PHARMACEUTICAL COMPOSITIONS OF PIMOBENDAN

• US 20150150820A1
• Filed: 12/03/2014
• Published: 06/04/2015
• Est. Priority Date: 12/04/2013
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: LACZAY, Pter
• Granted Patent: US 10,172,804 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention is directed to a composition comprising particles of pimobendan with an integral coating of a carrier matrix which serve to ensure a rapid dissolution of the active substance at each pH condition representing the gastrointestinal tract and therefore a reliable absorption, and a method of pimobendan microencapsulation using the spray congealing technology and incorporating the coated particles into oral formulations, for example into tablets.

Claims

1. A composition comprising pimobendan in particulate form coated with a carrier matrix, wherein the carrier matrix consists essentially of one or more pharmaceutically acceptable carriers selected from the following groups:

a. polyglycolized glycerides,

b. polyethylene glycols (PEGs).

2. The composition according to claim 1, wherein the coating with the carrier matrix serves to ensure a rapid and substantial dissolution of pimobendan irrespective of the pH conditions.

3. The composition according to claim 1, wherein the carrier matrix comprises essentially both of the following:

(a) stearoyl macrogol-32 glycerides and (b) polyethylene glycol 6000; and

preferably is a mixture of stearoyl macrogol-32 glycerides and polyethylene glycol 6000.

4. The composition according to claim 3, wherein the stearoyl macrogol-32 glycerides and the polyethylene glycol 6000 are independently from each other present in amounts to make up 10% by weight to 100% by weight of the carrier matrix component of the composition, preferably 20% by weight to 75% by weight of the carrier matrix component of the composition, more preferably 20% by weight to 50% by weight of the carrier matrix component of the composition.

5. The composition according to claim 1, wherein the median particle size distribution value (D50 value) of the coated particles, i.e. pimobendan in particulate form coated with a carrier matrix, is less than 500 μ

m, preferably less than 300 μ

m, more preferably less than 250 μ

m, and even more preferably less than 200 μ

m; and

wherein preferably the coated particles are spherical in shape.

6. The composition according to claim 1, wherein the pimobendan content of the coated particles ranges from 1% by weight to 80% by weight, preferably from 5% by weight to 30% by weight, more preferably from 10% by weight to 20% by weight.

7. A process for the preparation of a composition according to claim 1, which comprises

a. dispersing particulate pimobendan in a molten carrier matrix,

b. atomizing the dispersion obtained in step (a), and

c. cooling and collecting the coated particles.

8. The process for the preparation of a composition according to claim 7, which comprises

a. dispersing particulate pimobendan, preferably with a mean particle size of less than 20 μ

m, in a molten carrier matrix, such as polyglycolized glycerides, preferably stearoyl macrogol-32 glycerides, more preferably Gelucire 50/13, and/or polyethylene glycols, preferably with an average molecular weight of 1.500 to 20.000 g/mol, more preferably with an average molecular weight of 4.000 to 6.000 g/mol, most preferably PEG 6000, wherein the carrier matrix preferably has a melting point from 40°

C. to 80°

C., more preferably from 50°

C. to 70°

C., by using conventional dispersion techniques, for example, using a high shear mixer, to yield a dispersion, preferably a homogenous suspension;

b. atomizing the dispersion obtained in step (a) by using conventional atomizers, such as rotary atomizers, pressure or pneumatic nozzles and/or sonic nozzles, preferably fitted in a standard spray congealing/chilling apparatus, more preferably by using a two-fluid pressure or pneumatic nozzle atomization system fitted in a standard spray congealing/chilling apparatus, using atomizing gas pressures of 1 to 10 bar, preferably 2 to 8 bar and more preferably 3 to 6 bar; and

c. cooling and collecting the coated particles by conventional cooling and collecting techniques, for example, by applying a stream of cool air or an inert gas, such as dry nitrogen, preferably at a temperature of 0°

to 30°

C., more preferably at a temperature of 3°

to 15°

C., even more preferably at a temperature of 5°

to 15°

C., most preferably at a temperature of 4°

to 8°

C., to the spray apparatus and collecting the particles, preferably in a cyclone separator or a bag filter.

9. A method for the treatment of warm-blooded animals, preferably companion animals, in particular dogs, comprising oral administration of a veterinarily effective amount of the composition according to claim 1, one or more physiologically acceptable excipients, and optionally, veterinarily effective amounts of one or more further active ingredients selected from the groups of angiotensin enzyme (ACE) inhibitors, aldosterone antagonists and/or loop diuretics.

10. The method of treatment according to claim 9, wherein the optional one or more further active ingredients selected from the groups of angiotensin enzyme (ACE) inhibitors, aldosterone antagonists and/or loop diuretics are independently from each other benazepril, spironolactone, furosemide and/or derivatives thereof, in free form or in the form of a physiologically acceptable salt, which preferably is embedded into a carrier matrix;

wherein preferably the optional one or more further active ingredients is benazepril, in free form or in the form of a physiologically acceptable salt, which preferably is embedded into a carrier matrix.

11. The method of treatment according to claim 9, in the form of tablets.

12. The method of treatment according to claim 9, comprising pimobendan in the range of from 0.01% by weight to 10% by weight based on the weight of the entire pharmaceutical composition, preferably from 0.5% by weight to 1.0% by weight based on the weight of the entire pharmaceutical composition.

13. The method of treatment according to claim 9, wherein the optional one or more further active ingredients are independently from each other present in the composition in the range of from 0.01% by weight to 50% by weight based on the weight of the entire pharmaceutical composition, preferably from 0.1% by weight to 20% by weight based on the weight of the entire pharmaceutical composition.

14. The method of treatment according to claim 9, characterized by dissolution of pimobendan that is more substantial from the relevant drug forms at all pH conditions representing the milieu(s) of the gastrointestinal tract of animals.