PHARMACEUTICAL TABLET FORMULATION FOR THE VETERINARY MEDICAL SECTOR, METHOD OF PRODUCTION AND USE THEREOF

• US 20150064249A1
• Filed: 03/14/2013
• Published: 03/05/2015
• Est. Priority Date: 03/15/2012
• 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: Folger, Martin, Hoffmann, Ragna, Robin, Florent
• Granted Patent: US 10,398,705 B2
• Time in Patent Office: Days
• US Class Current: 424/465
• 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 31/501 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 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5078 with drug-free core

Abstract

The invention is directed to a pharmaceutical tablet formulation for the veterinary medical sector containing an instable ACE inhibitor or a pharmaceutically acceptable salt thereof as a first pharmaceutically active substance, and pimobendan or a pharmaceutically acceptable salt thereof as a second pharmaceutically active substance, comprising granules which contain carrier core particles coated with at least one layer wherein the first pharmaceutically active substance is present, the granules being embedded in a tablet matrix wherein the second pharmaceutically active substance is present. It is provided a “fixed-dose-combination” which allows to ease the treatment and administration of the medication, improves the medication compliance by reducing the pill burden to the animal holder and enables the better observation of and adherence to the therapy by decreasing the number of tablets to be administered. The lower number of tablets leads to a lower treatment failure rate, minimizes dosage mistakes and avoids confusions by false dose intake and slower development of resistance.

Claims

1. A pharmaceutical tablet formulation for the veterinary medical sector containing an instable ACE inhibitor or a pharmaceutically acceptable salt thereof as a first pharmaceutically active substance, and pimobendan or a pharmaceutically acceptable salt thereof as a second pharmaceutically active substance, comprising granules which contain carrier core particles coated with at least one layer wherein the first pharmaceutically active substance is present, the granules being embedded in a tablet matrix wherein the second pharmaceutically active substance is present.

2. The pharmaceutical tablet formulation of claim 1, characterized in that the carrier core particles are coated with a layer (first layer) containing the first pharmaceutically active substance and at least a coating and/or matrix forming polymer.

3. The pharmaceutical tablet formulation of claim 1, characterized in that the coated carrier core particles are additionally coated with a layer (second layer) containing at least a coating and/or matrix forming polymer.

4. The pharmaceutical tablet formulation of claim 1, characterized in that the carrier core particles of the granules are selected from a pharmaceutically acceptable material which upon contact with water shows an overall minimal or negligible swelling, preferably selected from lactose, carbohydrates, sugar alcohols, such as mannitol, sorbitol, maltitol, glucose, non-pareil-seeds, calcium phosphate, cellulose, preferably microcrystalline cellulose (MCC), and starch, and mixtures thereof, more preferably lactose, most preferably spray dried lactose or agglomerated α

-lactose-monohydrate, particularly preferred agglomerated α

-lactose-monohydrate and mixtures of agglomerated α

-lactose-monohydrate with one or more of the materials as above-listed.

5. The pharmaceutical tablet formulation of claim 1, characterized in that the first pharmaceutically active substance is a pharmaceutically acceptable salt of an instable ACE-inhibitor, and the second pharmaceutically active substance is pimobendan.

6. The pharmaceutical tablet formulation of claim 2, characterized in that the coating and/or matrix forming polymer is a polymer on methacrylic acid basis.

7. The pharmaceutical tablet formulation of claim 2, characterized in that the ratio of the first pharmaceutically active substance to the at least one coating and/or matrix forming polymer in the first layer is from about 0.5 to 2:

1 to 4.

9. The pharmaceutical tablet formulation of claim 1, characterized in that the at least one layer comprise one or more excipients, whereby the excipients are selected from release modifying agents, binders, carriers, crystallization retarders, sweeteners, solubilizers, coloring agents, flavoring substances, pH control agents, taste masking agents, surfactants, anti-tacking agents, plasticizers, anti-static agents, and emulsifiers.

10. The pharmaceutical tablet formulation of claim 1, characterized in that the tablet matrix comprises one or more excipients, whereby the excipients are selected from binders, carriers, diluents, disintegrants, fillers, lubricants, acidifying agents, glidants, crystallization retarders, sweeteners, solubilizers, coloring agents, pH control agents, taste masking agents, anti-tacking agents, plasticizers, surfactants and emulsifiers.

11. The pharmaceutical tablet formulation of claim 1, characterized in that the ratio of granules (carrier core particles+first layer containing first pharmaceutically acceptable substance+optional second layer) to extra-granular material (tablet matrix+second pharmaceutically substance) is about 10:

90 to about 90;

10, preferably about 20;

80 to about 80;

20 (w/w) in the pharmaceutical tablet formulation.

12. The pharmaceutical tablet formulation of claim 1, characterized in that the pharmaceutical tablet formulation is a chewable tablet.

16. A process for preparing the pharmaceutical tablet formulation according to claim 1, comprising:

preparing a first fluid bed coating using a coating solution comprising an instable ACE-inhibitor or a pharmaceutically acceptable salt thereof and at least one coating and/or matrix forming polymer using carrier core particles to obtain a coated granulate;

preparing a second fluid bed coating using a further coating solution comprising at least one coating and/or matrix forming polymer to obtain a double coated granulate;

mixing pimobendan or a pharmaceutically acceptable salt thereof with the excipient/s of a tablet matrix to obtain a premix;

optionally sieving the obtained coated granulate through a screen;

mixing the coated granulate and the premix to obtain a blend;

mixing the blend with one or more lubricants and/or glidants to obtain a final blend, and compressing said final blend to a tablet.

17. The process of claim 16, characterised in that the fluid bed coating is a top-spray fluid bed process.

18. A method of preventing and/or treating heart diseases, disorders, or complications associated therewith, preferably selected from heart failure, congestive heart failure, increased size of the heart, and hypertension, particularly the prevention and/or the treatment of congestive heart failure originating from dilated cardiomyopathy or valvular insufficiency (mitral and/or tricuspid regurgitation), in mammals, preferably in pet animals, more preferably in dogs, cats, and rodents, most preferably in dogs comprising administration of the pharmaceutical tablet formulation of claim 1.

8. The pharmaceutical tablet formulation of 3, characterized in that the ratio of the first pharmaceutically active substance to the at least one coating and/or matrix forming polymer in the first and second layers together is from about 0.5 to 2:

4 to 16.

13. Granules comprising carrier core particles coated with a layer containing an instable ACE-inhibitor or a pharmaceutically acceptable salt thereof as a first pharmaceutically active substance and at least a coating and/or matrix forming polymer.

14. The granules of claim 13, characterized in that the coated carrier core particles are additionally coated with a layer containing at least a coating and/or matrix forming polymer.

15. The granules of claim 13, having a particle size distribution where ≧

90% of the particles have a diameter of 125-750 μ

m and/or 50-80% of the particles have a diameter of 250-500 μ

m.