US20050169971A1 - Tasted masked veterinary solid compositions - Google Patents

Tasted masked veterinary solid compositions Download PDF

Info

Publication number
US20050169971A1
US20050169971A1 US10/506,937 US50693704A US2005169971A1 US 20050169971 A1 US20050169971 A1 US 20050169971A1 US 50693704 A US50693704 A US 50693704A US 2005169971 A1 US2005169971 A1 US 2005169971A1
Authority
US
United States
Prior art keywords
active ingredient
animal
carrier material
polymer
london
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/506,937
Other languages
English (en)
Inventor
Hubert Thoma
Uwe Schote
Ute Isele
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Elanco Tiergesundheit AG
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27798784&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20050169971(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Publication of US20050169971A1 publication Critical patent/US20050169971A1/en
Priority to US12/630,422 priority Critical patent/US8617587B2/en
Assigned to NOVARTIS TIERGESUNDHEIT AG reassignment NOVARTIS TIERGESUNDHEIT AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS AG
Abandoned legal-status Critical Current

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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the preparation of an animal medicine in an application form, which contains the active ingredient in a stabilised form that masks the taste, and which is readily taken orally by an animal.
  • the present invention is concerned in particular with those embodiments that contain bitter, bad-tasting active ingredients or those which are unpleasant for the animal in another respect.
  • medicaments may be administered in a wide variety of application forms, such as tablets, coated tablets, emulsions, injection solutions, suppositories and the like, because the discipline and the desire to recover in human patients can be relied upon, in the case of animals practical problems are soon encountered, since a few application forms, such as the usage of suppositories, either have to be dispensed with all together or other forms, such as injections, must only be carried out by the veterinarian.
  • Treating humans with medicines is generally not problematic, because the human patient follows the advice of the doctor or reads the directions on the leaflet in the pack and complies with them since this is in his own interest, and because the manufacturer usually prepares the tablet, capsule or coated tablet in a form which is appropriate for oral consumption and has been tailored for human patients.
  • an unpleasant tasting active ingredient can be masked relatively easily, e.g. by coating it with a neutral-tasting or sweet layer. Everybody has come across gelatin capsules or tablets coated with sugar or lacquer at some time or other. It is easy to instruct the human patient to take the preparation without chewing.
  • feed is not restricted exclusively to substances which would normally be described as feed, but also to nutritional additives, e.g. yeast, starch, various types of sugar, etc.
  • domestic animals and productive livestock e.g. pigs, also cattle, sheep and poultry
  • animal housing which is equipped with the most modern, fully automatic feeding installations.
  • the fodder is apportioned fully automatically in accordance with the age and weight of the animal, and is transported to each animal at quite specific times of day and in daily amounts, and is either placed on its own in the trough or is mixed with the usual feed ration.
  • feed pellets are used.
  • the feed in question is compressed, highly compacted energy feed on a vegetable and/or animal basis, which may be enriched with additives such as proteins, vitamins and minerals.
  • These feed pellets are no more than artificial, free-flowing, round or oblong grains, balls or even rod-shaped objects, depending on the manufacturing process, of a uniform size tailored to the species and age of the animals, which may have an average cross-section from a few millimetres for poultry to ca. one centimetre for adult pigs and cattle.
  • Feed pellets are prepared by commercial fodder mills by grinding the organic starting material, mixing the components in the desired composition and finally compressing into pellets, then filled into sacks and delivered to the animal keeper, who fills and dispenses them into the distribution plant.
  • An important advantage of these pellets is their simple handling which is a result of their uniformity, their fluidity and their stability in storage. They can be easily filled and dispensed, transported via conveyor belts or pipelines and administered to each animal in a precisely proportioned amount, all fully automatically.
  • pellets take up significantly less space than fresh feed and, in particular, are eaten willingly and without problems by the animals, provided that they do not contain components which are found to be unpleasant or repulsive by the animal's sense of taste and smell.
  • feed pellets there are stability problems when manufacturing feed pellets.
  • dry organic starting material of animal or vegetable origin is ground, mixed thoroughly with the particles which are masked according to the invention and optionally with further additives, vitamins or trace elements, etc., i.e. substantially homogenised and then moistened with ca. 5 to 10 percent by weight water and compressed into pellets at elevated temperatures of ca. 80 to 100° C., preferably 60 to 90° C., under a pressure of ca. 1 to 100 kbar.
  • the retention time in the press is ca. 5 to 180 seconds, preferably 10 to 90 seconds, and depends inter alia on the size of the pellets.
  • benazepril has been selected as the model active ingredient.
  • benazepril has an extremely bitter taste and is not willingly taken orally by pigs, dogs and in particular cats.
  • Benazepril is the chemical substance [S—(R*,R*)]-3-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid with the CAS registration number [86541-75-5].
  • Benazepril has the following chemical structure:
  • Benazepril is known from EP-0,072,352, and is used in animal medicine under the name FORTEKOR®, especially in the form of tablets, to treat cardiac and renal insufficiency.
  • benazepril only represents a preferred embodiment of the present invention and is only intended to illustrate the invention by way of an application example.
  • any other active ingredient which is suitable for animals can be administered according to the invention, but especially those active ingredients that have the taste disadvantages mentioned initially and are therefore not willingly taken orally by animals.
  • a diversity of individual active ingredients or mixtures of active ingredients may be considered, e.g. those acting against external or internal parasites or active ingredients acting against viral or bacterial diseases, active ingredients acting against behavioural disorders, active ingredients acting against dysfunction, such as hypo- or hyper-activity, and the like.
  • External parasites are understood in this case to be parasites which normally live on the animal, e.g.
  • biting insects such as mosquitos, fleas or lice, or members of the order Acarina, e.g. mites or ticks.
  • the internal parasites include all species of worm infestation and bacterial diseases, in particular those infections that infest the organs or parts of the body designated as being preferred, such as the lungs, heart, alimentary tract or extremities, or which spread through the whole organism. Substances which can be used for these diseases are e.g.
  • avermectins such as ivermectin, selamectin, doramectin, moxidectin, nemadectin, abamectin, cydectin, milbemycinoxim, and also praziquantel, pyrantel, triclabendazol, and many more.
  • Antimicrobial active ingredients are suitable, e.g.
  • Biocides that may be used according to the invention have been known to specialists for a long time. They include insecticides and acaricides with a varying mechanism of activity, e.g. chitin synthesis inhibitors, growth regulators; active ingredients which act as juvenile hormones; active ingredients which act as adulticides; and similarly, broad-band insecticides, broad-band acaricides. Nematicides may also be used according to the invention against helminthic infestations; and also the long-known anthelminthics and insect- and/or acarid-deterring substances.
  • Non-limitative examples of suitable insecticides and acaricides are: 1. Abamectin 2. AC 303 630 3. Acephat 4. Acrinathrin 5. Alanycarb 6. Aldicarb 7. alpha-Cypermethrin 8. Alphamethrin 9. Amitraz 10. Avermectin B 1 11. AZ 60541 12. Azinphos A 13. Azinphos M 14. Azinphos-methyl 15. Azocyclotin 16. Bacillus subtil. toxin 17. Bendiocarb 18. Benfuracarb 19. Bensultap 20. Cyfluthrin 21. Bifenthrin 22. BPMC 23. Brofenprox 24. Bromophos A 25. Bufencarb 26. Buprofezin 27.
  • insect-active nematodes 101. insect-active viruses 102. Iprobenfos 103. Isofenphos 104. Isoprocarb 105. Isoxathion 106. Ivermectin 107. Cyhalothrin 108. Lufenuron 109. Malathion 110. Mecarbam 111. Mesulfenphos 112. Metaldehyd 113. Methamidophos 114. Methiocarb 115. Methomyl 116. Methoprene 117. Metolcarb 118. Mevinphos 119. Milbemectin 120. Moxidectin 121. Naled 122. NC 184 123.
  • anthelminthics are named in the following, a few representatives have insecticidal and acaricidal activity in addition to the anthelminthic activity, and are partly already in the above list.
  • compositions are known from the field of human medicine and veterinary medicine, which are intended to ease or simplify the oral consumption of active ingredients.
  • a few of these compositions are suitable for human application, but cannot be used for animals, and others can also be used for animals if they are problem-free active ingredients, but they have significant failings if they are unpleasant tasting or smelling active ingredients.
  • the following patent specifications are mentioned by way of example:
  • WO 95/31963 describes an oral anthelminthic dosage form for the active ingredient flubendazole. These are lozenges based on brewer's yeast, preferably for dogs. Here, in order to increase acceptance, the active ingredient is mixed intimately with the yeast and other formulation excipients and is pressed into tablets or granulates.
  • WO 01/35925 describes animal feed products which contain medicaments (medicated food).
  • the active ingredient here is not mixed directly with the feed, but is in the form of small particles, which consist of a palatable matrix, into which the active ingredient is homogeneously dispersed. In addition, these particles are provided with a protective layer.
  • WO 01/37808 describes solid pharmaceutical dosage forms with an improved delivery of active ingredient. It consists essentially of particles provided with an outer layer. This outer layer contains the active ingredient and at least one hydrophilic surfactant. This application form should, in particular, improve the release of hydrophobic active ingredients.
  • U.S. Pat. No. 4,708,867 describes an oral dosage form for the active ingredient prednisone, which consists of gelatin capsules into which small palatable particles have been filled, the capsules being coated with the active ingredient and a protective layer consisting of a copolymer of dimethylaminoethyl and methyl methacrylate.
  • WO 01/49272 describes palatable dosage forms for animals, based on lipid.
  • the active ingredient is micro-encapsulated and homogeneously embedded in a melt consisting of fat, a surfactant, a filler and other excipients, and is finally processed into particles of the desired size.
  • WO 97/25066 describes enteric oral dosage forms for proton blockers against heartburn in human medicine.
  • the aim of this invention is to allow the active ingredient to pass unchanged to the stomach, in order to be released in the intestines.
  • This dosage form consists of particles of neutral carrier material, which are coated with the proton blocker and in this way have a protective coating which is resistant to hydrochloric acid. These coated particles are mixed with conventional pharmaceutical formulation excipients, and pressed into tablets or granulates which are suitable for oral administration.
  • the cat has been chosen as the model of a test animal, since it is particularly choosy and fastidious regarding its eating habits.
  • random testing has shown that the animal medicinal forms according to the invention, which were willingly consumed orally by cats, are also fully accepted by dogs, pigs, chickens and other domestic animals and productive livestock.
  • yeast tablets e.g. of brewer's yeast
  • B vitamins already has per se a positive influence on the health care of animals' skin and fur, and it is eaten very willingly by all cats.
  • Yeast tablets for usage by humans and animals consist of dried, pressed and lysed yeast cells. This is often so-called brewer's yeast, which occurs in large quantities in beer breweries.
  • yeast cells are mixed with an extremely bitter active ingredient, such as benazepril or another unpleasant tasting active ingredient, prior to compressing into tablets, it is observed that the test cat first of all is curious about the tablet, as would be expected, but then quickly crunches it, spits it out and turns away in disgust.
  • an extremely bitter active ingredient such as benazepril or another unpleasant tasting active ingredient
  • yeast tablet It is also of no use to coat the yeast tablet with a layer of neutral taste, since the yeast then loses its natural attraction and acceptance and is rejected by the cat from the start. It is then not even prepared to try out the placebo.
  • bitter active ingredient is firstly micro-encapsulated or embedded in particles consisting of a neutral matrix, e.g. modified starch, acceptance by individual cats is increased in the short term, but the long-term test likewise results in negative conditioning.
  • a neutral matrix e.g. modified starch
  • fine-grained carrier material preferably small balls, granulates, grains, etc.
  • this fine-grained carrier material is referred to hereinafter as particles.
  • Said particles are coated with the active ingredient, so that the active ingredient encases the particles.
  • This active ingredient casing is coated with a masking protective layer consisting of a physiologically compatible polymer matrix, which prevents direct contact of the active ingredient with the gustatory cells in the animal's mouth.
  • particles prepared in this manner are intimately mixed with a substrate which is attractive to animals and pressed into tablets or pellets of a suitable size.
  • a deciding factor to animal acceptance is, however, the size of the coated particles. It has been shown that particles with a diameter above 0.8 mm do not lead to reproducible acceptance. In contrast, reliable results are achieved with diameters of less than 0.4 mm even with very choosy cats. A lower limit for the diameter is not indicated per se, since at best full acceptance can be achieved also with such small diameters. For manufacturing and cost reasons, the lower limit is ca. 0.09 mm.
  • Suitable physiologically compatible carrier materials for producing the particles may be numerous solid formulation excipients, which are known from the production of pharmaceutical medicaments, e.g. cellulose, starch, saccharose, lactose or other different types of sugar.
  • the generally solid active ingredient is conveniently dissolved in a suitable, physiologically acceptable solvent or solvent mixture, e.g. a low-boiling alcohol, or alcohol-water mixture, for example ethanol:water (1:1), and applied to the particles by a spraying process.
  • a suitable, physiologically acceptable solvent or solvent mixture e.g. a low-boiling alcohol, or alcohol-water mixture, for example ethanol:water (1:1)
  • solvent or solvent mixture e.g. a low-boiling alcohol, or alcohol-water mixture, for example ethanol:water (1:1)
  • masked in connection with the present invention is understood screening of the active ingredient against the action of saliva and its constituents upon oral administration, and the protection of the active ingredient thereby obtained against contact with the gustatory and olfactory cells in the mouth, throat and nose of the animal.
  • a masked active ingredient has neutral behaviour, i.e. a neutral taste and smell.
  • Polymers which are suitable for masking have been known for a long time in the production of medicaments.
  • Suitable classes of polymer are e.g. those selected from the group consisting of: shellac, a polymer on a cellulose, acrylic acid or methacrylic acid, maleic acid anhydride, polyvinyl pyrrolidone and polyvinyl alcohol basis.
  • the shellac in question is often used to coat coated tablets.
  • other polymers may also be considered, e.g. polymers on a cellulose basis, which are produced for example from cellulose acetate phthalate or cellulose acetate-N,N-di-n-butylhydroxypropylether.
  • the starting materials for polymers on an acrylic acid or methacrylic acid basis may be e.g. methacrylate/methacrylic acid copolymer, 2-methyl-5-vinyl-pyridine/methacrylate/methacrylic acid copolymer, methyl methacrylate/methacrylic acid copolymer, methyl methacrylate/methacrylic acid copolymer, methyl methacrylate/maleic acid anhydride copolymer or methyl methacrylate/maleic acid anhydride copolymer.
  • Suitable starting materials for polymers on a maleic acid anhydride basis are e.g. vinyl-methylether/maleic acid anhydride copolymer or styrene/maleic acid anhydride copolymer.
  • Polymers on an acrylic acid or methacrylic acid basis are most preferred as a casing for the microspheres in the context of the present invention. It is best to use commercial products for their production. These are polymerisation products of acrylic acid and acrylic acid esters with a low content of quaternary ammonium groups. Owing to their easy handling, commercial products, such as Eudragit® E, L or S from the company Röhm, Darmstadt, Germany, are especially suitable.
  • Eudragit® E is a cationic polymer of dimethylaminoethyl methacrylate and a neutral methacrylic acid ester.
  • Eudragit® L and S are anionic copolymers of methacrylic acid and methacrylic acid methylester.
  • Polyvinyl pyrrolidone is suitable e.g. as a starting material for polymers on a polyvinyl pyrrolidone basis.
  • Polyvinyl alcohol itself is suitable as a starting material for polymers on a polyvinyl alcohol basis.
  • Eudragit® E 100 is a pH-dependent cationic polymer, which dissolves in the gastric juices at an acidic pH value of up to pH 5.0.
  • Eudragit® EPO has the advantage that the process can be carried out in an aqueous medium and without organic solvents.
  • Masking is effected in such a way that the shellac or the polymer is dissolved in an organic solvent optionally adding water, and this solution is sprayed by a spraying process onto the particles which are already encased by the active ingredient.
  • the solvent or solvent mixture is subsequently removed under careful conditions, e.g. in a vacuum.
  • Suitable organic solvents for dissolution of the polymer are, for example, solvents which are relatively readily volatile.
  • the following table shows a few such solvents by way of example.
  • the pure solvents or mixtures of such solvents may be used, e.g. an acetone-ethanol mixture (1:1). Very good results are obtained by adding a little water, i.e. about 1 to 5 parts by volume of water to 10 to 50 parts by volume of organic solvent. Acetone-water mixtures (ca. 1:30) are preferred.
  • aqueous suspensions and solutions may be used.
  • coating is carried out with EUDRAGIT EPO from an aqueous suspension. This has the advantage that in the commercial preparation of a product, no measures to protect against explosion need be taken.
  • an aqueous process is to be recommended for environmental protection reasons, since no organic solvents reach the environment or have to be extracted in an expensive procedure.
  • the masked particles are mixed with a feed material of high acceptance, e.g. the yeasts mentioned above, and are pressed into suitable administrable units, such as tablets or feed pellets.
  • a feed material of high acceptance e.g. the yeasts mentioned above
  • suitable administrable units such as tablets or feed pellets.
  • the procedure is carried out in detail as follows:
  • the active ingredient is applied advantageously in a fluidised bed process to the neutral-tasting, physiologically compatible, solid, fine-grained particles and subsequently masked.
  • a layer of said particles is added to a reaction container having a sieve-like base.
  • a gas preferably air, is passed through this layer against the force of gravity.
  • the flow speed is chosen such that the layer is whirled up until the individual particles no longer touch and can be held in the suspension, so that a stationary fluidised bed is obtained. In this way, the whole surface of each individual particle is accessible.
  • a precisely measured solution, emulsion or suspension of the active ingredient is sprayed, in the opposite direction to a stream of gas, through a spray nozzle which is usually approximately in the centre of the stationary fluidised bed.
  • this was carried out by the so-called Wurster process (bottom spray process), since the best results in respect of yield and process time were achieved in this way.
  • Wurster process bottom spray process
  • any type of fluidised bed process is suitable.
  • the particles are moistened with the solution, emulsion or suspension of active ingredient.
  • the supply of active ingredient is stopped and the particles continue to whirl and are dried by the streaming gas. Warmed gas may be used to accelerate the drying procedure. The degree of warming depends on the heat stability of the active ingredient used.
  • the outcome of the drying procedure is that the active ingredient crystallises on the surface of the particles.
  • a solution of the physiologically compatible polymer matrix is sprayed through the spray nozzle, with the result that the particles receive a second coating which thus masks the active ingredient. Drying of the masking layer takes place in the same way as for the active ingredient, in the stream of gas.
  • the end product obtained is the desired, double-coated, free-flowing particles, which do not have a tendency to agglomerate and are mixed according to the invention with an appropriate substrate and in a final step are pressed into tablets or pellets.
  • the double coating guarantees excellent palatability, meaning the all the senses perceived by the sensory cells for taste and smell in the mouth and nose areas.
  • the size of the coated particles have been shown to be essential to the invention and crucial to acceptance of the finished product. As already mentioned, surprisingly, they may not exceed a certain minimum size. If relatively small, compact carrier particles of 0.09 to 0.8 mm, preferably 0.15 to 0.4 mm diameter are produced, coated with the active ingredient, then encased with a layer which masks the taste and if these encased particles are then mixed with yeast or another suitable feed material, and the mixture is pressed into tablets or feed pellets, it is observed that these yeast tablets or feed pellets are eaten just as willingly by cats as tablets or pellets without active ingredient, i.e. placebos. Clearly, the cat no longer sniffs out the active ingredient.
  • the coated particles must however be of exactly the correct size and have the said double coating, so that only very few of them, or practically none at all, are destroyed when the yeast tablet is crunched and practically no active ingredient is released.
  • the size of the coated particles increases, the acceptance by cats decreases. Particles with a diameter of 0.15 to 0.4 mm have proved to be ideal. The larger the particles, the more likely it is that some of them will be bitten and more bitter active ingredient will be released. The particles themselves cannot be made too small, as the lower limit is determined by the available manufacturing technology and by the technical efforts that one is prepared to make.
  • Double-coated particles are also significantly better accepted than particles of the same size, in which the active ingredient is homogeneously incorporated, and also significantly better than particles of the same size, which are encased with the active ingredient, but in which a further protective layer is missing.
  • attractive, physiologically compatible substrate in connection with the present invention is understood for example the yeast mentioned initially, but also organic material of vegetable or animal origin, which is usually used as a dry feed for the species of animal to be treated, and is either already attractive to the animal to be treated because of its origin, or is made attractive by adding artificial or natural aromatic substances or taste improvers.
  • Suitable aromatic substances or taste improvers are natural or synthetic meat, fish and cheese aromas.
  • Natural or artificial vanilla essence is also eminently suitable. A whole range of such substances is available to the nutrition specialist. These substances are commercial and are used on a large scale in the animal feed industry.
  • particles with an average diameter of 0.09 to 0.8 mm of a neutral-tasting, physiologically compatible, solid carrier material are coated with an active ingredient or active ingredient for veterinary medicine, so that the active ingredient encases the particles;
  • this active ingredient casing is coated with a masking protective layer consisting of a physiologically compatible polymer matrix, which prevents direct contact of the active ingredient with the gustatory and olfactory cells and the saliva of the animal.
  • Ethanol and water are mixed in a vessel until a homogeneous solution is formed.
  • Benazepril hydrochloride is added to the solvent mixture and stirred for 5 minutes until a clear solution is obtained.
  • Polyvinyl polypyrrolidone is subsequently added and stirred for a further 10 minutes until a clear solution is obtained.
  • Celphere® is a commercial product of the company ASAHI, Japan. It consists of round microcrystalline cellulose particles or pellets.
  • Celphere pellets are placed in fluidised bed equipment and heated to a product temperature of 35° C.
  • the required amount of active ingredient solution here: benazepril solution, see point 1 (23.9 kg) is sprayed onto the pellets. After spraying, the pellets are dried at an admission temperature of 55° C. until attaining residual moisture of ⁇ 4%. The pellets are subsequently sieved through a 0.5 mm sieve. The yield of benazepril pellets is >95%.
  • Outstanding pellets are obtained by coating CP-102, CP-203 and CP-305 or substrate particles, which have the same average diameter.
  • Eudragit® is a commercial product of the company Röhm, Germany. It consists of butyl methacrylate-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1). Syloid 244 FP® is a precipitated silicon dioxide, which is obtainable from the company Grace GmbH, in Worms, Germany. Aerosil 200® is colloidal silicon dioxide from the company Degussa in Frankfurt/Main, Germany.
  • the coating suspension is sprayed onto the active ingredient pellets. After spraying, the pellets are dried at an admission temperature of 55° C. until attaining residual moisture of ⁇ 4%. The pellets are subsequently sifted through a 0.5 mm sieve. The yield of benazepril pellets is >90%. In order to avoid adhesion of the taste-masked pellets during storage, 0.26 kg of Aerosil200® are sifted onto the pellets through a 1.4 mm sieve. The dry mixture is mixed for 10 minutes in a drum mixer.
  • yeast tablets with 22.5 kg of taste-masked benazepril pellets
  • Avicel PH 102® is a microcrystalline cellulose of the company FMC Corporation in Philadelphia, USA.
  • the benazepril pellets already prepared (5% active ingredient), as well as Avicel PH 102®, yeast powder, polyvinyl polypyrrolidone, Aerosil® and vanilla are sifted through a 0.75 mm sieve into a drum and mixed for 30 minutes at a speed of 15 rpm. Subsequently, the hydrogenated castor oil is added to the mixture, the whole mixture is sifted through a 0.75 mm sieve and mixed for 15 minutes. This powder mixture is then pressed into tablets.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fodder In General (AREA)
US10/506,937 2002-03-11 2003-03-10 Tasted masked veterinary solid compositions Abandoned US20050169971A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/630,422 US8617587B2 (en) 2002-03-11 2009-12-03 Tasted masked veterinary solid compositions

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP02005511.7 2002-03-11
EP02005511 2002-03-11
PCT/EP2003/002446 WO2003075895A1 (en) 2002-03-11 2003-03-10 Tasted masked veterinary solid compositions

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/630,422 Continuation US8617587B2 (en) 2002-03-11 2009-12-03 Tasted masked veterinary solid compositions

Publications (1)

Publication Number Publication Date
US20050169971A1 true US20050169971A1 (en) 2005-08-04

Family

ID=27798784

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/506,937 Abandoned US20050169971A1 (en) 2002-03-11 2003-03-10 Tasted masked veterinary solid compositions
US12/630,422 Active 2025-08-05 US8617587B2 (en) 2002-03-11 2009-12-03 Tasted masked veterinary solid compositions

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/630,422 Active 2025-08-05 US8617587B2 (en) 2002-03-11 2009-12-03 Tasted masked veterinary solid compositions

Country Status (22)

Country Link
US (2) US20050169971A1 (es)
EP (2) EP1803448A3 (es)
JP (1) JP4663985B2 (es)
KR (1) KR20040101302A (es)
CN (1) CN1652754B (es)
AR (1) AR038899A1 (es)
AT (1) ATE390129T1 (es)
AU (1) AU2003218722B2 (es)
BR (1) BR0308378B1 (es)
CA (1) CA2478811C (es)
CO (1) CO5400144A1 (es)
DE (1) DE60319969T2 (es)
DK (1) DK1490037T3 (es)
ES (1) ES2301784T3 (es)
MX (1) MXPA04008845A (es)
NZ (1) NZ535167A (es)
PT (1) PT1490037E (es)
RU (1) RU2318498C2 (es)
SI (1) SI1490037T1 (es)
TW (1) TWI309557B (es)
WO (1) WO2003075895A1 (es)
ZA (1) ZA200407010B (es)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050169941A1 (en) * 2004-01-29 2005-08-04 Andrew Lees Use of amino-oxy functional groups in the preparation of protein-polysaccharide conjugate vaccines
CN109673848A (zh) * 2018-12-29 2019-04-26 广州智特奇生物科技股份有限公司 一种肠溶包被材料、肠道缓释单宁酸及其制备方法

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
JP2008502727A (ja) * 2004-06-10 2008-01-31 グラット エアー テクニクス インコーポレーテッド 徐放性基材医薬品製剤
EP1753405A4 (en) * 2004-06-10 2008-09-17 Glatt Air Tech Inc SLOW RELEASE PHARMACEUTICAL PREPARATION
EP1920785A1 (en) 2006-11-07 2008-05-14 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising a complex of pimobendan and cyclodextrin
EP1935405A1 (en) * 2006-12-22 2008-06-25 LEK Pharmaceuticals D.D. Orally disintegrating tablets
EP2741736B1 (en) 2011-08-12 2017-11-22 Boehringer Ingelheim Vetmedica GmbH Taste masked pharmaceutical composition
WO2014033230A1 (fr) 2012-08-31 2014-03-06 Friulchem Spa Compositions pour administration orale aux animaux, leurs procedes d'obtention et leurs utilisations
BR112014005909B1 (pt) 2011-09-15 2021-05-18 Friulchem Spa composições para administração oral a animais, métodos de produção das mesmas e usos das mesmas
CZ308210B6 (cs) * 2011-11-02 2020-03-04 Veterinární A Farmaceutická Univerzita Brno Farmaceutická kompozice ve formě pelet majících velikost částic v rozmezí od 0,1 do 10 mm pro perorální podání vodním živočichům a způsob její výroby
RS54475B1 (en) 2011-12-21 2016-06-30 Novartis Tiergesundheit Ag NEW COMBINATION
EP2825159B1 (en) 2012-03-15 2022-06-22 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
CL2013001262A1 (es) * 2012-05-08 2013-09-27 Novartis Ag Uso de lufenuron para control de los piojos marinos en una poblacion de peces; alimento para peces que comprende lufenuron.
FR2991179B1 (fr) 2012-06-01 2016-11-11 Ceva Sante Animale Compositions veterinaires orales appetentes
WO2014053555A1 (en) 2012-10-04 2014-04-10 Novartis Ag Veterinary drug system
FR3002736B1 (fr) 2013-03-04 2015-06-26 Virbac Composition orale nutritionnelle et medicamenteuse a usage veterinaire
FR3002735B1 (fr) 2013-03-04 2015-07-03 Virbac Composition orale nutritionnelle et medicamenteuse a usage veterinaire
MX2016000727A (es) 2013-07-19 2016-04-13 Boehringer Ingelheim Vetmed Composicion farmaceutica acuosa liquida que contiene derivados de ciclodextrina eterificada con conservante.
HUE056143T2 (hu) 2013-12-04 2024-01-28 Boehringer Ingelheim Vetmedica Gmbh Pimobendán javított gyógyászati készítményei
KR101687973B1 (ko) * 2015-12-08 2016-12-21 주식회사 씨티씨바이오 마이크로필름 코팅을 이용한 동물 사료용 프리믹스 제조방법
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
CN105963270B (zh) * 2016-06-30 2019-01-15 齐鲁动物保健品有限公司 一种盐酸贝那普利软咀嚼片及其制备方法
JP7534139B2 (ja) 2020-07-03 2024-08-14 獣医医療開発株式会社 動物用医薬製剤
CN112220769A (zh) * 2020-08-13 2021-01-15 浙江海正动物保健品有限公司 一种米尔贝肟吡喹酮风味片及其制备方法
WO2022051478A1 (en) 2020-09-04 2022-03-10 Elanco Us Inc. Palatable formulations
DK4037666T3 (da) 2020-12-08 2024-06-24 Ruminant Biotech Corp Ltd Forbedring af anordninger og fremgangsmåder til indgivelse af substanser til dyr
CN113768038A (zh) * 2021-09-14 2021-12-10 江苏省协同医药生物工程有限责任公司 一种精准定量实验动物功能性饲料及制备方法与设备
JP7109827B1 (ja) * 2021-11-16 2022-08-01 株式会社ハニック・ホワイトラボ 抗ウイルス剤

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3231466A (en) * 1962-10-26 1966-01-25 Walter H Hoffman Composition and method for treating animals and poultry
US3824233A (en) * 1972-07-06 1974-07-16 Lilly Co Eli Anthelmintic phenylhydrazones
US3937825A (en) * 1973-09-21 1976-02-10 American Cyanamid Company Anthelmintic composition and method of use
US4708867A (en) * 1983-12-19 1987-11-24 Key Pharmaceuticals, Inc. Minipellets
US6149943A (en) * 1998-09-04 2000-11-21 Mcneil-Ppc, Inc. Microcrystalline cellulose particles having active core
US20030190343A1 (en) * 2002-03-05 2003-10-09 Pfizer Inc. Palatable pharmaceutical compositions for companion animals

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4800087A (en) * 1986-11-24 1989-01-24 Mehta Atul M Taste-masked pharmaceutical compositions
JPS63188621A (ja) 1987-01-30 1988-08-04 Taisho Pharmaceut Co Ltd 矯味経口製剤
RU2101010C1 (ru) * 1990-04-11 1998-01-10 Дзе Апджон Компани Вкусовая маскировка ибупрофена полимерным покрытием
CA2137265C (en) * 1992-06-04 2003-10-28 Sanjay Bhardwaj Palatable pharmaceutical compositions
SE9301489D0 (sv) * 1993-04-30 1993-04-30 Ab Astra Veterinary composition
DE69523912T2 (de) * 1994-05-20 2002-06-27 Janssen Pharmaceutica N.V., Beerse Flubendazole-kautabletten für haustiere
SE9402422D0 (sv) 1994-07-08 1994-07-08 Astra Ab New beads for controlled release and a pharmaceutical preparation containing the same
SE9600071D0 (sv) * 1996-01-08 1996-01-08 Astra Ab New oral formulation of two active ingredients I
DK0935417T3 (da) 1996-10-16 2009-08-10 Napo Pharmaceuticals Inc Enteroformuleringer af proanthocyanidin-polymer-sammensætninger mod diarré
DE69942777D1 (de) * 1998-07-28 2010-10-28 Takeda Pharmaceutical Leicht zerfallende feste Zubereitung
US6432448B1 (en) * 1999-02-08 2002-08-13 Fmc Corporation Edible coating composition
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
GB2356346A (en) * 1999-11-19 2001-05-23 Mars Uk Ltd Food product for oral delivery of a pharmaceutical agent to a non-human animal comprising encapsulated particles of said agent distributed within the product
US6541025B1 (en) * 1999-12-30 2003-04-01 Shear/Kershman Laboratories, Inc. Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals
GB0008332D0 (en) * 2000-04-04 2000-05-24 Pfizer Ltd Treament
IL157367A0 (en) 2001-03-09 2004-02-19 Nestle Sa Composition improving age-related physiological deficits and increasing longevity

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3231466A (en) * 1962-10-26 1966-01-25 Walter H Hoffman Composition and method for treating animals and poultry
US3824233A (en) * 1972-07-06 1974-07-16 Lilly Co Eli Anthelmintic phenylhydrazones
US3937825A (en) * 1973-09-21 1976-02-10 American Cyanamid Company Anthelmintic composition and method of use
US4708867A (en) * 1983-12-19 1987-11-24 Key Pharmaceuticals, Inc. Minipellets
US6149943A (en) * 1998-09-04 2000-11-21 Mcneil-Ppc, Inc. Microcrystalline cellulose particles having active core
US20030190343A1 (en) * 2002-03-05 2003-10-09 Pfizer Inc. Palatable pharmaceutical compositions for companion animals

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050169941A1 (en) * 2004-01-29 2005-08-04 Andrew Lees Use of amino-oxy functional groups in the preparation of protein-polysaccharide conjugate vaccines
CN109673848A (zh) * 2018-12-29 2019-04-26 广州智特奇生物科技股份有限公司 一种肠溶包被材料、肠道缓释单宁酸及其制备方法

Also Published As

Publication number Publication date
JP4663985B2 (ja) 2011-04-06
ATE390129T1 (de) 2008-04-15
EP1803448A3 (en) 2007-09-12
EP1490037B1 (en) 2008-03-26
EP1803448A2 (en) 2007-07-04
ES2301784T3 (es) 2008-07-01
JP2005526756A (ja) 2005-09-08
AU2003218722A1 (en) 2003-09-22
PT1490037E (pt) 2008-05-05
SI1490037T1 (sl) 2008-08-31
EP1490037A1 (en) 2004-12-29
RU2318498C2 (ru) 2008-03-10
DE60319969T2 (de) 2009-04-30
TW200304774A (en) 2003-10-16
CO5400144A1 (es) 2004-05-31
CA2478811C (en) 2010-12-14
BR0308378A (pt) 2005-01-11
DE60319969D1 (de) 2008-05-08
MXPA04008845A (es) 2004-11-26
ZA200407010B (en) 2006-06-28
TWI309557B (en) 2009-05-11
NZ535167A (en) 2006-08-31
WO2003075895A1 (en) 2003-09-18
DK1490037T3 (da) 2008-07-21
CN1652754B (zh) 2013-05-22
BR0308378B1 (pt) 2013-12-24
US20100074952A1 (en) 2010-03-25
US8617587B2 (en) 2013-12-31
KR20040101302A (ko) 2004-12-02
CN1652754A (zh) 2005-08-10
CA2478811A1 (en) 2003-09-18
RU2004130433A (ru) 2005-08-10
AR038899A1 (es) 2005-02-02
AU2003218722B2 (en) 2006-08-31

Similar Documents

Publication Publication Date Title
US8617587B2 (en) Tasted masked veterinary solid compositions
US4874613A (en) Taste concealing pharmaceutical dosage unit
US20110129539A1 (en) Oral pharmaceutical formulation in the form of an aqueous suspension of microcapsules for modified release of amoxicillin
AU2002234588B2 (en) Organic compounds
AU6699100A (en) Oral pharmaceutical forms of administration with a delayed action
US7063856B2 (en) Pharmaceutical composition containing aminocetonitrile compounds and the use thereof for the preparation of a pharmaceutical composition for the treatment of endoparasitic pests in animals
JP2005526756A5 (es)
WO2000069420A1 (en) Pulse-delivery oral compositions
TWI236341B (en) Aminoacetonitrile compounds for use in the control of endoparasites
AU2002345043A1 (en) Amenoacetonitrile compounds for controlling endoparasites
EP1759692A2 (en) Taste-masked solid veterinary compositions
KR20010033206A (ko) 약학 조성물
CN101389633B (zh) 有机化合物
JP7534139B2 (ja) 動物用医薬製剤
WO2001095909A1 (en) New use as antihelmintics of albofungin and analogs
AU2013204087C1 (en) Pharmaceutical composition comprising pimobendan

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: NOVARTIS TIERGESUNDHEIT AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:034926/0273

Effective date: 20150101