US20140363510A1 - Pharmaceutical composition including pimobendan - Google Patents

Pharmaceutical composition including pimobendan Download PDF

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US20140363510A1
US20140363510A1 US14/465,273 US201414465273A US2014363510A1 US 20140363510 A1 US20140363510 A1 US 20140363510A1 US 201414465273 A US201414465273 A US 201414465273A US 2014363510 A1 US2014363510 A1 US 2014363510A1
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months
solid formulation
pimobendan
starch
formulation according
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Martin A. FOLGER
Bernhard Hassel
Stefan Henke
Jens Lehmann
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Boehringer Ingelheim Vetmedica GmbH
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Boehringer Ingelheim Vetmedica GmbH
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Priority to US14/465,273 priority Critical patent/US20140363510A1/en
Publication of US20140363510A1 publication Critical patent/US20140363510A1/en
Priority to US15/695,334 priority patent/US20170368062A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the invention relates to the field of animal health.
  • the invention relates to novel oral pharmaceutical compositions comprising, as part of the pharmaceutically active compounds, pimobendan.
  • 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.
  • 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).
  • 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.
  • 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.
  • solid formulations are granules or tablets.
  • 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:
  • 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 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.
  • the method comprises administering a tablet according to the invention, as defined above.
  • the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure
  • 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.
  • 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.
  • PVP micronized pimobendan and binder solution
  • PVP micronized pimobendan and binder solution
  • 6 Heating device for inlet air 7 Sieve
  • 8 Nozzle 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m in size.
  • lactose consists of coarse particles greater than 200 ⁇ m 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 ⁇ m in size or spray-dried lactose.
  • Preferred is lactose consisting of coarse particles greater than 200 ⁇ m 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:
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 France, http://www.pheur.org) and the United States Pharmacopoeia (http://www.usp.org; in print: USP-NF, catalog No. 2270001).
  • a skilled man is in a position to prepare such solid formulations, preferably a tablet.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, .
  • 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, . . .
  • the amount of citric acid anhydrous may be 10, 11, 12, . . . 18, 19, 20 etc.; 21, 22, . . . 28, 29, 30 etc.; 31, 32, .
  • 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, . . .
  • the amount of polyyidone 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.
  • the amount of croscarmellose-sodium may be 4, 5, 6, .
  • 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, . . .
  • 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.
  • the invention relates to a fluid-bed granulation process comprising the following steps:
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition A Composition A
  • 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 ⁇ m 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) Croscannellose 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 ⁇ m 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
  • 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
  • Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 3 .
  • Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 4 .
  • Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 5 .
  • Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 6 .
  • Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in FIG. 7 .
  • 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
  • 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 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
  • Pimobendan chewable tablets 1.25 mg Batch No.: PB020049 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) Dissolution 25° C./60° C. 0 months 95 (min)-102 0 months 95 (min)-102 0 months 95 (min)-102 (max)/97 (avg) ; 24 (max)/97 (avg) ; 24 (max)/97 (avg) ; 24 months 96-99/97 months 96-99/97 months 92-96/94 30° C./70° C.

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Abstract

A solid formulation includes pimobendan or a pharmaceutically acceptable salt thereof, which is homogenously dispersed with a polyvalent acid and a flavor suitable to animals.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • The present application claims priority to U.S. Nonprovisional application Ser. No. 13/802,989, filed 14 Mar. 2013 and entitled “Packaging Assembly for Pharmaceutical Composition Including Pimobendan,” which 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 off) 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 off) 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 polyyidone 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 off) 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
  • 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) Croscannellose 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
  • 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
    Thickness About 4.2 mm About 5.6 mm About 6.0 mm
    • 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: 140 N
    Tolerance: 60-250 N
    2) 2.5 mg Target: 160 N
    Tolerance: 60-250 N
    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° 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% in 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) 70 N 105 N 135 N 157 N
    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
    Batch No. Time (min) 117 N 150 N 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
  • 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. 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
    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
    Batch No.: PB020049
    HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m)
    Dissolution 25° C./60° C. 0 months 95 (min)-102 0 months 95 (min)-102 0 months 95 (min)-102
    (max)/97 (avg) ; 24 (max)/97 (avg) ; 24 (max)/97 (avg) ; 24
    months 96-99/97 months 96-99/97 months 92-96/94
    30° C./70° C. 0 months 95 (min)-102 0 months 95 (min)-102 0 months 95 (min)-102
    (max)/97 (avg) ; 24 (max)/97 (avg) ; 24 (max)/97 (avg) ; 24
    months 96-97/97 months 96-98/97 months 95-99/97
    40° C./75° C. 0 months 95 (min)-102 0 months 95 (min)-102 0 months 95 (min)-102
    (max)/97 (avg) ; 6 (max)/97 (avg) ; 6 (max)/97 (avg) ; 6
    months 92-94/93 months 91-94/93 months 92-95/94
    Assay of 25° C./60° C. 0 months 1.251; 24 0 months 1.251; 24 0 months 1.251; 24
    Pimobendan months 1.233 months 1.236 months 1.237
    30° C./70° C. 0 months 1.251; 24 0 months 1.251; 24 0 months 1.251; 24
    months 1.229 months 1.242 months 1.236
    40° C./75° C. 0 months 1.251; 6 0 months 1.251; 6 months 0 months 1.251; 6
    months 1.221 1.214 months 1.231
    Degradation of 25° C./60° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    Pimobendan 2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total;
    unspecified) ; 4) <0.10 (total; 24 months 1) <0.10; 24 months 1) <0.10;
    24 months 2) <0.10; 3) <0.10; 4) <0.10 2) <0.10; 3) <0.10;
    1) <0.10; 2) <0.10; 4) <0.10
    3) <0.10; 4) <0.10
    30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;
    unspecified) ; 4) <0.10 (total) ; 24 months 1) 0.35; 24 months 1) <0.10;
    24 months 2) <0.10; 3) <0.10; 4) 0.35 2) <0.10; 3) <0.10;
    1) <0.10; 2) 0.10; 4) <0.10
    3) <0.10; 4) 0.10
    40° C./75° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;
    unspecified) ; 4) <0.10 (total) ; 6 months 1) 0.55; 6 months 1) <0.10;
    6 months 1) 0.10; 2) <0.10; 3) <0.10; 4) 0.55 2) <0.10; 3) <0.10;
    2) 0.11; 3) <0.10; 4) 0.21 4) <0.10
    Batch No.: PB020050
    HDPE bottle (m) PVC/PVCD (m) Aluminium blister (m)
    Dissolution 25° C./60° C. 0 months 91 (min)-96 0 months 91 (min)-96 0 months 91 (min)-96
    (max)/94 (avg) ; 24 (max)/94 (avg) ; 24 (max)/94 (avg) ; 24
    months 96-104/99 months 84-101/95 months 92-96/94
    30° C./70° C. 0 months 91 (min)-96 0 months 91 (min)-96 0 months 91 (min)-96
    (max)/94 (avg) ; 24 (max)/94 (avg) ; 24 (max)/94 (avg) ; 24
    months 94-102/97 months 93-102/97 months 97-105/99
    40° C./75° C. 0 months 91 (min)-96 0 months 91 (min)-96 0 months 91 (min)-96
    (max)/94 (avg) ; 6 (max)/94 (avg) ; 6 (max)/94 (avg) ; 6
    months 91-92/91 months 91-93/92 months 91-92/91
    Assay of 25° C./60° C. 0 months 1.231; 24 0 months 1.231; 24 0 months 1.231; 24
    Pimobendan months 1.224 months 1.201 months 1.228
    30° C./70° C. 0 months 1.231; 24 0 months 1.231; 24 0 months 1.231; 24
    months 1.213 months 1.217 months 1.230
    40° C./75° C. 0 months 1.231; 6 0 months 1.231; 6 months 0 months 1.231; 6
    months 1.205 1.202 months 1.215
    Degradation of 25° C./60° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    Pimobendan 2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;
    unspecified) ; 4) <0.10 (total) ; 24 months 1) <0.10; 24 months 1) <0.10;
    24 months 2) <0.10; 3) <0.10; 4) <0.10 2) <0.10; 3) <0.10;
    1) <0.10; 2) <0.10; 4) <0.10
    3) <0.10; 4) <0.10
    30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;
    unspecified) ; 4) <0.10 (total) ; 24 months 1) <0.37; 24 months 1) <0.10;
    24 months1) <0.10; 2) <0.10; 3) <0.10; 4) <0.37 2) <0.10; 3) <0.10;
    2) <0.10; 3) <0.10; 4) <0.10
    4) <0.10
    40° C./75° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;
    unspecified) ; 4) <0.10 (total) ; 6 months 1) 0.58; 6 months 1) <0.10;
    6 months 1) <0.10; 2) <0.10; 3) <0.10; 4) 0.58 2) <0.10; 3) <0.10;
    2) <0.10; 3) <0.10; 4) <0.10
    4) <0.10
    Batch No.: PB020051
    HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m)
    Dissolution 25° C./60° C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months 92 (min)-95
    (max)/94 (avg) ; 24 (max)/94 (avg) ; 24 (max)/94 (avg) ; 24
    months 92-100/96 months 94-101/97 months 91-100/95
    30° C./70° C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months 92 (min)-95
    (max)/94 (avg) ; 24 (max)/94 (avg) ; 24 (max)/94 (avg) ; 24
    months 92-99/96 months 95-98/97 months 92-100/97
    40° C./75° C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months 92 (min)-95
    (max)/94 (avg) ; 6 (max)/94 (avg) ; 6 (max)/94 (avg) ; 6
    months 91-93/92 months 90-92/91 months 91-94/92
    Assay of 25° C./60° C. 0 months 1.230; 24 0 months 1.230; 24 0 months 1.230; 24
    Pimobendan months 1.222 months 1.225 months 1.228
    30° C./70° C. 0 months 1.230; 24 0 months 1.230; 24 0 months 1.230; 24
    months 1.214 months 1.221 months 1.230
    40° C./75° C. 0 months 1.230; 6 0 months 1.230; 6 months 0 months 1.230; 6
    months 1.210 1.202 months 1.218
    Degradation of 25° C./60° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    Pimobendan 2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-GG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;
    unspecified) ; 4) <0.10 (total) ; 24 months 1) <0.10;
    24 months 2) <0.10; 3) <0.10; 4) <0.10
    1) <0.10; 2) <0.10;
    3) <0.10; 4) <0.10
    30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;
    unspecified) ; 4) <0.10 (total) ; 24 months 1) <0.33;
    24 months 2) <0.10; 3) <0.10; 4) 0.33
    1) <0.10; 2) <0.10;
    3) <0.10; 4) <0.10
    40° C./75° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG
    CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any
    BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;
    unspecified) ; 4) <0.10 (total) ; 6 months 1) <0.54;
    6 months 1) <0.10; 2) <0.10; 3) <0.10; 4) <0.54
    2) 0.10; 3) <0.10; 4) 0.10
  • Product: Pimobendan chewable tablets 2.5 mg
    Batch No.: PB020052
    HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m)
    Dissolution 30° C./70° C. 0 months 97 (min)-99 0 months 97 (min)-99 0 months 97 (min)-99
    (max)/98 (avg) ; 12 (max)/98 (avg) ; 12 (max)/98 (avg) ; 12
    Months 93-95/94 months 93-94/94 months 94-97/96
    40° C./75° C. 0 months 97 (min)-99 0 months 97 (min)-99 0 months 97 (min)-99
    (max)/98 (avg) ; 6 (max)/98 (avg) ; 6 (max)/98 (avg) ; 6
    months 93-94/93 months 91-93/92 months 93-95/94
    Assay of 30° C./70° C. 0 months 2.49; 12 0 months 2.49; 12 months 0 months 2.49; 12
    Pimobendan months 2.49 2.47 months 2.50
    40° C./75° C. 0 months 2.49; 6 0 months 2.49; 6 months 0 months 2.49; 6 months
    months 2.41 2.41 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 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134
    BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (any
    unspecified) ; unspecified) ; unspecified) ;
    4) <0.10 (total) ; 12 4) <0.10 (total) ; 12 months 4) <0.10 (total) ; 12
    months 1) <0.10; 1) <0.10; 2) <0.10; months 1) <0.10;
    2) <0.10; 3) <0.10; 3) <0.10; 4) <0.10 2) <0.10; 3) <0.10;
    4) <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 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134
    BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (any
    unspecified) ; unspecified) ; unspecified) ;
    4) <0.10 (total) ; 6 4) <0.10 (total) ; 6 months 4) <0.10 (total) ; 6 months
    months 1) <0.10; 1) 0.43; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10;
    2) <0.10; 3) <0.10; 4) 0.43 3) <0.10; 4) <0.10
    4) <0.10
    Batch No.: PB020053
    HDPE bottle (m) PVC/PVCD (m) Aluminium blister (m)
    Dissolution 30° C./70° C. 0 months 96 (min)-98 0 months 96 (min)-98 0 months 96 (min)-98
    (max)/97 (avg) ; 12 (max)/97 (avg) ; 12 (max)/97 (avg) ; 12
    months 92-94/93 months 90-93/92 months 91-95/93
    40° C./75° C. 0 months 96 (min)-98 0 months 96 (min)-98 0 months 96 (min)-98
    (max)/97 (avg) ; 6 (max)/97 (avg) ; 6 (max)/97 (avg) ; 6
    months 89-93/91 months 91-91/91 months 90-92/91
    Assay of 30° C./70° C. 0 months 2.44; 12 0 months 2.44; 12 months 0 months 2.44; 12
    Pimobendan months 2.44 2.41 months 2.46
    40° C./75° C. 0 months 2.44; 6 0 months 2.44; 6 months 0 months 2.44; 6 months
    months 2.41 2.40 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 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134
    BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (any
    unspecified) ; unspecified) ; unspecified) ;
    4) <0.10 (total) ; 12 4) <0.10 (total) ; 12 months 4) <0.10 (total) ; 12
    months 1) <0.10; 1) <0.10; 2) <0.10; months 1) <0.10;
    2) <0.10; 3) <0.10; 3) <0.10; 4) <0.10 2) <0.10; 3) <0.10;
    4) <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 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134
    BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (any
    unspecified) ; unspecified) ; unspecified) ;
    4) <0.10 (total) ; 6 4) <0.10 (total) ; 6 months 4) <0.10 (total) ; 6 months
    months 1) <0.10; 1) 0.39; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10;
    2) <0.10; 3) <0.10; 4) 0.39 3) <0.10; 4) <0.10
    4) <0.10
    Batch No.: PB020054
    HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m)
    Dissolution 30° C./70° C. 0 months 96 (min)-98 0 months 96 (min)-98 0 months 96 (min)-98
    (max)/97 (avg) ; 12 (max)/97 (avg) ; 12 (max)/97 (avg) ; 12
    months 93-95/94 months 90-93/91 months 93-94/94
    40° C./75° C. 0 months 96 (min)-98 0 months 96 (min)-98 0 months 96 (min)-98
    (max)/97 (avg) ; 6 (max)/97 (avg) ; 6 (max)/97 (avg) ; 6
    months 90-92/91 months 90-92/91 months 91-93/92
    Assay of 30° C./70° C. 0 months 2.45; 12 0 months 2.45; 12 months 0 months 2.45; 12
    Pimobendan months 2.47 2.45 months 2.44
    40° C./75° C. 0 months 2.45; 6 0 months; 6 months 2.39 0 months 2.45; 6 months
    months 2.40 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 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134
    BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (any
    unspecified) ; unspecified) ; unspecified) ;
    4) <0.10 (total) ; 12 4) <0.10 (total) ; 12 months 4) <0.10 (total) ; 12
    months 1) <0.10; 1) <0.10; 2) <0.10; months 1) <0.10;
    2) <0.10; 3) <0.10; 3) <0.10; 4) <0.10 2) <0.10; 3) <0.10;
    4) <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 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134
    BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (any
    unspecified) ; unspecified) ; unspecified) ;
    4) <0.10 (total) ; 6 4) <0.10 (total) ; 6 months 4) <0.10 (total) ; 6 months
    months 1) <0.10; 1) 0.36; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10;
    2) <0.10; 3) <0.10; 4) 0.36 3) <0.10; 4) <0.10
    4) <0.10
  • Product: Pimobendan chewable tablets 5 mg
    Batch No.: PB020059
    HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m)
    Dissolution 25° C./60% 0 months 94 (min)-96 0 months 94 (min)-96 0 months 94 (min)-96
    (max)/95 (avg) ; (max)/95 (avg) ; 24 (max)/95 (avg) ; 24
    24 months 83-90/88 months 83-92/88 months 85-89/87
    30° C./70° C. 0 months 94 (min)-96 0 months 94 (min)-96 0 months 94 (min)-96
    (max)/95 (avg) ; (max)/95 (avg) ; 24 (max)/95 (avg) ; 24
    24 months 83-95/89 months 82-97/88 months 83-91/87
    40° C./75° C. 0 months 94 (min)-96 0 months 94 (min)-96 0 months 94 (min)-96
    (max)/95 (avg) ; 6 (max)/95 (avg) ; 6 months (max)/95 (avg) ; 6
    months 91-92/91 90-92/91 months 81-93/92
    Assay of 25° C./60% 0 month 4.95; 24 0 month 4.95; 24 month 0 month 4.95; 24 month
    Pimobendan month 4.94 4.92 4.92
    30° C./70° C. 0 month 4.95; 24 0 month 4.95; 24 month 0 month 4.95; 24 month
    month 4.90 4.92 4.96
    40° C./75° C. 0 month 4.95; 6 0 month 4.95; 6 month 0 month 4.95; 6 month
    month 4.88 4.91 4.95
    Degradation of 25° C./60% 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    Pimobendan 2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 24 months 1) <0.10 (total) ; 24 months
    <0.10 (total) ; 24 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 4) <0.10 <0.10; 4) <0.10
    <0.10; 3) <0.10; 4)
    <0.10
    30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 24 months 1) <0.10 (total) ; 24 months
    <0.10 (total) ; 24 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 4) <0.10 <0.10; 4) <0.10
    <0.10; 3) <0.10; 4)
    <0.10
    40° C./75° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 6 months 1) 0.23; <0.10 (total) ; 6 months
    <0.10 (total) ; 6 2) <0.10; 3) <0.10; 4) 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 0.23 <0.10; 4) <0.10
    <0.10; 3) <0.10; 4) <0.10
    Batch No.: PB020060
    HDPE bottle (m) Aluminium blister (m)
    PVC/PVCD (m)
    Dissolution 25° C./60% 0 months 91 (min)-94 0 months 91 (min)-94 0 months 91 (min)-94
    (max)/92 (avg) ; (max)/92 (avg) ; 24 (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)-94 0 months 91 (min)-94 0 months 91 (min)-94
    (max)/92 (avg) ; (max)/92 (avg) ; 24 (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)-96 0 months 91 (min)-94 0 months 91 (min)-94
    (max)/95 (avg) ; 6 (max)/92 (avg) ; 6 months (max)/92 (avg) ; 6
    months 88-89/89 88-90/89 months 89-92/90
    PVC/PVDC (m)
    Assay of 25° C./60% 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.87; 24 month
    Pimobendan month 4.88 4.86 4.90
    30° C./70° C. 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.84; 24 month
    month 4.83 4.86 4.89
    40° C./75° C. 0 month 4.87; 6 0 month 4.87; 6 month 0 month 4.87; 6 month
    month 4.86 4.87 4.86
    PVC/PVCD (m)
    Degradation of 25° C./60% 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    Pimobendan 2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 24 months 1) <0.10 (total) ; 24 months
    <0.10 (total) ; 24 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 4) <0.10; <0.10; 4) <0.10;
    <0.10; 3) <0.10; 4)
    <0.10;
    30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 24 months 1) <0.10 (total) ; 24 months
    <0.10 (total) ; 24 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 4) <0.10; <0.10; 4) <0.10;
    <0.10; 3) <0.10; 4)
    <0.10;
    40° C./75° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 24 months 1) <0.10 (total) ; 6 months
    <0.10 (total) ; 6 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 4) <0.10; 6 months 1) <0.10; 4) <0.10
    <0.10; 3) <0.10; 4) 0.22; 2) <0.10; 3) <0.10;
    <0.10 4) 0.22
    Batch No.: PB020061
    HDPE bottle (m) Aluminium blister (m)
    PVC/PVDC (m)
    Dissolution 25° C./60% 0 months 92 (min)-95 0 months 92 (min)-95 0 months 92 (min)-95
    (max)/94 (avg) ; (max)/94 (avg) ; 24 (max)/94 (avg) ; 24
    24 months 83-90/87 months 86-91/88 months 65-92/84
    30° C./70° C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months 92 (min)-95
    (max)/94 (avg) ; (max)/94 (avg) ; 24 (max)/94 (avg) ; 24
    24 months 84-88/87 months 81-87/85 months 88-91/90
    40° C./75° C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months 92 (min)-95
    (max)/94 (avg) ; 6 (max)/94 (avg) ; 6 months (max)/94 (avg) ; 6
    months 88-90/89 88-90/89 months 88-91/90
    PVC/PVCD (m)
    Assay of 25° C./60% 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.87; 24 month
    Pimobendan month 4.83 4.85 4.88
    30° C./70° C. 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.87; 24 month
    month 4.82 4.80 4.90
    40° C./75° C. 0 month 4.87; 6 0 month 4.87; 6 month 0 month 4.87; 6 month
    month 4.83 4.82 4.88
    PVC/PVDC (m)
    Degradation of 25° C./60% 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    Pimobendan 2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 24 months 1) <0.10 (total) ; 24 months
    <0.10 (total) ; 24 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 4) <0.10; <0.10; 4) <0.10
    <0.10; 3) <0.10; 4)
    <0.10;
    30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 24 months 1) <0.10 (total) ; 24 months
    <0.10 (total) ; 24 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 4) <0.10; <0.10; 4) <0.10;
    <0.10; 3) <0.10; 4)
    <0.10;
    40° C./75° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;
    2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
    (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10
    <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)
    unspecified) ; 4) (total) ; 6 months 1) 0.22; <0.10 (total) ; 6 months
    <0.10 (total) ; 6 2) <0.10; 3) <0.10; 4) 1) <0.10; 2) <0.10; 3)
    months 1) <0.10; 2) 0.22 <0.10; 4) <0.10
    <0.10; 3) <0.10; 4)
    <0.10

Claims (20)

1. A solid formulation comprising a homogenous dispersion of:
pimobendan or a pharmaceutically acceptable salt thereof;
a polyvalent acid selected from the group consisting of citric acid, acetic acid, maleic acid, tartaric acid or their anhydrides; and
a flavor acceptable to small animals;
wherein the flavor is homogenously dispersed within such solid formulation.
2. The solid formulation according to claim 1, further comprising one or more pharmaceutically acceptable carriers and/or excipients.
3. The solid formulation according to claim 1, wherein the one or several excipients are selected from the group consisting of diluents, disintegrants, carriers, binders, flow regulators, lubricants and solvents.
4. The solid formulation according to claim 2, wherein the binder is selected from the group consisting of polyvidone/povidone, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose, starch and gelatine.
5. The solid formulation according to claim 2, wherein the disintegrant/carrier is selected from the group consisting of lactose, starch, cellulose, microcrystalline cellulose and methylcellulose.
6. The solid formulation according to claim 5, wherein the lactose consists of coarse particles greater than 200 μm in size.
7. The solid formulation according to claim 2, 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 swellable physically modified starch.
8. The solid formulation according to claim 2, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, pregelatinised starch and cross-linked polyvinylpyrrolidone.
9. The solid formulation according to claim 2, wherein the flow regulator is selected from the group consisting of silica, preferably colloidal anhydrous silica, calcium silicate, magnesium silicate and talc.
10. The solid formulation according to claim 2, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, glyceryl behenate, polyethylene glycol, stearic acid and talc.
11. The solid formulation according to claim 2, wherein the flavor is selected from the group consisting of artificial beef flavors, artificial chicken flavors, pork liver extract, artificial meat flavor and honey flavor.
12. The solid formulation according to claim 1, further comprising 0.5 to 20 mg of pimobendan.
13. The solid formulation according to claim 1, wherein the content of pimobendan in relation to citric acid anhydrous is 1:10 to 1:40.
14. The solid formulation according to claim 1, wherein the weight of the whole solid formulation is in the range of 250 mg to 3000 mg.
15. The solid formulation according to claim 1, wherein the solid formulation is a tablet or a granule.
16. The solid formulation according to claim 1, wherein the solid formulation is a tablet and 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, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate.
17. The solid formulation according to claim 1, wherein the solid formulation is a tablet and consists of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further consists of 35 to 50% (w/w) lactose, 25 to 50% (w/w) corn starch, 1 to 5% (w/w) croscarmellose-sodium, 2.5 to 10% (w/w) citric acid, 5 to 30% (w/w) artificial beef flavor, 1 to 5% (w/w) polyvidone, 0.1 to 1% (w/w) colloidal anhydrous silica and 0.25 to 1.5% (w/w) magnesium stearate.
18. A method of prevention and/or treatment of congestive heart failure in a mammal, the method comprising administering the solid formulation of claim 1 to the mammal.
19. A fluid-bed granulation process comprising:
a) spraying an aqueous dispersion of pimobendan and an aqueous solution of a binder onto a solid support comprising one or several carriers and/or excipients, flavor and citric acid anhydrous;
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);
f) blending the mixture of e) for uniformity of granules to obtain final granules; and
g) compressing the final granules off) to tablets.
20. The fluid-bed granulation process according to claim 19, wherein the binder of step a) is povidone, and the solid support of step a) comprises lactose, starch, flavor and citric acid anhydrous.
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US13/402,292 US8846680B2 (en) 2004-03-08 2012-02-22 Pharmaceutical composition comprising pimobendan
US13/802,989 US8859554B2 (en) 2004-03-08 2013-03-14 Packaging assembly for pharmaceutical composition including pimobendan
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US13/802,989 Active US8859554B2 (en) 2004-03-08 2013-03-14 Packaging assembly for pharmaceutical composition including pimobendan
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10537588B2 (en) 2004-03-25 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease
US10639305B2 (en) 2006-11-07 2020-05-05 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US11413285B2 (en) 2004-03-25 2022-08-16 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004011512B4 (en) * 2004-03-08 2022-01-13 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical preparation containing pimobendan
JP4572296B2 (en) * 2004-07-21 2010-11-04 トーアエイヨー株式会社 Pimobendan oral dosage formulation
JP4572293B2 (en) * 2004-07-21 2010-11-04 トーアエイヨー株式会社 Pimobendan oral dosage formulation
JP2006028130A (en) * 2004-07-21 2006-02-02 Toa Eiyo Ltd Pimopendan preparation for oral administration
JP4572300B2 (en) * 2006-01-19 2010-11-04 トーアエイヨー株式会社 Pimobendan oral dosage formulation
GB0818473D0 (en) 2008-10-08 2008-11-12 Probio Nutraceuticals As Composition
WO2010055119A2 (en) * 2008-11-17 2010-05-20 Novartis Ag Pharmaceutical composition comprising pimobendan
ES2436716T3 (en) 2008-11-25 2014-01-03 Boehringer Ingelheim Vetmedica Gmbh Pimobendan for use in the treatment of hypertrophic cardiomyopathy in cats
NL1037569C2 (en) 2009-12-18 2011-06-21 Eurovet Animal Health B V Crystalline pimobendan, process for the preparation thereof, pharmaceutical composition and use.
BR112014003117A2 (en) 2011-08-12 2017-06-13 Boehringer Ingelheim Vetmedica Gmbh funny (if) current inhibitors for use in a method of treatment and prevention of feline heart failure
EP3034071B1 (en) 2011-12-21 2017-12-06 Elanco Tiergesundheit AG New combination
EP3167876B1 (en) * 2012-03-15 2021-09-08 Boehringer Ingelheim Vetmedica GmbH Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof
WO2013135853A1 (en) * 2012-03-15 2013-09-19 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical packaging product for the veterinary medical sector
US10543170B2 (en) * 2012-12-19 2020-01-28 Bayer Animal Health Gmbh Tablets with improved acceptance and good storage stability
CN113181110A (en) 2013-07-19 2021-07-30 勃林格殷格翰动物保健有限公司 Liquid aqueous pharmaceutical composition containing preserved etherified cyclodextrin derivatives
BR112016011111B1 (en) 2013-12-04 2022-11-16 Boehringer Ingelheim Vetmedica Gmbh IMPROVED PHARMACEUTICAL COMPOSITIONS OF PIMOBENDAN
DK3389638T3 (en) 2015-12-17 2023-11-06 Ceva Sante Animale PHARMACEUTICAL COMPOSITION COMPRISING PIMOBENDAN
CN106729723A (en) * 2016-11-21 2017-05-31 青岛农业大学 A kind of pharmaceutical composition containing UD-CG115BS.acardi and preparation method thereof
KR102116712B1 (en) * 2017-12-22 2020-05-29 주식회사 고려비엔피 Formulations for canine heart disease containing oral dosing formulations with highly palatable excipients
CN114599353A (en) * 2019-10-23 2022-06-07 皮埃蒙特动物健康公司 Pimopenzene formulations and methods of use thereof
US20240197727A1 (en) 2022-12-15 2024-06-20 Boehringer Ingelheim Vetmedica Gmbh Solid dispersions comprising amorphous pimobendan and one or more stabilizing polymers

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002045693A1 (en) * 2000-12-07 2002-06-13 Altana Pharma Ag Pharmaceutical preparation comprising an active dispersed on a matrix

Family Cites Families (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES8101067A1 (en) 1978-08-25 1980-12-01 Thomae Gmbh Dr K Benzimidazoles, their preparation and pharmaceutical compositions containing them.
JPS5636911A (en) * 1979-09-05 1981-04-10 Aisin Seiki Mechanism for adjusting headrest
DE3237575A1 (en) * 1982-10-09 1984-04-12 Dr. Karl Thomae Gmbh, 7950 Biberach NEW ORAL MOPIDAMOL SHAPES
DE3346123A1 (en) 1983-12-21 1985-06-27 Janssen Pharmaceutica, N.V., Beerse PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF
GB8400863D0 (en) * 1984-01-13 1984-02-15 Smith Kline French Lab Chemical compounds
US6407079B1 (en) * 1985-07-03 2002-06-18 Janssen Pharmaceutica N.V. Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation
PT83530B (en) * 1985-10-17 1989-05-31 Smith Kline French Lab PREPARATION PROCESS OF PYRIDONE DERIVATIVES, IN PARTICULAR PHENYLER DERIVATIVES
US4868182A (en) * 1986-11-05 1989-09-19 Merrell Dow Pharmaceuticals Inc. Enhancement of prazosin
ZA878182B (en) 1986-11-05 1988-05-02 Merrell Dow Pharmaceuticals Inc. Enhancement of prazosin
DE3728244A1 (en) 1987-08-25 1989-03-09 Thomae Gmbh Dr K Novel (-)-benzimidazoles, their preparation and medicaments containing these compounds
EP0306846A3 (en) 1987-09-11 1990-05-02 Dr. Karl Thomae GmbH Synergistic combination comprising a phosphodiesterase inhibitor and a thromboxane-a2 antagonist, and its use or preparation
US5002935A (en) * 1987-12-30 1991-03-26 University Of Florida Improvements in redox systems for brain-targeted drug delivery
DE3804490A1 (en) * 1988-02-12 1989-08-24 Heumann Pharma Gmbh & Co SUBSTITUTED 6-PHENYLDIHYDRO-3 (2H) -PYRIDAZINONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
DE3805635A1 (en) 1988-02-24 1989-09-07 Thomae Gmbh Dr K USE OF BENZIMIDAZOLES FOR THE MANUFACTURE OF A MEDICAMENT WITH ANTI-MIXIC EFFECTS ON THE HEART AND ITS COMBINATIONS WITH SS-BLOCKERS OR BRADYCARDICA
IE62095B1 (en) 1988-03-29 1994-12-14 Univ Florida Pharmaceutical formulations for parenteral use
DE68906942T3 (en) 1988-03-29 1999-05-12 University Of Florida, Gainesville, Fla. Pharmaceutical compositions for parenteral use.
GB8824458D0 (en) * 1988-10-19 1988-11-23 Orion Yhtymae Oy Substituted pyridazinones
GB8903130D0 (en) 1989-02-11 1989-03-30 Orion Yhtymae Oy Substituted pyridazinones
DE4001622A1 (en) * 1990-01-20 1991-07-25 Thomae Gmbh Dr K ORAL DRUGS OF PIMOBENDAN
US5364646A (en) * 1990-01-10 1994-11-15 Dr. Karl Thomae Gmbh Oral pharmaceutical forms of pimobendan
DE4001623A1 (en) * 1990-01-20 1991-07-25 Thomae Gmbh Dr K Use of known 5-pyridazinyl-benzimidazole derivs. - for treatment of acute or chromic obstructive respiratory disorders e.g. asthma bronchitis etc.
GB2251615B (en) * 1991-01-03 1995-02-08 Orion Yhtymae Oy (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]pro panedinitrile
JPH0570612A (en) 1991-09-12 1993-03-23 Toyobo Co Ltd Biaxially orientated polyester film
ES2167436T3 (en) * 1994-05-20 2002-05-16 Janssen Pharmaceutica Nv CHEATABLE FLUBENDAZOL TABLETS FOR COMPANY ANIMALS.
JPH11228302A (en) 1998-02-18 1999-08-24 Taisho Technos Co Ltd Antimicrobial, antifungal composition
US6476078B2 (en) * 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6369087B1 (en) * 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
WO2001056562A1 (en) * 2000-02-04 2001-08-09 Takeda Chemical Industries, Ltd. Stable emulsion compositions
WO2001064190A1 (en) * 2000-03-01 2001-09-07 Eisai Co., Ltd. Rapidly disintegrable tablet containing polyvinyl alcohol
AU2001271435A1 (en) 2000-06-21 2002-01-02 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
KR100949539B1 (en) * 2000-06-27 2010-03-25 벡투라 리미티드 Method of making particles for use in a pharmaceutical composition
IL156136A0 (en) 2000-12-18 2003-12-23 Novartis Ag Therapeutic combination of amlodipine and benazepril
EP1247456A3 (en) 2001-02-28 2003-12-10 Pfizer Products Inc. Palatable pharmaceutical compositions for companion animals
JP2004532838A (en) 2001-03-02 2004-10-28 ブリストル−マイヤーズ スクイブ カンパニー Compounds useful as melanocortin receptor modulators and pharmaceutical compositions containing them
DE60237696D1 (en) 2001-08-01 2010-10-28 Univ Utah AT N-TERMINUS TRUNCATED ISOFORMS OF CYCLIC PHOSPHODIESTERASES PDE3A
US20030190343A1 (en) * 2002-03-05 2003-10-09 Pfizer Inc. Palatable pharmaceutical compositions for companion animals
DE10209982A1 (en) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Dosage form to be administered orally for poorly soluble basic active ingredients
PE20040468A1 (en) 2002-05-17 2004-09-14 Novartis Ag ORGANIC COMPOUND COMBINATION
WO2003099194A2 (en) 2002-05-23 2003-12-04 Pfizer Limited Pharmaceutical combination of pde5 inhibitors with ace inhibitors
DE10228049A1 (en) 2002-06-24 2004-01-15 Merck Patent Gmbh Liquid preparation containing oligopeptides
US20040037869A1 (en) 2002-08-16 2004-02-26 Douglas Cleverly Non-animal product containing veterinary formulations
CA2501534A1 (en) 2002-10-07 2004-04-22 Artesian Therapeutics, Inc. Dihydropyridine compounds having simultaneous ability to block l-type calcium channels and to inhibit phosphodiesterase type 3 activity
WO2004050657A2 (en) 2002-11-27 2004-06-17 Artesian Therapeutics, Inc. COMPOUNDS WITH MIXED PDE-INHIBITORY AND β-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE
US20070117978A1 (en) 2002-12-23 2007-05-24 Artesian Therapecutics, Inc Cardiotonic compounds with inhibitory activity against beta-adrenergic receptors and phosphodiesterase
WO2005035505A2 (en) 2003-09-30 2005-04-21 Artesian Therapeutics, Inc. Compounds with phosphodiesterase inhibiting and calcium channel blocking activities
DE102004011512B4 (en) * 2004-03-08 2022-01-13 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical preparation containing pimobendan
EP1579862A1 (en) * 2004-03-25 2005-09-28 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure
US8980894B2 (en) * 2004-03-25 2015-03-17 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure
JP2005281283A (en) 2004-03-31 2005-10-13 Akira Matsumori Combined pharmaceutical comprising benzimidazole agent
FI20040675A0 (en) 2004-05-12 2004-05-12 Orion Corp A method of treating and preventing cardiac hypertrophy
NZ534939A (en) 2004-08-26 2007-04-27 Bomac Research Ltd Injectable formulation comprising an anthelmintic compound with complexing compound for improved solubility
US20080090827A1 (en) 2004-11-30 2008-04-17 Artesian Therapeutics, Inc. Compounds With Mixed Pde-Inhibitory and Beta-Adrenergic Antagonist or Partial Agonist Activity For Treatment of Heart Failure
EP1833480A2 (en) 2004-11-30 2007-09-19 Artesian Therapeutics, Inc. Cardiotonic compounds with inhibitory activity against beta-adrenergic receptors and phosphodiesterase
CN1702243A (en) 2005-05-31 2005-11-30 刘坚雄 Combined building with non-wainscot frame structure and construction method thereof
CA2611917A1 (en) 2005-06-13 2006-12-21 Takeda Pharmaceutical Company Limited Injection
CA2629367C (en) 2005-11-14 2016-05-03 Boehringer Ingelheim Vetmedica Gmbh Use of pde iii inhibitors and/or calcium sensitizers for the treatment of asymptomatic (occult) heart failure
EP1920785A1 (en) 2006-11-07 2008-05-14 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising a complex of pimobendan and cyclodextrin
ES2436716T3 (en) * 2008-11-25 2014-01-03 Boehringer Ingelheim Vetmedica Gmbh Pimobendan for use in the treatment of hypertrophic cardiomyopathy in cats

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002045693A1 (en) * 2000-12-07 2002-06-13 Altana Pharma Ag Pharmaceutical preparation comprising an active dispersed on a matrix

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10537588B2 (en) 2004-03-25 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
US11413285B2 (en) 2004-03-25 2022-08-16 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure
US10639305B2 (en) 2006-11-07 2020-05-05 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease
US12011441B2 (en) 2016-04-06 2024-06-18 Boehringer Ingelheim Vetmedica Gmbh Pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease

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