WO2010055119A2 - Pharmaceutical composition comprising pimobendan - Google Patents
Pharmaceutical composition comprising pimobendan Download PDFInfo
- Publication number
- WO2010055119A2 WO2010055119A2 PCT/EP2009/065106 EP2009065106W WO2010055119A2 WO 2010055119 A2 WO2010055119 A2 WO 2010055119A2 EP 2009065106 W EP2009065106 W EP 2009065106W WO 2010055119 A2 WO2010055119 A2 WO 2010055119A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pimobendan
- carboxylic acid
- optionally
- acid
- solution
- Prior art date
Links
Classifications
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- 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
- A61K9/205—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- A61P9/12—Antihypertensives
Definitions
- composition comprising pimobendan
- the present invention relates to a pimobendan and a pharmaceutical composition comprising pimobendan, in particular in the form of an oral dosage preparation.
- Pimobendan (4,5-dihydro-6-(2-(4-methoxyphenyl)-1 H-benzimidazol-5-yl)-5-methyl- 3(2H))-pyridazinone, is a benzimidazole derivative with cardiotonic, hypotensive and antithrombotic effect. It is commercially available as chewing tablets or capsules under the brand name Vetmedin ® (Boehringer Ingelheim) and is in particular useful in veterinary medicine. Pimobendan is a cardiac pharmaceutical, termed an "inodilator" because it possesses both positive inotropic and balanced peripheral vasodilation properties. Unlike historical positive inotropes (e.g.
- pimobendan acts as a positive inotrope principally by enhancing the affinity of myocardial troponin C to existing intracellular calcium.
- pimobendan is a phosphodiesterase III (PDE III) inhibitor, resulting in balanced peripheral vasodilation through increased efflux of intracellular calcium from vascular smooth muscle. Additional properties include reversal of desensitization of baroreceptors, improved cardiac relaxation (lusitropy), reduced platelet aggregation, and an anti-inflammatory effect mediated through favourable cytokine modulation.
- pimobendan 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.
- pimobendan's originator company proposes to overcome low solubility and high pH dependency of solubility by implementing a method, intimately mixing pimobendan with citric acid and subsequently processing it with conventional excipients to form a powder, pellets or granules for oral administration.
- citric acid is a safe and well tolerated excipient, a great amount of said citric acid is required for achieving said method, so that the obtained preparation has a high water- absorbing property and lacks storage stability.
- JP2006-056880A discloses pimobendan oral dosage preparations comprising (A) pimobendan and (B) alginic acid and fumaric acid, alginic acid and succinic acid, or alginic acid, fumaric acid and succinic acid.
- JP2007-191419A discloses pimobendan oral dosage preparations comprising (A) pimobendan and (B) fumaric acid and (C) polyoxyethylene (105) polyoxypropylene (5) glycol.
- the pimobendan preparation for oral administration of JP2006-028130A is produced by compounding a finely powdered composition obtained by mixing and pulverizing pimobendan and one or more bases selected from light anhydrous silicic acid, polyvinylpyrrolidone and D-mannitol.
- the pimobendan preparation for oral administration contains pimobendan and polyoxyethylene (105) polyoxypropylene (5) glycol.
- WO2005084647 discloses a solid formulation, comprising pimobendan or a pharmaceutically acceptable salt thereof which is homogenously dispersed in a polyvalent acid selected from the group of acetic acid, tartaric acid or its anhydride, and a flavour.
- Object of the present invention is to provide a pimobendan preparation with good storage stability, preferably when compared to the originator's product, and which still has good dissolution property. Moreover, it would be desirable to provide such a pimobendan preparation with beneficial press formability and flowability characteristics, consequently being easy to process into a solid preparation.
- a novel composition has been found that provides for a stable composition for oral administration of pimobendan.
- a composition comprising pimobendan and an organic carboxylic acid, wherein the only organic carboxylic acid is succinic acid and wherein the weight ratio of succinic acid to pimobendan is at least 11 :1.
- a composition comprising pimobendan and a carboxylic acid in an intimate mixture obtained by dissolving both pimobendan and carboxylic acid and optionally a binder substance in an organic solvent optionally containing less than 50 vol.-% water relative to the whole solvent component, and subsequently using said obtained solution as a granulation liquid in a process of fluid bed granulation.
- composition according to item 2 wherein said carboxylic acid is a polycarboxylic acid, preferably succinic acid.
- a CrC 4 -alcanol such as methanol, ethanol, n- or isopropanol or n-, iso-, sec- or tert.-butanol, in particular ethanol.
- composition according to any one of the preceding items wherein the weight ratio of carboxylic acid to pimobendan is in a range of 11 : 1 to 20:1.
- composition according to any one of the preceding items further comprising a surfactant.
- composition according to item 6 wherein the surfactant is a non-ionic surfactant.
- composition according to item 6 wherein the non-ionic surfactant is polyoxyethylene (20) sorbitan monooleate.
- composition according to any one of the preceding items characterized by a weight ratio of carboxylic acid to pimobendan of between 1 1 :1 and 15:1 , preferably from 12:1 to 15.1 , and in particular 12:1 to 13.1.
- a pharmaceutical composition comprising a composition according to any one of the preceding items, further comprising one or more pharmaceutically acceptable excipients.
- composition according to item 10 in the form of granulates, powders or pellets, optionally packed into capsules.
- the pharmaceutical composition according to item 1 1 the granulates, powders or pellets being compressed with suitable excipients into tablets.
- a method of preparing a formulation comprising pimobendan and a carboxylic acid comprising: - A - providing a solution comprising dissolved pimobendan and dissolved carboxylic acid in an organic solvent, wherein the organic solvent optionally contains less than 50 vol.-% water relative to the whole solvent component; and using said solution comprising pimobendan, organic carboxylic acid and optionally binder substance as granulation liquid in the process of fluid bed granulation.
- the whole solvent component constitutes at least 50wt.%, preferably at least 60wt.% of the whole solution comprising pimobendan and organic carboxylic acid which is used as granulation liquid in the process of fluid bed granulation.
- said organic solvent comprises lower alcohol or aqueous lower alcohol, in particular ethanol or aqueous ethanol.
- the solution further comprises a surfactant, preferably non-ionic surfactant and further preferably polyoxyethylene (20) sorbitan monooleate as non-ionic surfactant.
- a surfactant preferably non-ionic surfactant and further preferably polyoxyethylene (20) sorbitan monooleate as non-ionic surfactant.
- a pharmaceutical composition comprising pimobendan and succinic acid as the sole organic carboxylic acid for use in the prophylaxis or treatment of a disease or condition selected from cardiovascular diseases or conditions, hypertension, thrombosis and thrombosis-associated diseases or conditions, wherein the pharmaceutical composition preferably is in an oral dosage form, especially a tablet.
- the novel composition possesses superior dissolution properties and proves better storage stability in comparison to the reference composition of the originator. Therefore it can be used for obtaining high concentration of pimobendan in blood.
- FIGURE 1 Comparative dissolution profiles of samples prepared according to Examples and a Comparative Example in neutral pH region (water) - conditions of testing:
- the flow rate was 1.0 ml/min and the detection wavelength 332 nm.
- the method of preparing the pimobendan formulation according to the present invention allows to improve dissolution property of pimobendan, without however necessitating to increase the surface area by intensive milling the drug to gain smaller particle size.
- micronised drug powders are extremely cohesive due to high energy milling processes causing significant dislocation of crystal structure on the particle surface. Such particles would tend to agglomerate during the solid state processing, leading to poor dissolution performance.
- the inventors of the present invention extensively studied a pimobendan oral dosage preparation to improve its poor solubility in order to obtain desirable dissolution properties.
- succinic acid is chosen according to one aspect of the present invention when the pharmaceutical composition is devised independent from process technology, because the quantity of dissolved pimobendan when used in combination with succinic acid as the only organic carboxylic acid was sufficient to ensure adequate resorption, even when fluctuations in pH of the solution occurred.
- a particular status of intimate mixture between pimobendan and an organic carboxylic acid in general and a polycarboxylic acid in particular such as succinic acid, oxalic acid, fumaric acid, tartaric acid, citric acid, maleic acid and malic acid, provides an alternative means to obtain good balance of properties in terms of good storage stability and dissolution property, beneficial press formability and flowability characteristics.
- a single organic carboxylic acid, especially a single polycarboxylic acid is sufficient.
- the intimate mixture formed as disclosed herein significantly contributes to achieve such good balance of properties, that is when the mixture is obtained by dissolving both pimobendan and organic carboxylic acid and optionally a binder substance in an organic solvent, preferably in a lower alcohol, in particular ethanol, optionally respectively containing less than 50 vol.-% water, and subsequently using the obtained solution as a granulation liquid in the process of fluid bed granulation.
- an organic solvent preferably in a lower alcohol, in particular ethanol, optionally respectively containing less than 50 vol.-% water
- the whole solvent component constitutes at least 50wt.%, preferably at least 60wt.% of the whole granulation liquid. It is further preferred that the solvent component consists essentially or only of the organic solvent, notably a lower alcohol, in particular ethanol, or acetone, without water being added.
- the pimobendan formation of the present invention particularly one formulated as oral dosage preparation, preferably contains a surfactant, most preferably a non-ionic surfactant.
- the non-ionic surfactant is preferably selected from the series of partial fatty acid esters of sorbitol copolymerized with approximately 20, 5, or 4 moles of ethylene oxide for each mole of sorbitol, and its anhydrides (polyoxyethylene sorbitan fatty acid esters).
- Polysorbate 80 (monooleic acid polyoxyethylene (20) sorbitan) is particularly preferred.
- excipients can be added to the pimobendan oral dosage preparation of the present invention.
- Said excipients include but are not limited to: a vehicle, preferably selected from lactose, mannitol, xylitol and sorbitol; a disintegrating agent, preferably selected from starch, croscarmellose sodium and low-substituted hydroxypropyl cellulose; a binding agent, preferably selected from polyvinylpyrrolidone, vinylpyrrolidone- vinyl acetate copolymer, dextrates and microcrystalline cellulose; a lubricant, preferably selected from magnesium stearate and talc; a glidant, preferably silica colloidal; a colorant, preferably selected from Iron oxide red and yellow; a flavouring agent; preferably selected from artificial beef flavour and vegetarian meat flavour; etc.
- the preparation of the present invention can be a tablet, a powder preparation, a granule preparation, or a capsule preparation
- both, the organic carboxylic acid and pimobendan can be effectively and completely dissolved using aqueous/alcoholic or non aqueous lower alcohol solvent (the alcohol having carbon atoms of less than 8), most suitably ethanol.
- aqueous/alcoholic or non aqueous lower alcohol solvent the alcohol having carbon atoms of less than 8
- the term "solution comprising dissolved pimobendan and dissolved carboxylic acid” shall mean that each of the mentioned components are essentially dissolved, preferably completely dissolved.
- succinic acid can fully develop its solubilizing effect when it is intimately mixed with pimobendan as disclosed herein.
- organic carboxylic acid and preferably succinic acid as the sole organic carboxylic acid
- aqueous/alcoholic (e.g. ethanolic) granulation solution and non aqueous granulation solution with lower alcohol (e.g. ethanol).
- Binder and preferably in addition surfactant can also be admixed with the granulation liquid.
- said binder can also comprise a particulate matter or/and can be added to dry granulate before tabletting. If binder is added to the granulation liquid then the preferred binder substance is povidone.
- the preferred binder substance is vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA 64). Distinct from wet or dry granulation and from spray drying, a further significant feature preferably applied in commonly processing pimobendan and organic carboxylic acid is using the aforementioned, pimobendan-containing granulation liquid for carrying out the fluid bed granulation process, especially with paying attention to spraying the granulation liquid onto suitable excipient particles.
- the excipient particles preferably comprise a particulate matter, and more preferably are selected from starch and lactose.
- the organic carboxylic acid notably succinic acid
- the organic carboxylic acid can fully display its solubilizing effects on pimobendan in the obtained intimate mixture in which both substances are present in fine powder form or as very small particles or crystals and thus are in intimate contact over a large surface area.
- the granules obtained by abovementioned fluid bed granulation process may optionally be sieved through an appropriate sieve. This may be followed by mixing the dry granulate with one or more further excipients, and tabletting.
- organic carboxylic acids and especially succinic acid in preferred embodiments of the pharmaceutical composition according to the invention is contained with a preferred weight ratio of succinic acid to pimobendan of at least 11 :1 , preferably in the range of 1 1 :1 to 20:1 , more preferably 1 1 :1 to 15:1 , in particular 12:1 to 13:1 , and especially about 12:1.
- compositions of the present invention are prepared in several steps.
- pimobendan and carboxylic acid notably polycarboxylic acid and most preferably succinic acid can be dissolved in ethanol, and then surfactant, preferably of non-ionic type and more preferably polyoxyethylene (20) sorbitan monooleate, and optionally binder, preferably povidone, and surfactant, preferably of non-ionic type and more preferably polyoxyethylene (20) sorbitan monooleate, are added to the formed solution.
- the granulation liquid can then be sprayed onto a mixture of particulate excipients, preferably starch and lactose particles which can be blended with other optional additives such as croscarmellose sodium and microcrystalline cellulose and optionally binder, preferably vinylpyrrolidone-vinyl acetate copolymer.
- the granulate can be dried in a fluid bed dryer, and the dry mixture obtained can be sieved through an appropriate sieve. This may be followed by mixing the dry granulate with further excipients as desired, for example silica colloidal, magnesium stearate, a flavouring agent and optionally binder, preferably vinylpyrrolidone-vinyl acetate copolymer.
- such preparation can be compressed on a rotary tablet machine to provide palatable tablets.
- a 1.25 mg palatable tablet of the originator (Vetmedin ® ) has been used.
- a palatable tablet was prepared according to the procedure described in EP0439030 from the following preparation:
- a palatable tablet was prepared from the following:
- the tablet was prepared according to the following procedure: First, succinic acid and pimobendan were added to water, which lead to a dispersion wherein succinic acid was dissolved whereas pimobendan was only partially dissolved. Then povidone was added into the formed solution. The granulation liquid was then sprayed onto a mixture of starch and lactose particles blended with croscarmellose sodium and microcrystalline cellulose. The granulate was dried in a fluid bed dryer and the dry mixture obtained was sieved through an appropriate sieve. This was followed by mixing the dry granulate with silica colloidal, magnesium stearate and a flavouring agent. Finally, such preparation was compressed on rotary tablet machine to provide the palatable tablets.
- Example 1 a relatively large amount of succinic acid is used (weight ratio pimobendan to succinic acid of 1 :28), and water is used as a granulation liquid. Compared to the high amount of citric acid in the Comparative Example, the use of succinic acid however is less prone to problems of press formability and flowability and thus difficulty to process into solid preparation. Further, selection of succinic acid is useful from the standpoint of reduced tendency of hygroscopic water absorption and chemical stability, and thus good product reproducibility and less product interchange. Thus, overall properties are improved.
- succinic acid weight ratio pimobendan to succinic acid of 1 :28
- a palatable tablet was prepared from the following:
- the tablet was prepared according to the following procedure: First, succinic acid and pimobendan were dissolved in ethanol, and then povidone was added into the formed solution. The granulation liquid was then sprayed onto a mixture of starch and lactose particles blended with croscarmellose sodium and colorant. The granulate was dried in a fluid bed dryer and the dry mixture obtained was sieved through an appropriate sieve. This was followed by mixing the dry granulate with silica colloidal, magnesium stearate and a flavouring agent. Finally, such preparation was compressed on rotary tablet machine to provide the palatable tablets.
- Example 2 ethanol was used as a granulation liquid together with a smaller amount of succinic acid compared to Example 1.
- the weight ratio of pimobendan to succinic acid was 1 : 12.
- a palatable tablet was prepared from the following:
- the tablet was prepared according to the following procedure: First, succinic acid, surfactant and pimobendan were dissolved in ethanol, and then povidone was added into the formed solution. The granulation liquid was then sprayed onto a mixture of starch and lactose particles blended with croscarmellose sodium and colorant. The granulate was dried in a fluid bed dryer and the dry mixture obtained was sieved through an appropriate sieve. This was followed by mixing the dry granulate with silica colloidal, magnesium stearate and a flavouring agent. Finally, such preparation was compressed on rotary tablet machine to provide the palatable tablets.
- Example 3 ethanol was used as a granulation liquid together with the same amount of succinic acid as in the Example 2 (weight ratio of pimobendan to succinic acid of 1 :12).
- a surfactant Polisorbate 80 was added to the granulation solution.
- a palatable tablet was prepared from the following:
- the tablet was prepared according to the following procedure: First, succinic acid, surfactant and pimobendan were dissolved in ethanol. The granulation liquid was then sprayed onto a mixture of starch and lactose particles blended with Kollidon VA 64 and colorant. The granulate was dried in a fluid bed dryer and the dry mixture obtained was sieved through an appropriate sieve. This was followed by mixing the dry granulate with silica colloidal, magnesium stearate, the rest of Kollidon VA 64, and a flavouring agent. Finally, such preparation was compressed on rotary tablet machine to provide the palatable tablets.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An oral pharmaceutical composition comprising Pimobendan and improvements for storage stability and dissolution performance is disclosed.
Description
Pharmaceutical composition comprising pimobendan
Background of the Invention
The present invention relates to a pimobendan and a pharmaceutical composition comprising pimobendan, in particular in the form of an oral dosage preparation.
Pimobendan, (4,5-dihydro-6-(2-(4-methoxyphenyl)-1 H-benzimidazol-5-yl)-5-methyl- 3(2H))-pyridazinone, is a benzimidazole derivative with cardiotonic, hypotensive and antithrombotic effect. It is commercially available as chewing tablets or capsules under the brand name Vetmedin® (Boehringer Ingelheim) and is in particular useful in veterinary medicine. Pimobendan is a cardiac pharmaceutical, termed an "inodilator" because it possesses both positive inotropic and balanced peripheral vasodilation properties. Unlike historical positive inotropes (e.g. digoxin, milrinone) that function by increasing intracellular calcium concentrations, resulting in increased cardiac energy and oxygen requirements, pimobendan acts as a positive inotrope principally by enhancing the affinity of myocardial troponin C to existing intracellular calcium. Peripherally, pimobendan is a phosphodiesterase III (PDE III) inhibitor, resulting in balanced peripheral vasodilation through increased efflux of intracellular calcium from vascular smooth muscle. Additional properties include reversal of desensitization of baroreceptors, improved cardiac relaxation (lusitropy), reduced platelet aggregation, and an anti-inflammatory effect mediated through favourable cytokine modulation.
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.
For developing a pharmaceutical preparation, there is a problem that the compound is difficult to be dissolved in water. It is especially sparingly soluble in near neutral pH region so that dissolution from a preparation is poor and thus a sufficient blood concentration of the compound cannot be obtained. There is an ever increasing number of pharmaceutical drugs being formulated that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges in delivering them in an absorbable form to the desired absorption site. Pharmaceutical compositions for delivery of poorly soluble drugs must carry the drug through the aqueous environment, while maintaining the drug in an absorbable form and concomitantly avoiding the use of physiologically harmful excipients.
As described in EP0439030, pimobendan's originator company proposes to overcome low solubility and high pH dependency of solubility by implementing a method, intimately mixing pimobendan with citric acid and subsequently processing it with conventional excipients to form a powder, pellets or granules for oral administration. Although citric acid is a safe and well tolerated excipient, a great amount of said citric acid is required for achieving said method, so that the obtained preparation has a high water- absorbing property and lacks storage stability.
JP2006-056880A discloses pimobendan oral dosage preparations comprising (A) pimobendan and (B) alginic acid and fumaric acid, alginic acid and succinic acid, or alginic acid, fumaric acid and succinic acid. Further, JP2007-191419A discloses pimobendan oral dosage preparations comprising (A) pimobendan and (B) fumaric acid and (C) polyoxyethylene (105) polyoxypropylene (5) glycol. The pimobendan preparation for oral administration of JP2006-028130A is produced by compounding a finely powdered composition obtained by mixing and pulverizing pimobendan and one or more bases selected from light anhydrous silicic acid, polyvinylpyrrolidone and D-mannitol. In JP2006- 028131 A, the pimobendan preparation for oral administration contains pimobendan and polyoxyethylene (105) polyoxypropylene (5) glycol. Further, WO2005084647 discloses a solid formulation, comprising pimobendan or a pharmaceutically acceptable salt thereof which is homogenously dispersed in a polyvalent acid selected from the group of acetic acid, tartaric acid or its anhydride, and a flavour.
Object of the present invention is to provide a pimobendan preparation with good storage stability, preferably when compared to the originator's product, and which still has good dissolution property. Moreover, it would be desirable to provide such a pimobendan preparation with beneficial press formability and flowability characteristics, consequently being easy to process into a solid preparation.
Summary of Invention
A novel composition has been found that provides for a stable composition for oral administration of pimobendan.
Said composition is described by the following embodiments of the invention. In particular, various aspects, advantageous features and preferred embodiments of the present invention will be summarized in the following items which, respectively alone or in combination, further contribute to solving the object of the invention:
1. A composition, comprising pimobendan and an organic carboxylic acid, wherein the only organic carboxylic acid is succinic acid and wherein the weight ratio of succinic acid to pimobendan is at least 11 :1.
2. A composition comprising pimobendan and a carboxylic acid in an intimate mixture obtained by dissolving both pimobendan and carboxylic acid and optionally a binder substance in an organic solvent optionally containing less than 50 vol.-% water relative to the whole solvent component, and subsequently using said obtained solution as a granulation liquid in a process of fluid bed granulation.
3. The composition according to item 2, wherein said carboxylic acid is a polycarboxylic acid, preferably succinic acid.
4. The composition according to item 2 or 3, wherein said organic solvent is lower alcohol, for example a CrC4-alcanol such as methanol, ethanol, n- or isopropanol or n-, iso-, sec- or tert.-butanol, in particular ethanol.
5. The composition according to any one of the preceding items, wherein the weight ratio of carboxylic acid to pimobendan is in a range of 11 : 1 to 20:1.
6. The composition according to any one of the preceding items, further comprising a surfactant.
7. The composition according to item 6, wherein the surfactant is a non-ionic surfactant.
8. The composition according to item 6, wherein the non-ionic surfactant is polyoxyethylene (20) sorbitan monooleate.
9. The composition according to any one of the preceding items, characterized by a weight ratio of carboxylic acid to pimobendan of between 1 1 :1 and 15:1 , preferably from 12:1 to 15.1 , and in particular 12:1 to 13.1.
10. A pharmaceutical composition comprising a composition according to any one of the preceding items, further comprising one or more pharmaceutically acceptable excipients.
1 1. The pharmaceutical composition according to item 10 in the form of granulates, powders or pellets, optionally packed into capsules.
12. The pharmaceutical composition according to item 1 1 , the granulates, powders or pellets being compressed with suitable excipients into tablets. 13. A pharmaceutical composition according to item 12, wherein the tablet is a palatable tablet.
14. A pharmaceutical composition according to any one of items 10 to 13, for use by oral administration.
15. A method of preparing a formulation comprising pimobendan and a carboxylic acid, comprising:
- A - providing a solution comprising dissolved pimobendan and dissolved carboxylic acid in an organic solvent, wherein the organic solvent optionally contains less than 50 vol.-% water relative to the whole solvent component; and using said solution comprising pimobendan, organic carboxylic acid and optionally binder substance as granulation liquid in the process of fluid bed granulation.
16. The method according to item 15 or 16, wherein the whole solvent component constitutes at least 50wt.%, preferably at least 60wt.% of the whole solution comprising pimobendan and organic carboxylic acid which is used as granulation liquid in the process of fluid bed granulation. 17. The method according to any one of items 15 to 16, wherein said organic solvent comprises lower alcohol or aqueous lower alcohol, in particular ethanol or aqueous ethanol.
18. The method according to any one of items 15 to 17, wherein said organic solution comprises only one type of organic carboxylic acid, preferably succinic acid, as the only organic carboxylic acid.
19. The method according to any one of items 15 to 18, wherein the solution further comprises a surfactant, preferably non-ionic surfactant and further preferably polyoxyethylene (20) sorbitan monooleate as non-ionic surfactant.
20. The method according to any one of items 15 to 19, wherein the binder substance comprises povidone.
21. The method according to any one of items 15 to 20, wherein the fluid bed granulation process involves spraying said solution comprising pimobendan, organic carboxylic acid and optionally binder substance onto other excipient(s).
22. The method according to item 21 , wherein the other excipient(s) comprise a particulate matter, preferably wherein the particulate matter comprises a substance selected from starch and lactose, and optionally a binder.
23. The method according to item 22, wherein the particulate matter is further blended with other excipients, preferably at least with croscarmellose sodium and microcrystalline cellulose. 24. The method according to any one of items 15 to 23, further comprising the steps of: drying the granulate obtained after spraying said solution comprising pimobendan, organic carboxylic acid and optionally binder substance onto other excipient(s); optionally sieving the obtained dry granulate; mixing the obtained dry granulate with one or more further excipients; and tabletting.
25. The method according to item 24, wherein drying the granulate is performed, preferably in a fluid bed dryer.
26. The method according to item 24 or 25, wherein the obtained granulate is mixed at least with silica colloidal and magnesium stearate as further excipients. 27. The method according to any one of items 21 to 26, wherein the binder substance comprises a vinylpyrrolidone-vinyl acetate copolymer.
28. A pharmaceutical composition comprising pimobendan and succinic acid as the sole organic carboxylic acid for use in the prophylaxis or treatment of a disease or condition selected from cardiovascular diseases or conditions, hypertension, thrombosis and thrombosis-associated diseases or conditions, wherein the pharmaceutical composition preferably is in an oral dosage form, especially a tablet.
The novel composition possesses superior dissolution properties and proves better storage stability in comparison to the reference composition of the originator. Therefore it can be used for obtaining high concentration of pimobendan in blood.
Brief Description of the Figure
FIGURE 1 : Comparative dissolution profiles of samples prepared according to Examples and a Comparative Example in neutral pH region (water) - conditions of testing:
A2/50 rpm, V=900 ml_, HPLC conditions: Waters system equipped with a C6- phenyl, 3.5 μm, 150 x 4.6 mm column which was maintained in a column oven at 30 0C. The mobile phase consisted of a mixture of a phosphate buffer of pH
2.5 and acetonitrile in ratio 80:20 (VA/). The flow rate was 1.0 ml/min and the detection wavelength 332 nm.
Detailed Description of the Invention
The method of preparing the pimobendan formulation according to the present invention allows to improve dissolution property of pimobendan, without however necessitating to increase the surface area by intensive milling the drug to gain smaller particle size. Theoretically, with micronization one should be able to achieve large surface areas, however, micronised drug powders are extremely cohesive due to high energy milling processes causing significant dislocation of crystal structure on the particle surface. Such particles would tend to agglomerate during the solid state processing, leading to poor dissolution performance. These problems can be avoided by the process of the invention, together with the advantage of providing beneficial press formability and flowability
characteristics, consequently being easy to process into a solid preparation. A certain drug particle size control may, if desired, be unnecessary according to the present invention.
The inventors of the present invention extensively studied a pimobendan oral dosage preparation to improve its poor solubility in order to obtain desirable dissolution properties.
Due to the low water solubility of pimobendan and its high pH dependency, several pharmaceutically acceptable acids were tested in order to increase the solubility of pimobendan and to lower the fluctuations in the resorption of pimobendan when administered orally. Among the tested acids, succinic acid is chosen according to one aspect of the present invention when the pharmaceutical composition is devised independent from process technology, because the quantity of dissolved pimobendan when used in combination with succinic acid as the only organic carboxylic acid was sufficient to ensure adequate resorption, even when fluctuations in pH of the solution occurred.
According to another aspect of the present invention, it was surprisingly found that a particular status of intimate mixture between pimobendan and an organic carboxylic acid in general and a polycarboxylic acid in particular, such as succinic acid, oxalic acid, fumaric acid, tartaric acid, citric acid, maleic acid and malic acid, provides an alternative means to obtain good balance of properties in terms of good storage stability and dissolution property, beneficial press formability and flowability characteristics. A single organic carboxylic acid, especially a single polycarboxylic acid is sufficient. Instead of mere mechanically mixing or co-milling respective particles of the pimobendan and the organic carboxylic acid components, it has been found that the intimate mixture formed as disclosed herein significantly contributes to achieve such good balance of properties, that is when the mixture is obtained by dissolving both pimobendan and organic carboxylic acid and optionally a binder substance in an organic solvent, preferably in a lower alcohol, in particular ethanol, optionally respectively containing less than 50 vol.-% water, and subsequently using the obtained solution as a granulation liquid in the process of fluid bed granulation. The effects can be even further enhanced when the particular intimate mixture according to this aspect of the present invention is made of pimobendan and succinic acid. In order to facilitate complete dissolution of both pimobendan and organic carboxylic acid, it is preferred that the whole solvent component constitutes at least 50wt.%, preferably at least 60wt.% of the whole granulation liquid. It is further preferred that the solvent component consists essentially or only of the organic solvent, notably a lower alcohol, in particular ethanol, or acetone, without water being added. In addition to the carboxylic acid (notably succinic acid), the pimobendan formation of the present invention, particularly one formulated as oral dosage preparation, preferably
contains a surfactant, most preferably a non-ionic surfactant. The non-ionic surfactant is preferably selected from the series of partial fatty acid esters of sorbitol copolymerized with approximately 20, 5, or 4 moles of ethylene oxide for each mole of sorbitol, and its anhydrides (polyoxyethylene sorbitan fatty acid esters). Polysorbate 80 (monooleic acid polyoxyethylene (20) sorbitan) is particularly preferred.
Other pharmaceutically acceptable excipients can be added to the pimobendan oral dosage preparation of the present invention. Said excipients include but are not limited to: a vehicle, preferably selected from lactose, mannitol, xylitol and sorbitol; a disintegrating agent, preferably selected from starch, croscarmellose sodium and low-substituted hydroxypropyl cellulose; a binding agent, preferably selected from polyvinylpyrrolidone, vinylpyrrolidone- vinyl acetate copolymer, dextrates and microcrystalline cellulose; a lubricant, preferably selected from magnesium stearate and talc; a glidant, preferably silica colloidal; a colorant, preferably selected from Iron oxide red and yellow; a flavouring agent; preferably selected from artificial beef flavour and vegetarian meat flavour; etc. The preparation of the present invention can be a tablet, a powder preparation, a granule preparation, or a capsule preparation. These preparations can be prepared according to a publicly known method. The preferred preparation of the present invention is a palatable tablet.
It has been found that both, the organic carboxylic acid and pimobendan, can be effectively and completely dissolved using aqueous/alcoholic or non aqueous lower alcohol solvent (the alcohol having carbon atoms of less than 8), most suitably ethanol. Alternatively, there may be used other organic solvents optionally containing less than 50 vol.-% water, such as acetone. As used herein, the term "solution comprising dissolved pimobendan and dissolved carboxylic acid" shall mean that each of the mentioned components are essentially dissolved, preferably completely dissolved. Especially succinic acid can fully develop its solubilizing effect when it is intimately mixed with pimobendan as disclosed herein. That is, organic carboxylic acid, and preferably succinic acid as the sole organic carboxylic acid, is subjected together with pimobendan to form aqueous/alcoholic (e.g. ethanolic) granulation solution and non aqueous granulation solution with lower alcohol (e.g. ethanol). Binder and preferably in addition surfactant can also be admixed with the granulation liquid. In addition to admixing binder substance with the granulation liquid, said binder can also comprise a particulate matter or/and can be added to dry granulate before tabletting. If binder is added to the granulation liquid then the preferred binder substance is povidone. On the other hand, in case binder comprises a particulate matter and/or is added to dry granulate before tabletting then the preferred binder substance is vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA 64). Distinct from wet or dry granulation and from spray
drying, a further significant feature preferably applied in commonly processing pimobendan and organic carboxylic acid is using the aforementioned, pimobendan-containing granulation liquid for carrying out the fluid bed granulation process, especially with paying attention to spraying the granulation liquid onto suitable excipient particles. The excipient particles preferably comprise a particulate matter, and more preferably are selected from starch and lactose. As a result, the organic carboxylic acid, notably succinic acid, can fully display its solubilizing effects on pimobendan in the obtained intimate mixture in which both substances are present in fine powder form or as very small particles or crystals and thus are in intimate contact over a large surface area. The granules obtained by abovementioned fluid bed granulation process may optionally be sieved through an appropriate sieve. This may be followed by mixing the dry granulate with one or more further excipients, and tabletting.
For improving solubility and pH-independency of dissolution of pimobendan, organic carboxylic acids and especially succinic acid in preferred embodiments of the pharmaceutical composition according to the invention is contained with a preferred weight ratio of succinic acid to pimobendan of at least 11 :1 , preferably in the range of 1 1 :1 to 20:1 , more preferably 1 1 :1 to 15:1 , in particular 12:1 to 13:1 , and especially about 12:1.
According to preferred embodiments, the compositions of the present invention are prepared in several steps. First, pimobendan and carboxylic acid, notably polycarboxylic acid and most preferably succinic acid can be dissolved in ethanol, and then surfactant, preferably of non-ionic type and more preferably polyoxyethylene (20) sorbitan monooleate, and optionally binder, preferably povidone, and surfactant, preferably of non-ionic type and more preferably polyoxyethylene (20) sorbitan monooleate, are added to the formed solution. The granulation liquid can then be sprayed onto a mixture of particulate excipients, preferably starch and lactose particles which can be blended with other optional additives such as croscarmellose sodium and microcrystalline cellulose and optionally binder, preferably vinylpyrrolidone-vinyl acetate copolymer. In the next step, the granulate can be dried in a fluid bed dryer, and the dry mixture obtained can be sieved through an appropriate sieve. This may be followed by mixing the dry granulate with further excipients as desired, for example silica colloidal, magnesium stearate, a flavouring agent and optionally binder, preferably vinylpyrrolidone-vinyl acetate copolymer. Finally, such preparation can be compressed on a rotary tablet machine to provide palatable tablets.
The following examples describe the invention in further detail. However, by no means the present invention is limited by these examples.
Examples:
Two similar pharmaceutical compositions comprising pimobendan and succinic acid were prepared with different technological procedures (see Examples 1 to 3), and dissolution testing of the described samples was performed. The obtained results were compared to a Comparative Example corresponding to the originator's product. Results are presented in Figure 1. Since pimobendan is a low soluble drug, with maximal solubility determined in the aqueous solution with pH around 2, water (pH around 7) was chosen as a discriminatory media for testing the dissolution properties of the pimobendan tablets.
COMPARATIVE EXAMPLE
As a comparative example a 1.25 mg palatable tablet of the originator (Vetmedin®) has been used. A palatable tablet was prepared according to the procedure described in EP0439030 from the following preparation:
A palatable tablet was prepared from the following:
The tablet was prepared according to the following procedure: First, succinic acid and pimobendan were added to water, which lead to a dispersion wherein succinic acid was dissolved whereas pimobendan was only partially dissolved. Then povidone was added into the formed solution. The granulation liquid was then sprayed onto a mixture of starch and lactose particles blended with croscarmellose sodium and microcrystalline cellulose. The granulate was dried in a fluid bed dryer and the dry mixture obtained was sieved through an appropriate sieve. This was followed by mixing the dry granulate with silica colloidal, magnesium stearate and a flavouring agent. Finally, such preparation was compressed on rotary tablet machine to provide the palatable tablets.
In Example 1 a relatively large amount of succinic acid is used (weight ratio pimobendan to succinic acid of 1 :28), and water is used as a granulation liquid. Compared to the high amount of citric acid in the Comparative Example, the use of succinic acid however is less prone to problems of press formability and flowability and thus difficulty to process into solid preparation. Further, selection of succinic acid is useful from the standpoint of reduced tendency of hygroscopic water absorption and chemical stability, and thus good product reproducibility and less product interchange. Thus, overall properties are improved.
EXAMPLE 2
A palatable tablet was prepared from the following:
The tablet was prepared according to the following procedure: First, succinic acid and pimobendan were dissolved in ethanol, and then povidone was added into the formed solution. The granulation liquid was then sprayed onto a mixture of starch and lactose particles blended with croscarmellose sodium and colorant. The granulate was dried in a fluid bed dryer and the dry mixture obtained was sieved through an appropriate sieve. This was followed by mixing the dry granulate with silica colloidal, magnesium stearate and a flavouring agent. Finally, such preparation was compressed on rotary tablet machine to provide the palatable tablets.
In Example 2, ethanol was used as a granulation liquid together with a smaller amount of succinic acid compared to Example 1. The weight ratio of pimobendan to succinic acid was 1 : 12.
EXAMPLE 3
A palatable tablet was prepared from the following:
The tablet was prepared according to the following procedure: First, succinic acid, surfactant and pimobendan were dissolved in ethanol, and then povidone was added into the formed solution. The granulation liquid was then sprayed onto a mixture of starch and lactose particles blended with croscarmellose sodium and colorant. The granulate was dried in a fluid bed dryer and the dry mixture obtained was sieved through an appropriate sieve. This was followed by mixing the dry granulate with silica colloidal, magnesium stearate and a flavouring agent. Finally, such preparation was compressed on rotary tablet machine to provide the palatable tablets.
In Example 3, ethanol was used as a granulation liquid together with the same amount of succinic acid as in the Example 2 (weight ratio of pimobendan to succinic acid of 1 :12). In addition, a surfactant Polisorbate 80 was added to the granulation solution.
Evaluating dissolution properties as depicted from the results shown in Fig. 1 , it is revealed that a certain amount of polycarboxylic acid (succinic acid) should be used. Control of such amount into a ratio to pimobendan being below 20:1 is beneficial in terms of enhanced solubility (cf. Examples 1 to 3). Also, complete dissolution of both pimobendan and polycarboxyilc acid (succinic acid) properly in a lower alcoholic solution (ethanol) as performed in Examples 2 and 3 is significantly beneficial over water solution in which pimobendan is only partially dissolved (Example 1 ). It is followed that preparing such aqueous/alcoholic (ethanolic) granulation liquid and substantially non-aqueous granulation liquid with lower alcohol (ethanol) respectively involving subsequent use of this granulation
liquid in a fluid bed granulation process have significant enhancing effects on the dissolution performance of the obtained pimobendan containing formulation. Moreover, the use of surfactant, notably non-ionic surfactant has a further substantially enhancing effect on the dissolution performance (cf. Example 3).
EXAMPLE 4
A palatable tablet was prepared from the following:
The tablet was prepared according to the following procedure: First, succinic acid, surfactant and pimobendan were dissolved in ethanol. The granulation liquid was then sprayed onto a mixture of starch and lactose particles blended with Kollidon VA 64 and colorant. The granulate was dried in a fluid bed dryer and the dry mixture obtained was sieved through an appropriate sieve. This was followed by mixing the dry granulate with silica
colloidal, magnesium stearate, the rest of Kollidon VA 64, and a flavouring agent. Finally, such preparation was compressed on rotary tablet machine to provide the palatable tablets.
Claims
1. A composition, comprising pimobendan and an organic carboxylic acid, wherein the only organic carboxylic acid is succinic acid and wherein the weight ratio of succinic acid to pimobendan is at least 11 :1.
2. A composition comprising pimobendan and a carboxylic acid in an intimate mixture obtained by dissolving both pimobendan and organic acid and optionally a binder substance in an organic solvent optionally containing less than 50 vol.-% water relative to the whole solvent component, and subsequently using said obtained solution as a granulation liquid in a process of fluid bed granulation.
3. The composition according to claim 2, wherein said carboxylic acid is succinic acid, and/or wherein said organic solvent is ethanol.
4. The composition according to any one of the preceding claims, wherein the weight ratio of carboxylic acid to pimobendan is in a range of 11 :1 to 20:1.
5. The composition according to any one of the preceding claims, further comprising a surfactant, preferably a non-ionic surfactant and particularly polyoxyethylene (20) sorbitan monooleate as non-ionic surfactant.
6. A pharmaceutical composition comprising a composition according to any one of the preceding claims, further comprising one or more pharmaceutically acceptable excipients.
7. The pharmaceutical composition according to claim 6 in the form of granulates or powders, optionally packed into capsules or wherein the granulates or powders are compressed with suitable excipients into tablets.
8. A method of preparing a formulation comprising pimobendan and a carboxylic acid, comprising: providing a solution comprising dissolved pimobendan and dissolved carboxylic acid and optionally a binder substance in an organic solvent, wherein the organic solvent optionally contains less than 50 vol.-% water relative to the whole solvent component; and using said solution comprising pimobendan, organic carboxylic acid and optionally binder substance as granulation liquid in a process of fluid bed granulation.
9. The method according to claim 8, wherein the whole solvent component constitutes at least 50wt.% of the whole solution comprising pimobendan and organic carboxylic acid which is used as granulation liquid in the process of fluid bed granulation.
10. The method according to claim 8 or 9, wherein said organic solvent comprises ethanol or aqueous ethanol.
1 1. The method according to any one of claims 8 to 10, wherein said solution comprises only one type of carboxylic acid, preferably succinic acid, as the only carboxylic acid.
12. The method according to any one of claims 8 to 11 , wherein said solution further comprises a surfactant, preferably non-ionic surfactant and further preferably polyoxyethylene (20) sorbitan monooleate as non-ionic surfactant.
13. The method according to any one of claims 8 to 12, wherein fluid bed granulation process involves spraying the obtained granulation liquid onto other excipient(s), wherein said other excipient(s) preferably comprise a particulate matter, particularly wherein the particulate matter comprises a substance selected from starch, lactose, microcrystalline cellulose, and optionally a binder substance.
14. The method according to any one of claims 8 to 13, further comprising the steps of: drying the granulate obtained after spraying the obtained granulation liquid onto other excipient(s); optionally sieving the obtained dry granulate; mixing the obtained dry granulate with one or more further excipients; and tabletting.
15. A pharmaceutical composition comprising pimobendan and succinic acid as the sole organic carboxylic acid for use in the prophylaxis or treatment of a disease or condition selected from cardiovascular diseases or conditions, hypertension, thrombosis and thrombosis-associated diseases or conditions, wherein the pharmaceutical composition preferably is in an oral dosage form, especially a tablet.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08169298.0 | 2008-11-17 | ||
EP08169298 | 2008-11-17 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2010055119A2 true WO2010055119A2 (en) | 2010-05-20 |
WO2010055119A3 WO2010055119A3 (en) | 2010-08-05 |
Family
ID=40433918
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2009/065106 WO2010055119A2 (en) | 2008-11-17 | 2009-11-13 | Pharmaceutical composition comprising pimobendan |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2010055119A2 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013092673A2 (en) | 2011-12-21 | 2013-06-27 | Novartis Ag | New combination |
US20150025082A1 (en) * | 2013-07-19 | 2015-01-22 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
US9107952B2 (en) | 2006-11-07 | 2015-08-18 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising pimobendan |
EP3106150A1 (en) | 2013-12-04 | 2016-12-21 | Boehringer Ingelheim Vetmedica GmbH | Improved pharmaceutical compositions of pimobendan |
WO2017103054A1 (en) * | 2015-12-17 | 2017-06-22 | Ceva Sante Animale | Pharmaceutical composition comprising pimobendan |
US10398705B2 (en) | 2012-03-15 | 2019-09-03 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof |
US10449195B2 (en) | 2016-03-29 | 2019-10-22 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
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 |
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 |
US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0439030A2 (en) * | 1990-01-20 | 1991-07-31 | Dr. Karl Thomae GmbH | Oral dosage forms containing pimobendan |
WO2005084647A1 (en) * | 2004-03-08 | 2005-09-15 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical composition comprising pimobendan |
EP1818047A2 (en) * | 2002-03-07 | 2007-08-15 | Boehringer Ingelheim Pharma GmbH & Co. KG | Oral administration form for difficulty soluble basic active ingredients |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006028130A (en) * | 2004-07-21 | 2006-02-02 | Toa Eiyo Ltd | Pimopendan preparation for oral administration |
JP4572296B2 (en) * | 2004-07-21 | 2010-11-04 | トーアエイヨー株式会社 | Pimobendan oral dosage formulation |
JP4572300B2 (en) * | 2006-01-19 | 2010-11-04 | トーアエイヨー株式会社 | Pimobendan oral dosage formulation |
-
2009
- 2009-11-13 WO PCT/EP2009/065106 patent/WO2010055119A2/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0439030A2 (en) * | 1990-01-20 | 1991-07-31 | Dr. Karl Thomae GmbH | Oral dosage forms containing pimobendan |
EP1818047A2 (en) * | 2002-03-07 | 2007-08-15 | Boehringer Ingelheim Pharma GmbH & Co. KG | Oral administration form for difficulty soluble basic active ingredients |
WO2005084647A1 (en) * | 2004-03-08 | 2005-09-15 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical composition comprising pimobendan |
Non-Patent Citations (3)
Title |
---|
DATABASE WPI Week 200613 Thomson Scientific, London, GB; AN 2006-121993 XP002520487 -& JP 2006 028130 A (TOA FOOD CHEM CO LTD) 2 February 2006 (2006-02-02) cited in the application * |
DATABASE WPI Week 200619 Thomson Scientific, London, GB; AN 2006-178263 XP002520486 -& JP 2006 056880 A (TOA FOOD CHEM CO LTD) 2 March 2006 (2006-03-02) cited in the application * |
DATABASE WPI Week 200767 Thomson Scientific, London, GB; AN 2007-712118 XP002520087 -& JP 2007 191419 A (TOA FOOD CHEM CO LTD) 2 August 2007 (2007-08-02) cited in the application * |
Cited By (28)
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 |
US9107952B2 (en) | 2006-11-07 | 2015-08-18 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising pimobendan |
US10639305B2 (en) | 2006-11-07 | 2020-05-05 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising pimobendan |
EP3320894A1 (en) | 2011-12-21 | 2018-05-16 | Elanco Tiergesundheit AG | New combination |
EP3034071A1 (en) | 2011-12-21 | 2016-06-22 | Novartis Tiergesundheit AG | New combination |
WO2013092673A2 (en) | 2011-12-21 | 2013-06-27 | Novartis Ag | New combination |
US10398705B2 (en) | 2012-03-15 | 2019-09-03 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof |
US11185590B2 (en) | 2013-07-19 | 2021-11-30 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
CN105377235A (en) * | 2013-07-19 | 2016-03-02 | 勃林格殷格翰动物保健有限公司 | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
US20180339054A1 (en) * | 2013-07-19 | 2018-11-29 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
US10071162B2 (en) | 2013-07-19 | 2018-09-11 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
US20150025082A1 (en) * | 2013-07-19 | 2015-01-22 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
US20220040313A1 (en) * | 2013-07-19 | 2022-02-10 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
US11298325B2 (en) | 2013-12-04 | 2022-04-12 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical compositions of pimobendan |
US10653633B2 (en) | 2013-12-04 | 2020-05-19 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical compositions of pimobendan |
US10172804B2 (en) | 2013-12-04 | 2019-01-08 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical compositions of pimobendan |
US10874620B2 (en) | 2013-12-04 | 2020-12-29 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical compositions of pimobendan |
EP3106150A1 (en) | 2013-12-04 | 2016-12-21 | Boehringer Ingelheim Vetmedica GmbH | Improved pharmaceutical compositions of pimobendan |
WO2017103054A1 (en) * | 2015-12-17 | 2017-06-22 | Ceva Sante Animale | Pharmaceutical composition comprising pimobendan |
US11246867B2 (en) | 2015-12-17 | 2022-02-15 | Ceva Sante Animale | Pharmaceutical composition comprising pimobendan |
AU2016369367B2 (en) * | 2015-12-17 | 2021-12-02 | Ceva Sante Animale | Pharmaceutical composition comprising pimobendan |
US10813937B2 (en) | 2016-03-29 | 2020-10-27 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
US10894049B2 (en) | 2016-03-29 | 2021-01-19 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
US10449195B2 (en) | 2016-03-29 | 2019-10-22 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
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 |
US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
Also Published As
Publication number | Publication date |
---|---|
WO2010055119A3 (en) | 2010-08-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2010055119A2 (en) | Pharmaceutical composition comprising pimobendan | |
JP5282722B2 (en) | Nateglinide-containing preparation | |
CA2771403C (en) | Quinoline derivative-containing pharmaceutical composition | |
JP5295123B2 (en) | New pharmaceutical composition | |
KR101632079B1 (en) | Pharmaceutical composition containing dihydropyridine calcium channel antagonist and method for the preparation thereof | |
US20100209495A1 (en) | Granulates, process for preparing them and pharmaceutical products containing them | |
CN112402360A (en) | Solid pharmaceutical composition of androgen receptor antagonist | |
KR101237646B1 (en) | Solid dispersion comprising celecoxib with improved bioavailibity, pharmaceutical composition comprising the solid dispersion, and preparation method of the solid dispersion | |
TWI780270B (en) | Solid dispersion | |
US20080038332A1 (en) | Stable pharmaceutical formulation comprising atorvastatin calcium | |
US20100310668A1 (en) | Pharmaceutical compositions comprising n-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide | |
KR20210080225A (en) | Solubility and bioavailability enhanced formulation of Olaparib | |
WO2022004859A1 (en) | Oral pharmaceutical composition and method for producing same | |
KR20090028983A (en) | New pharmaceutical composition for treatment of hypercholesterolemia | |
KR20060030480A (en) | Tablet comprising fluvastatin and carmellose calcium | |
KR102306856B1 (en) | Celecoxib solid dispersion having improved dissolution rate, oral absorption and method for producing the same | |
JP6272328B2 (en) | Candesartan cilexetil-containing preparation | |
WO2023128905A1 (en) | Pharmaceutical composition comprising amorphous tolvaptan | |
AU2008254039B2 (en) | Method for producing pharmaceutical tablet | |
EP2090306A1 (en) | Pharmaceutical compositions comprising N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide | |
JP5106119B2 (en) | Drug for oral administration containing cyclooxygenase-2 inhibitor and method for preparing the same | |
JPWO2019194095A1 (en) | Solifenacin-containing pharmaceutical composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09753095 Country of ref document: EP Kind code of ref document: A2 |
|
NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09753095 Country of ref document: EP Kind code of ref document: A2 |