is the intended route. The test items were provided ready-to-use by the Sponsor. The tablet combination was offered to the animals simultaneously in the morning and in the afternoon always at the same time of the day according to a randomisation scheme. * As a first step, both tablets were placed on the floor/feeding bowl. . In a second step, both tablets were offered by hand (with or without dry dog - 47 food). * The animals were not forced to take the tablet. The test item administrations in the morning were carried out approximately 5 hours before start of feeding. The 2nd daily administration took place in the afternoon approximately 1 h after feeding. The interval between both administrations was at least 6 hours. The time of feeding and dosing were documented in the raw data. 4. OBSERVATIONS 4.1 Preference and acceptance of the test item For testing preference and acceptance, the two tablets were offered first by placing them on the floor in close proximity. The position of the two test tablets (right or left position) altered during the offering in the morning and in the afternoon according to the randomisation list. The two tablets were offered by a lab assistant placing them on the floor in close proximity. If the tablets were not taken from the floor after one minute, they were placed in a feeding bowl and offered for one minute again, as some dogs take the food from the floor only when it is in a feeding bowl. If the tablets were not taken from the feeding bowl after one minute, they were offered by hand at the same time, one in each hand, allowing free choice by the dog. If neither of the two tables was taken from hand after one minute, the tablets were covered with feed in order to facilitate intake. The manner in which the administration of the test item was accepted and any preference for one of the tablets occurred was documented as follows: Preference: Which of the two offered tablets was taken first Acceptance score, i.e. the following scores were applied: Score 1 = Immediate intake from floor Score 2 = Hesitating intake from floor > 10 sec or from a feeding bowl Score 3 = Immediate intake from hand Score 4 = Hesitating intake from hand > 10 sec or from hand after covering with feed Score 5 = No intake -48 5. RESULTS 5.1 Preference and acceptance of the test item The results of the preference and acceptance of the test items by group are presented in the table on the next page. High palatability corresponds with a high preference value and a small acceptance value. See Table 4 (next page): - 49 Vetmedin@ 1.25 mg Test tablet 2 Group 1 (animal nos. I m -5 m) 1. 2. 1. 2. Administration Administration Administration Administration (Morning, (Afternoon, fed) (Morning, (Afternoon. fed) fasted) fasted) Preference Mean number of 2.2 2.8 1.4 0.8 animals with first intake 2.5 1.1 Acceptance Mean score 3.4 3.3 3.6 3.7 3.4 3.7 Group 2 (animal nos. 6 m - 10 m) 1. 2. 1. 2. Administration Administration Administration Administration (Morning, (Afternoon. fed) (Morning, (Afternoon, fed) fasted) fasted) Preference Mean number of 3.4 3.2 0.6 0.8 animals with first intake 3.3 0.7 Acceptance 2.6 2.4 3.1 3.2 Mean scored 2.5 3.2 Group 1 and 2 (animal nos. 1 m - 10 m) 1. 2. 1. 2. Administration Administration Administration Administration (Morning, (Afternoon, fed) (Moming. (Afternoon, fed) fasted) fasted) Preference Mean number of 2.8 3.0 1.0 0.8 animals with first intake 2.9 0.9 Acceptance 3.0 2.9 3.43.5 Mean score 3.0 3.5 - 50 EXAMPLE 13 Further dissolution profiles have been obtained comparing the dissolution of the tablet 5 and capsule described in AU 630536 (the Australian equivalent of EP-A 0439030) with the tablet according to the invention. The following results have been achieved: Table 5 Comparison of dissolution results (mean of n = 6 tablets) in % 10 10 min. 15 min. 20 mi. 30 mini. 45 min. 60 miin. PO1-1649/EP/1 61 % 76 % 85 % 92 % 94% 94 % 5 mg tablet Batch 3633541 DI 5 ing 49% 73 % 91 % 97% 97% 97% capsule formulation compressed to tablets Batch 111003 D15 ing tablet 5 % 9% 13 % 25% 44% 66 % formulation (example) Batch 111001 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an 15 acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires 20 otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

权利要求:
Claims (18)
[1] 1. A solid formulation, comprising pimobendan or a pharmaceutically acceptable salt thereof which is homogenously dispersed in a polyvalent acid selected from citric 5 acid, tartaric acid or an anhydride thereof, and a flavor suitable for small animals.
[2] 2. A solid formulation according to claim 1, further comprising pharmaceutically acceptable carriers and/or excipients. 10
[3] 3. A solid formulation according to claim 2, wherein the carriers and/or excipients are selected from the group consisting of diluents, disintegrants, carriers, binders, flow regulators, lubricants and solvents.
[4] 4. A solid formulation according to claims 2 or 3, wherein the carriers are starch 15 and lactose.
[5] 5. A solid formulation according to claim 4, wherein the starch or various starches are selected from the group consisting of native starch, gelatinized starch, partly gelatinized starch, starch powder, starch granules, chemically modified starch and 20 swellable physically modified starch.
[6] 6. A solid formulation according to claim 4 or 5, wherein the starch is corn starch.
[7] 7. A solid formulation according to any one of claims 4 to 6, wherein the lactose 25 consists of coarse particles greater than 200 pm in size.
[8] 8. A solid formulation according to any one of claims 1 to 7, comprising 0.5 to 20 mg of pimobendan. 30
[9] 9. A solid formulation according to any one of claims 1 to 8, comprising a dose selected from the group of 1.25 mg, 2.5 mg, 5 mg or 10 mg of pimobendan. - 52
[10] 10. A solid formulation according to any one of claims 1 to 9, wherein the whole solid formulation has a weight range of 250 to 3000 mg.
[11] 11. A solid formulation according to any one of claims 1 to 10, wherein the solid 5 formulation consists of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, lactose, corn starch, croscarmellose-sodium, 50 mg/g citric acid, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate.
[12] 12. A solid formulation according to any one of claims 1 to 11, wherein the solid 10 formulation is a tablet or a granule.
[13] 13. Use of a solid formulation according to any one of claims I to 12 in the manufacture of a medicament for the prevention and/or treatment of diseases wherein cardiotonic, hypotensive and antithrombotic substances have a therapeutic effect. 15
[14] 14. Use of a solid formulation according to any one of claim 1 to 12 in the manufacture of a medicament for the prevention and/or treatment of congestive heart failure. 20
[15] 15. A kit, comprising a solid formulation according to any one of claims 1 to 12 and a package leaflet or user instruction including the information that said formulation is to use for the prevention and/or treatment of congestive heart failure in a mammal in need of such prevention or treatment. 25
[16] 16. A method of prevention and/or treatment of diseases wherein cardiotonic, hypotensive and antithrombotic substances have a therapeutic benefit, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation according to any one of claims 1 to 12. 30
[17] 17. A method of prevention and/or treatment of congestive heart failure comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation according to any one of claims 1 to 12. H~brInterwvenR onblDCC.RBR% 4 3_1.doc-8/erui - 53
[18] 18. A solid formulation as defined in any one of claims 1 to 12; or a use as defined in claim 13 or claim 14; or a kit as defined in claim 15; or a method as defined in claim 16 or 17 substantially as hereinbefore described and with reference to the examples.

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同族专利:

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公开号 | 公开日

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AU2013204087C1|2016-10-06|

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AU2013204087B2|2015-07-23|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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US5364646A|1990-01-10|1994-11-15|Dr. Karl Thomae Gmbh|Oral pharmaceutical forms of pimobendan|

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US6344153B1|1999-08-27|2002-02-05|The Trustees Of Columbia University In The City Of New York|Helical discotic switch|

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EP1247456A3|2001-02-28|2003-12-10|Pfizer Products Inc.|Palatable pharmaceutical compositions for companion animals|

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法律状态:
2015-11-05| CB| Opposition lodged by|Opponent name: JUROX PTY LTD |

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2016-04-21| CH| Opposition withdrawn|Opponent name: JUROX PTY LTD |

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2016-07-14| DA2| Applications for amendment section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 28 APR 2016 . |

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2016-10-06| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 28 APR 2016 |

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2016-10-20| FGA| Letters patent sealed or granted (standard patent)|

优先权:

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申请号 | 申请日 | 专利标题

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DE102004011512.5||2004-03-08||

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AU2005218912A|AU2005218912C1|2004-03-08|2005-03-01|Pharmaceutical composition comprising pimobendan|

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AU2013204087A|AU2013204087C1|2004-03-08|2013-04-08|Pharmaceutical composition comprising pimobendan|AU2013204087A| AU2013204087C1|2004-03-08|2013-04-08|Pharmaceutical composition comprising pimobendan|