# Patent

## Title
Packaging assembly for pharmaceutical composition including pimobendan

## Abstract

A packaging assembly or kit includes packaging material containing a solid formulation including pimobendan dispersed in a polyvalent acid. The kit may also include a package leaflet or user instruction including the information concerning use of the solid formulation, for example, via the oral route for the 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.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. Nonprovisional application Ser. No. 13/402,292, filed 22 Feb. 2012 and entitled “Pharmaceutical Composition Comprising Pimobendan,” which claims priority to U.S. Nonprovisional application Ser. No. 11/072,207, filed 4 Mar. 2005 and entitled “Pharmaceutical Composition Comprising Pimobendan,” which claims priority to German Patent Application No. 102004011512, filed on 8 Mar. 2004. The disclosure of each aforementioned application is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The invention relates to the field of animal health. In particular, the invention relates to novel oral pharmaceutical compositions comprising, as part of the pharmaceutically active compounds, pimobendan.
BACKGROUND OF THE INVENTION
Pimobendan, (4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazone) is disclosed in U.S. Pat. No. 4,361,563, herein incorporated by reference in its entirety. Pimobendan is a cardiotonic, hypotensive and anti-thrombotic. Said substance is useful in the treatment of congestive heart failure.
Pimobendan hardly dissolves in water. The resorption of pimobendan when 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 acid, in particular at a weight ratio of pimobendan to citric acid of between 1:10 and 1:20 (U.S. Pat. No. 5,364,646, herein incorporated by reference in its entirety). However, the high quantity of citric acid and the acidic taste of citric acid is not readily accepted by most animals—thus, such capsules have to be force-fed to the animals or mixed with food prior to application.
The problem underlying the present invention was to provide a pimobendan solid formulation readily acceptable by mammalian subjects, especially small animals.
SUMMARY OF THE INVENTION
The invention relates to novel solid formulations comprising as a pharmaceutically active compound pimobendan or a pharmaceutically acceptable salt thereof which is homogenously dispersed in a polyvalent acid and a flavor acceptable to small animals. Preferably, such solid formulations are granules or tablets. Most preferred is a tablet characterized in that the tablet comprises, 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further comprises 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 magnesium stearate.
The invention further relates to fluid-bed granulation processes for production of the solid formulations comprising the following steps:

    
    
        a) an aqueous solution of pimobendan and a binder as defined above is sprayed onto a solid carrier bed comprising one or more carriers and/or excipients, flavor and citric acid anhydride and
        b) the resulting mixture is dried and
        c) the dried mixture is sieved and de-agglomerated and
        d) a flow regulator is added to the sieved and de-agglomerated mixture and
        e) a lubricant is added to the resulting mixture and
        f) the resulting mixture with lubricant is blended for uniformity of granules to obtain final granules and/or
        g) the final granules are compressed to solid formulations.
    
    


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 therapeutic benefit, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation prepared as described 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 invention, as defined above.
Furthermore, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, Additionally, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterized in that a tablet comprising 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan and further comprising lactose, corn starch, croscarmellose-sodium, 50 mg/g citric acid, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate is made.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 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 micronized pimobendan and binder solution (PVP, HPMC, starch, gelatin); 6 Heating device for inlet air; 7 Sieve; 8 Nozzle, aqueous suspension is sprayed onto powder bed (citric acid, lactose, starch, flavor); 9 Powder bed.
FIG. 2: Flow Chart of Manufacturing Process.
FIG. 3: 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. Comparison of dissolution profiles of tablets which were stored 1 and 6 months at 40° C./75% in HDPE bottles; batch no. PB020049.
FIG. 4: 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. Comparison of dissolution profiles of tablets which were stored 12 days at 25° C./60% in open glass bottles; batch no. PB010080.
FIG. 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 3 and 6 months at 40.degree. C./75% in Alu-Alu Blister; batch no. PB010076
FIG. 6: Dissolution Profiles, Pimobendan 5.0 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 6 months at 40° C./75% in HDPE bottles; batch no. PB020059.
FIG. 7: Dissolution Profiles, Pimobendan 5.0 mg tablets, showing 95% 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.



DETAILED DESCRIPTION OF THE INVENTION
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 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 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. Accordingly, the term “about” is not used in the description.
Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are 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 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.
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 solid formulations according to the invention. With the process according to the invention, it was possible to formulate a long-term stable, capable of being produced on a large scale, homogenously dispersed, fast-releasing solid formulation. Despite the large size, pimobendan was homogenously dispersed. Such solid formulations comprise a flavor suitable for small animals, which surprisingly still allows a formulation having a polyvalent acid and yet have a palatibility rate of more than 70%—in many cases more than 90%. Thus, 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 pimobendan or a pharmaceutically acceptable salt thereof, see e.g. U.S. Pat. No. 4,361,563 or U.S. Pat. No. 5,364,646 (both herein incorporated by reference in its entirety), which is homogenously dispersed in a polyvalent acid selected from the group consisting of citric acid, acetic acid, maleic acid, tartaric acid and the anhydride of any of said polyvalent acids and mixtures thereof, and a flavor acceptable to small animals. Such flavors according to the invention preferably are selected from artificial beef flavors, artificial chicken flavors, pork liver extract, artificial meat flavor, honey flavor and the like. Said flavors not only disguise the taste of the polyvalent acid, but also the taste 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 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 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 & Wilkins Publishers, Philadelphia, 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 form part of the solid formulation according to the invention. See also Remington, J. P. The science and Practice of Pharmacy (2000). 20th ed. Lippincott Williams & Wilkins Publishers, Philadelphia, US.
One or several binders according to the invention are preferably selected from the group consisting of polyvidone (used synonymously for povidone), methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose, starch, gelatin, 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.).
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 formulation according to the invention may also be incorporated into 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 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 form part of 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 lubricants selected from the group consisting of magnesium stearate, calcium stearate, glyceryl behenate, polyethylene glycol, stearic acid, talc and the like. Any other lubricant known to the skilled person and found suitable for the solid formulation according to the invention may form part of 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 invention, characterized in that the carriers are starch and lactose. The invention preferably also relates to a solid formulation according to the invention, characterized in that the lactose consists of coarse particles greater than 200 μm 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 μm in size or spray-dried lactose. Preferred is lactose consisting of coarse particles greater than 200 μm 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, 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.
The invention preferably also relates to a solid formulation according to the invention, comprising 0.5 mg 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.
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 anhydride. The preferred ratio is 1:20.
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.
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 sprayed onto a solid carrier bed comprising one or several carriers and/or excipients as defined above, flavor and citric acid 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
        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.
    
    


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, 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 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
        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.
    
    


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 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 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 ensures immediate release of pimobendan. Surprisingly, it could be 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, which is especially important for long-term treatment.
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. Compared with the existing gelatin 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 chronic condition and long-term treatment.
Also, the palatability of the tablet is excellent. More than 90% of the dogs to whom the tablet according to this invention was given accepted the tablet voluntarily with only the tablet offered in a bowl. Compared with the existing gelatin capsule, the ease of administration has increased compliance with the prescribed treatment regime. This is important since the drug is administered for a chronic condition.
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.degree. 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 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 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 content uniformity fulfill the requirements of the European Pharmacopoeia (ISBN/ISSN 92-871-5106-7 of 4.sup.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.org; in print: USP-NF, catalog No. 2270001).
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 lactose (35-50% 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% 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 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) 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 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, which comprises 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 embodiment of the present invention, the solid formulation, preferably the tablet, comprises 1 mg pimobendan, 120-180 mg lactose, 120-180 mg corn starch, 8-18 mg croscarmellose-sodium, 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 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 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 knows that he can vary 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, 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 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 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 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 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, . . . 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 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 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 the following steps:

    
    
        a) an aqueous solution of pimobendan and a binder as defined above is sprayed onto a solid carrier bed comprising one or several carriers and/or excipients as defined above, flavor and citric acid 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
        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.
    
    


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 the following steps:

    
    
        a) an aqueous solution of pimobendan and polyvidone is sprayed onto a solid support comprising lactose, starch, flavor and citric acid 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
        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 tableted.
    
    


Step g) is omitted if the solid formulation is a granule. If the solid formulation is a 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 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 invention, characterized in that the tablet comprises 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further comprises 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 administering the solid formulation 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.
Furthermore, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterized 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, characterized 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.
The present invention furthermore relates to a kit, which comprises a solid formulation, preferably a tablet according to the present invention described herein, and a package leaflet or user instruction including the information concerning how the solid formulation, preferably the tablet, is to used via the oral route for the 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.
EXAMPLES
The following examples serve to further illustrate the present invention; but the same should not be construed as limiting the scope of the invention disclosed herein.
Example 1
Compositions










Composition A













mg/tablet
mg/tablet
mg/tablet





1.25 mg
2.5 mg
5.0 mg
Volatile


Ingredients
chewable
chewable
chewable
ingredient
kg/batch
















(01)
Pimobendan
1.250
2.500
5.000

0.175


(02)
Citric acid anhydrous <200 μm
25.000
50.000
100.00

3.500


(03)
Starch
163.125
326.250
652.500

22.8375


(04)
Lactose, coarse
163.125
326.250
652.500

22.8375


(05)
Polyvidone
20.000
40.000
80.000

2.800


(06)
Croscarmellose Sodium
20.000
40.000
80.000

2.800


(07)
Artificial Powdered Beef Flavour
100.000
200.000
400.000

14.000


(08)
Silica, colloidal anhydrous
2.500
5.000
10.000

0.350


(09)
Magnesium stearate
5.000
10.000
20.000

0.700


(10)
Purified water



+





500.000
1000.000
2000.000
−
70.000



















Composition B













mg/tablet
mg/tablet
mg/tablet





1.25 mg
2.5 mg
5.0 mg
Volatile


Ingredients
chewable
chewable
chewable
ingredient
kg/batch















Pimobendan
1.250
2.500
5.000

0.175


Citric acid anhydrous <200 μm
25.000
50.000
100.000

3.500


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









Example 2
Raw Materials
(01) Pimobendan
Function: Active Ingredient
(02) Citric acid anhydrous <200 μm
Function: Diluent, Disintegrant
(03) Starch
Function: Carrier, Disintegrant
(04) Lactose coarse
Function: Carrier, Disintegrant
(05) Povidone
Function: Binder
(06) Croscarmellose Sodium
Function: Disintegrant
(07) Artificial Powdered Beef Flavor
Function: Flavor
(08) Silica, colloidal anhydrous
Function: Flow regulator, Disintegrant
(09) Magnesium stearate
Function: Lubricant
(10) Purified water
Function: Solvent
Example 3
Product Description
Appearance: brownish, oblong tablets, with break line.















Tablet
Tablet
Tablet






















Weight
500
mg
1000
mg
2000
mg


Length
About 19.0
mm
About 24.0
mm
About 25.0
mm


Width
About 7.0
mm
About 7.5
mm
About 15.0
mm


Thick-
About 4.2
mm
About 5.6
mm
About 6.0
mm


ness









Example 4
Manufacturing Process
1 batch=140000 tablets (1.25 mg Dosage)
1 batch=70000 tablets (2.50 mg Dosage)
1 batch=35000 tablets (5.00 mg Dosage)
1. 1. Granulating
















Transfer in a suitable Granulator after prescreening:




(01)
Starch (e.g. 18 mesh sieve)
22.8375
kg


(02)
Lactose (e.g. 18 mesh sieve)
22.8375
kg


(03)
Citric acid anhydrous (e.g. 18 mesh sieve)
3.500
kg


(04)
Croscarmellose sodium (e.g. 18 mesh sieve)
2.800
kg


(05)
Artificial Beef Flavour (e.g. 45 mesh sieve)
14.000
kg


(05)
Povidone (Spray solution)
2.800
kg


(06)
UDCG 115 BS (Spray liquid)
0.175
kg



Premix in the granulator and granulate






68.950
kg





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 kg




68.950 kg









3. Final Mixing















Add



(07)
Sillica, colloidal anhydrous (e.g. 25 mesh sieve)
 0.350 kg


(08)
Magnesium stearate (e.g. 25 mesh sieve)
 0.700 kg



In a tumbling mixer, mix the screened premixture (2.)
70.000 kg



and the two ingredients





70.000 kg









4. Compression















Using a rotary press, compress the final mixture (3.)
70.000 kg



into tablets of 500 mg, 1000 mg, 2000 mg.





70.000 kg









5. Packaging
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
1. Granules
1.1 Appearance: Brownish, white-speckled granules
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%
    
    


2. Tablets
2.1 Appearance: Brownish, white-speckled, oblong tablets with breakline
2.2 Weight uniformity:















1) 1.25 mg chewable
Average weight: 475-525 mg



2) 2.5 mg chewable
Average weight: 950-1050 mg



3) 5 mg chewable
Average weight: 1900-2100 mg









2.3 Hardness: Determine the hardness















1) 1.25 mg
Target: 140N




Tolerance: 60-250N



2) 2.5 mg
Target: 160N




Tolerance: 60-250N



3) 5.0 mg
Target: 190N




Tolerance: 60-300N









2.4 Disintegration time: Determine the disintegration time according to USP/EP

    
    
        Tolerance limits: ≦15 minutes with water at 37° C., with disks
    
    


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 content of 5 mg/500 mg active ingredient were examined:











Ch. 010122 (tablets with 10%
Ch. 010123 (tablets with 10%


content of artificial beef flavor)
content of artificial beef flavor)




















Pimobendan
5
mg
Pimobendan
5
mg


(UD-CG 115 BS)


(UD-CG 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
50
mg
Artificial Beef
150
mg


Flavor


Flavor




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. 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%.
Example 7
Dissolution Profiles
Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 3.

    
    
        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 COMPARISON OF DISSOLUTION PROFILES OF TABLETS WHICH WERE STORED 1 AND 6 MONTHS AT 40° C./75% 1N HDPE BOTTLES
        BATCH NO. PB020049
    
    


Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 4.

    
    
        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 COMPARISON OF DISSOLUTION PROFILES OF TABLETS WHICH WERE STORED 12 DAYS AT 25° C./60% IN OPEN GLASS BOTTLES
        BATCH NO. PB010080
        DISSOLUTION PROFILES, PIMOBENDAN 1.25 MG TABLETS
        MANUFACTURING VARIABLE: DIFFERENT COMPRESSION FORCES
    
    

















% Dissolved, mean (n = 6)




Time
Tablet hardness















Batch No.
(min)
70N
105N
135N
157N

















020102
10
82
82
81
84




20
98
97
97
98




30
101
99
100
100




45
101
101
102
102









Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 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 3 AND 6 MONTHS AT 40° C./75% IN ALU-ALU BLISTER
        BATCH NO. PB010076
    
    


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
        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.degree. C./75% IN HDPE BOTTLES
        BATCH NO. PB020059
    
    


Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 7.

    
    
        DISSOLUTION PROFILES, PIMOBENDAN 5.0 MG TABLETS
        SHOWING 95% CONFIDENCE INTERVALS OF THE MEAN
        USP APPARATUS 2 (PADDLE), ROTATION SPEED 75 RPM, BUFFER pH 4.0 MANUFACTURING VARIABLE: DIFFERENT COMPRESSION FORCES
        BATCH NO. 020205
    
    














% Dissolved, mean (n = 6)



Tablet hardness















Time







Batch No.
(min)
117N
150N
186N
222N






020205
10
56
56
56
56




20
76
75
76
76




30
79
79
80
80




45
80
80
81
81



















Analytical Results for Pimobendan Chewable Tablet Batches Used in Stability Study









% dissolved in t = 30 minutes, mean (n = 6)













Tablet


Initial
6 Months
6 Months
6 Months


strength
Batch No.
Packaging
value
25° C./60%
30° C./70%
40° C./75%





1.25 mg 
PB020049
HDPE bottle
97
95
94
93



PB020049
Alu-Alu blister

95
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



PB020051
HDPE bottle
94
93
92
92



PB020051
Alu-Alu blister

94
93
92



PB020051
PVC/PVDC blister

93
93
91


2.5 mg
PB020052
HDPE bottle
98
n.d.
n.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.
n.d.
91



PB020054
Alu-Alu blister

n.d.
n.d.
91



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



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






Example 8
Content Uniformity
Samples were taken from both the final blend before tableting and from the tableting process. The following results demonstrate the uniformity of pimobendan content.










Blend Uniformity











Batch
Assay[mg/g]
% Target














0007LP - A
2.37
94.8



0007LP - B
2.48
99.2



0007LP - C
2.43
97.2



0007LP - D
2.44
97.6



0007LP - E
2.47
98.8



0007LP - F
2.50
100.0



0007LP - G
2.49
99.6



0007LP - H
2.49
99.6



0007LP - I
2.50
100.0



0007LP - J
2.43
97.2



Average
2.46
98.4



0008LP - A
2.41
96.4



0008LP - B
2.48
99.2



0008LP - C
2.45
98.0



0008LP - D
2.45
98.0



0008LP - E
2.46
98.4



0008LP - F
2.43
97.2



0008LP - G
2.46
98.4



0008LP - H
2.44
97.6



0008LP - I
2.47
98.8



0008LP - J
2.50
100.0



Average
2.46
98.2



















Uniformity of Process











Batch
Assay [mg/g]
% Target














PM020080 - 1
2.48
99.2



PM020080 - 2
2.52
100.8



PM020080 - 3
2.50
100.0



PM020080 - 4
2.52
100.8



PM020080 - 5
2.49
99.6



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



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 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 (mg
2.25-2.62
2.52
2.51
2.50



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



CU max. (mg)
≦0.718
0.664
0.650
0.645



CU average (mg
0.563-0.656
0.621
0.621
0.616



RSD (%)
≦6.0 
5.4
3.4
3.6









Example 10
Stability Data After 24 Months (Dissolution/Assay of Pimobendan/Degradation of Pimobendan)










Product: Pimobendan chewable tablets 1.25 mg











HDPE bottle (m)
PVC/PVDC (m)
Aluminium blister (m)
















Batch No.: PB020049




Dissolution
25° C./60° C.
0 months 95(min)-
0 months 95(min)-
0 months 95(min)-




102(max)/97(avg);
102(max)/97(avg);
102(max)/97(avg);




24 months 96-99/97
24 months 96-99/97
24 months 92-96/94



30° C./70° C.
0 months 95(min)-
0 months 95(min)-
0 months 95(min)-102




102(max)/97(avg);
102(max)/97(avg);
(max)/97(avg); 24




24 months 96-97/97
24 months 96-98/97
months 95-99/97



40° C./75° C.
0 months 95(min)-
0 months 95(min)-
0 months 95(min)-




102(max)/97(avg);
102(max)/97(avg);
102(max)/97(avg);




6 months 92-94/93
6 months 91-94/93
6 months 92-95/94


Assay of
25° C./60° C.
0 months 1.251;
0 months 1.251;
0 months 1.251;


Pimobendan

24 months 1.233
24 months 1.236
24 months 1.237



30° C./70° C.
0 months 1.251;
0 months 1.251;
0 months 1.251;




24 months 1.229
24 months 1.242
24 months 1.236



40° C./75° C.
0 months 1.251;
0 months 1.251;
0 months 1.251;




6 months 1.221
6 months 1.214
6 months 1.231


Degradation of
25° C./60° C.
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)<0.10
3)<0.10; 4)<0.10



30° C./7° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)0.10;
1)0.35; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)0.10
3)<0.10; 4)0.35
3)<0.10; 4)<0.10



40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 6 months
4)<0.10(total); 6 months




1)0.10; 2)0.11;
1)0.55; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)0.21
3)<0.10; 4)0.55
3)<0.10; 4)<0.10




Batch No.: PB020050




Dissolution
25° C./60° C.
0 months 91(min)-
0 months 91(min)-
0 months 91(min)-




96(max)/94(avg);
96(max)/94(avg);
96(max)/94(avg);




24 months 96-104/99
24 months 84-101/95
24 months 92-96/94



30° C./70° C.
0 months 91(min)-
0 months 91(min)-
0 months 91(min)-




96(max)/94(avg);
96(max)/94(avg);
96(max)/94(avg);




24 months 94-102/97
24 months 93-102/97
24 months 97-105/99



40° C./75° C.
0 months 91(min)-
0 months 91(min)-
0 months 91(min)-




96(max)/94(avg);
96(max)/94(avg);
96(max)/94(avg);




6 months 91-92/91
6 months 91-93/92
6 months 91-92/91


Assay of
25° C./60° C.
0 months 1.231;
0 months 1.231;
0 months 1.231;


Pimobendan

24 months 1.224
24 months 1.201
24 months 1.228



30° C./70° C.
0 months 1.231;
0 months 1.231;
0 months 1.231;




24 months 1.213
24 months 1.217
24 months 1.230



40° C./75° C.
0 months 1.231;
0 months 1.231;
0 months 1.231;




6 months 1.205
6 months 1.202
6 months 1.215


Degradation of
25° C./60° C.
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)<0.10
3)<0.10; 4)<0.10



30° C./7° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)0.37; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)0.37
3)<0.10; 4)<0.10



40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 6 months
4)<0.10(total); 6 months




1)<0.10; 2)<0.10;
1)0.58; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)0.58
3)<0.10; 4)<0.10




Batch No.: PB020051




Dissolution
25° C./60° C.
0 months 92(min)-
0 months 92(min)-
0 months 92(min)-




95(max)/94(avg);
95(max)/94(avg);
95(max)/94(avg);




24 months 92-100/96
24 months 94-101/97
24 months 91-100/95



30° C./70° C.
0 months 92(min)-
0 months 92(min)-
0 months 92(min)-




95(max)/94(avg);
95(max)/94(avg);
95(max)/94(avg);




24 months 92-99/96
24 months 95-98/97
24 months 92-100/97



40° C./75° C.
0 months 92(min)-
0 months 92(min)-
0 months 92(min)-




95(max)/94(avg);
95(max)/94(avg);
95(max)/94(avg);




6 months 91-93/92
6 months 90-92/91
6 months 91-94/92


Assay of
25° C./60° C.
0 months 1.230;
0 months 1.230;
0 months 1.230;


Pimobendan

24 months 1.222
24 months 1.225
24 months 1.228



30° C./70° C.
0 months 1.230;
0 months 1.230;
0 months 1.230;




24 months 1.214
24 months 1.221
24 months 1.230



40° C./75° C.
0 months 1.230;
0 months 1.230;
0 months 1.230;




6 months 1.210
6 months 1.202
6 months 1.218


Degradation of
25° C./60° C.
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total);




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;





3)<0.10; 4)<0.10
3)<0.10; 4)<0.10




30° C./7° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total);




1)<0.10; 2)<0.10;
1)<0.33; 2)<0.10;





3)<0.10; 4)<0.10
3)<0.10; 4)0.33




40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);
2)<0.10(DU-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 6 months
4)<0.10(total);




1)<0.10; 2)0.10;
1)<0.54; 2)<0.10;





3)<0.10; 4)0.10
3)<0.10; 4)<0.54



















Product: Pimobendan chewable tablets 2.5 mg











HDPE bottle (m)
PVC/PVDC (m)
Aluminium blister (m)
















Batch No.: PB020052




Dissolution
30° C./70° C.
0 months 97(min)-
0 months 97(min)-
0 months 97(min)-




99(max)/98(avg);
99(max)/98(avg);
99(max)/98(avg);




12 Months 93-95/94
12 months 93-94/94
12 months 94-97/96



40° C./75° C.
0 months 97(min)-
0 months 97(min)-
0 months 97(min)-




99(max)/98(avg);
99(max)/98(avg);
99(max)/98(avg);




6 months 93-94/93
6 months 91-93/92
6 months 93-95/94


Assay of
30° C./70° C.
0 months 2.49;
0 months 2.49;
0 months 2.49;


Pimobendan

12 months 2.49
12 months 2.47
12 months 2.50



40° C./75° C.
0 months 2.49;
0 months 2.49;
0 months 2.49;




6 months 2.41
6 months 2.41
6 months 2.45


Degradation of
30° C./7° C.
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 12 months
4)<0.10(total); 12 months
4)<0.10(total); 12 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)<0.10
3)<0.10; 4)<0.10



40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 6 months
4)<0.10(total); 6 months




1)<0.10; 2)<0.10;
1)0.43; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)0.43
3)<0.10; 4)<0.10




Batch No.: PB020053




Dissolution
30° C./70° C.
0 months 96(min)-
0 months 96(min)-
0 months 96(min)-




98(max)/97(avg);
98(max)/97(avg);
98(max)/97(avg);




12 months 92-94/93
12 months 90-93/92
12 months 91-95/93



40° C./75° C.
0 months 96(min)-
0 months 96(min)-
0 months 96(min)-




98(max)/97(avg);
98(max)/97(avg);
98(max)/97(avg);




6 months 89-93/91
6 months 91-91/91
6 months 90-92/91


Assay of
30° C./70° C.
0 months 2.44;
0 months 2.44;
0 months 2.44;


Pimobendan

12 months 2.44
12 months 2.41
12 months 2.46



40° C./75° C.
0 months 2.44;
0 months 2.44;
0 months 2.44;




6 months 2.41
6 months 2.40
6 months 2.40


Degradation of
30° C./7° C.
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 12 months
4)<0.10(total); 12 months
4)<0.10(total); 12 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)<0.10
3)<0.10; 4)<0.10



40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 6 months
4)<0.10(total); 6 months




1)<0.10; 2)<0.10;
1)0.39; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)0.39
3)<0.10; 4)<0.10




Batch No.: PB020054




Dissolution
30° C./70° C.
0 months 96(min)-
0 months 96(min)-
0 months 96(min)-




98(max)/97(avg);
98(max)/97(avg);
98(max)/97(avg);




12 months 93-95/94
12 months 90-93/91
12 months 93-94/94



40° C./75° C.
0 months 96(min)-
0 months 96(min)-
0 months 96(min)-




98(max)/97(avg);
98(max)/97(avg);
98(max)/97(avg);




6 months 90-92/91
6 months 90-92/91
6 months 91-93/92


Assay of
30° C./70° C.
0 months 2.45;
0 months 2.45;
0 months 2.45;


Pimobendan

12 months 2.47
12 months 2.45
12 months 2.44



40° C./75° C.
0 months 2.45;
0 months;
0 months 2.45;




6 months 2.40
6 months 2.39
6 months 2.41


Degradation of
30° C./7° C.
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 12 months
4)<0.10(total); 12 months
4)<0.10(total); 12 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)<0.10
3)<0.10; 4)<0.10



40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);
2)<0.10(UDCG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 6 months
4)<0.10(total); 6 months




1)<0.10; 2)<0.10;
1)0.36; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)0.36
3)<0.10; 4)<0.10



















Product: Pimobendan chewable tablets 5 mg











HDPE bottle (m)
PVC/PVDC (m)
Aluminium blister (m)
















Batch No.: PB020059




Dissolution
25° C./60%
0 months 94(min)-
0 months 94(min)-
0 months 94(min)-




96(max)/95(avg);
96(max)/95(avg);
96(max)/95(avg);




24 months 83-90/88
24 months 83-92/88
24 months 85-89/87



30° C./70° C.
0 months 94(min)-
0 months 94(min)-
0 months 94(min)-




96(max)/95(avg);
96(max)/95(avg);
96(max)/95(avg);




24 months 83-95/89
24 months 82-97/88
24 months 83-91/87



40° C./75° C.
0 months 94(min)-
0 months 94(min)-
0 months 94(min)-




96(max)/95(avg);
96(max)/95(avg);
96(max)/95(avg);




6 months 91-92/91
6 months 90-92/91
6 months 81-93/92


Assay of
25° C./60%
0 month 4.95;
0 month 4.95;
0 month 4.95;


Pimobendan

24 month 4.94
24 month 4.92
24 month 4.92



30° C./70° C.
0 month 4.95;
0 month 4.95;
0 month 4.95;




24 month 4.90
24 month 4.92
24 month 4.96



40° C./75° C.
0 month 4.95;
0 month 4.95;
0 month 4.95;




6 month 4.88
6 month 4.91
6 month 4.95


Degradation of
25° C./60%
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)<0.10
3)<0.10; 4)<0.10



30° C./7° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)<0.10
3)<0.10; 4)<0.10



40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 6 months
4)<0.10(total); 6 months




1)<0.10; 2)<0.10;
1)0.23; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)0.23
3)<0.10; 4)<0.10




Batch No.: PB020060




Dissolution
25° C./60%
0 months 91(min)-
0 months 91(min)-
0 months 91(min)-




94(max)/92(avg);
94(max)/92(avg); 24
94(max)/92(avg); 24




24 months 85-90/87
months 84-90/86
months 82-88/86



30° C./70° C.
0 months 91(min)-
0 months 91(min)-
0 months 91(min)-




94(max)/92(avg);
94(max)/92(avg); 24
94(max)/92(avg); 24




24 months 85-90/87
months 82-90/87
months 86-90/88



40° C./75° C.
0 months 94(min)-
0 months 91(min)-
0 months 91(min)-




96(max)/95(avg);
94(max)/92(avg);
94(max)/92(avg);




6 months 88-89/89
6 months 88-90/89
6 months 89-92/90


Assay of
25° C./60%
0 month 4.87;
0 month 4.87;
0 month 4.87;


Pimobendan

24 month 4.88
24 month 4.86
24 month 4.90



30° C./70° C.
0 month 4.87;
0 month 4.87;
0 month 4.84;




24 month 4.83
24 month 4.86
24 month 4.89



40° C./75° C.
0 month 4.87;
0 month 4.87;
0 month 4.87;




6 month 4.86
6 month 4.87
6 month 4.86


Degradation of
25° C./60%
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10;



30° C./7° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10 UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10;



40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 24 months
4)<0.10(total); 6 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10





6 months






1)0.22; 2)<0.10;






3)<0.10; 4)0.22





Batch No.: PB020061




Dissolution
25° C./60%
0 months 92(min)-
0 months 92(min)-
0 months 92(min)-




95(max)/94(avg);
95(max)/94(avg);
95(max)/94(avg);




24 months 83-90/87
24 months 86-91/88
24 months 65-92/84



30° C./70° C.
0 months 92(min)-
0 months 92(min)-
0 months 92(min)-




95(max)/94(avg);
95(max)/94(avg);
95(max)/94(avg);




24 months 84-88/87
24 months 81-87/85
24 months 88-91/90



40° C./75° C.
0 months 92(min)-
0 months 92(min)-
0 months 92(min)-




95(max)/94(avg);
95(max)/94(avg);
95(max)/94(avg);




6 months 88-90/89
6 months 88-90/89
6 months 88-91/90


Assay of
25° C./60%
0 month 4.87;
0 month 4.87;
0 month 4.87;


Pimobendan

24 month 4.83
24 month 4.85
24 month 4.88



30° C./70° C.
0 month 4.87;
0 month 4.87;
0 month 4.87;




24 month 4.82
24 month 4.80
24 month 4.90



40° C./75° C.
0 month 4.87;
0 month 4.87;
0 month 4.87;




6 month 4.83
6 month 4.82
6 month 4.88


Degradation of
25° C./60%
0 months
0 months
0 months


Pimobendan

1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10



30° C./7° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 24 months
4)<0.10(total); 24 months
4)<0.10(total); 24 months




1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10;
3)<0.10; 4)<0.10;



40° C./75° C.
0 months
0 months
0 months




1)<0.10(K2006a);
1)<0.10(K2006a);
1)<0.10(K2006a);




2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);
2)<0.10(UD-CG 134 BS);




3)<0.10(any unspecified);
3)<0.10(any unspecified);
3)<0.10(any unspecified);




4)<0.10(total); 6 months
4)<0.10(total); 6 months
4)<0.10(total); 6 months




1)<0.10; 2)<0.10;
1)0.22; 2)<0.10;
1)<0.10; 2)<0.10;




3)<0.10; 4)<0.10
3)<0.10; 4)0.22
3)<0.10; 4)<0.10

## Claims

1. A kit comprising:
packaging material; and
a solid formulation comprising a homogenous dispersion of:
pimobendan or a pharmaceutically acceptable salt thereof provided in an amount of 0.5 mq to 20 mq;
a polyvalent acid selected from the group consisting of citric acid, tartaric acid, an anhydride thereof and mixtures thereof, wherein the polyvalent acid is present in an amount of 2.5 percent to 10 percent by weight of said solid formulation, and wherein the solid formulation includes a weight ratio of 1:10 to 1:40 of pimobendan to polyvalent acid; and
a flavor acceptable to small animals, wherein the flavor is present in an amount of 5 to 30 percent by weight of said solid formulation.

2. The kit according to claim 1 further comprising user instructions including information that the formulation is to be used for the prevention or treatment of congestive heart failure in a mammal in need of such prevention or treatment.

3. The kit according to claim 1 further comprising pharmaceutically acceptable carriers or excipients.

4. The kit according to claim 3, wherein the carriers or excipients are selected from the group consisting of diluents, disintegrants, carriers, binders, flow regulators, lubricants, solvents and mixtures thereof.

5. The kit according to claim 3 further comprising starch and lactose.

6. The kit according to claim 5, wherein the starch is selected from the group consisting of native starch, gelatinized starch, partly gelatinized starch, starch powder, starch granules, chemically modified starch, swellable physically modified starch and mixtures thereof.

7. The kit according to claim 5, wherein the starch is corn starch.

8. The kit according to claim 5, wherein the lactose consists of coarse particles greater than 200 μm in size.

9. The kit according to claim 1, wherein the weight of the whole solid formulation is in the range of 250 to 3000 mg.

10. The kit according to claim 1, wherein the solid formulation comprises:
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.

11. The kit according to claim 1, wherein the sollid formulation comprises a tablet or a granule.

12. The kit according to claim 1, wherein a content uniformity of the pimobendan or the pharmaceutically acceptable salt thereof is 94.8 percent or greater.

13. The solid formulation of claim 12, wherein the content uniformity of the pimobendan or the pharmaceutically acceptable salt thereof is at least 98.0 percent.

14. The kit according to claim 1, wherein the packaging material comprises at least one of aluminum material, polyvinyl chloride material, polyvinylidene chloride material, and high density polyethylene material.

15. The kit according to claim 1, wherein the flavor is homogenously dispersed within the solid formulation.

16. The kit according to claim 1, wherein the solid formulation is obtained by an aqueous manufacturing process.

17. The kit according to claim 1, wherein the solid formulation is obtained by an aqueous fluid-bed granulation process.

18. The kit according to claim 1, wherein the solid formulation is obtained by a fluid-bed granulation process, the fluid-bed granulation process comprising the following steps:
a) spraying an aqueous solution of pimobendan and a binder onto a solid support comprising at least one excipient, a flavor and citric acid anhydrous to form a mixture;
b) drying the mixture of a);
c) sieving and de-agglomerating the mixture of b);
d) adding a flow regulator to the mixture of c);
e) adding a lubricant to the mixture of d); and
f) blending the mixture of e) for uniformity of granules to obtain final granules.

19. The kit according to claim 18, wherein the fluid-bed granulation process further comprises:
g) compressing the final granules of f) to tablets.