WO2014053555A1 - Veterinary drug system - Google Patents
Veterinary drug system Download PDFInfo
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- WO2014053555A1 WO2014053555A1 PCT/EP2013/070561 EP2013070561W WO2014053555A1 WO 2014053555 A1 WO2014053555 A1 WO 2014053555A1 EP 2013070561 W EP2013070561 W EP 2013070561W WO 2014053555 A1 WO2014053555 A1 WO 2014053555A1
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- Prior art keywords
- veterinary drug
- administration system
- drug administration
- container
- veterinary
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- 0 *C1C(*)=N*C1(C(F)(F)F)N Chemical compound *C1C(*)=N*C1(C(F)(F)F)N 0.000 description 4
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- 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
Definitions
- the present invention relates to a new veterinary drug administration system imparting an improved palatability to a given drug which is especially useful for administration to non- human animals, in particular cats.
- Oral administration of a drug to a non-human animal can be a real challenge depending on the nature of the drug and animal.
- cats are known to be delicate with respect to any kind of oral medication, and administration thereof often requires special measures.
- many veterinary drugs have an unpleasant taste and therefore have to be made attractive, for example, by adding suitable flavors.
- Various solutions to increase the palatability of veterinary drugs have been proposed, such as the addition of suitable aromas or flavors, coating drugs with one or more protective layers, creation of a specific drug consistency like a soft chewable or a more crunchy formulation.
- said known solutions often don't provide a satisfactory palatability, especially in cases of drugs which have to be taken on a regular basis, such as endoparasiticides, ectoparasiticides or drugs for treating chronic diseases.
- a further approach would be to include the drug into a suitable animal food which is, however, problematic from a regulatory perspective.
- the food must have a constant, reproducible quality.
- the drug must be stable within the animal food, and the veterinary drug product as a whole has to have a sufficient shelf life, for example, of at least one year or more.
- solid products such as coated drug pellets incorporated in yeast or a drug incorporated in a chewable formulation with high meat contents, are known, for example, from WO2003/075895 or WO2005/013714
- no products of a veterinary drug in a liquid animal food have been contemplated yet, most likely for stability reasons.
- a liquid consistency would be very beneficial , as animals such as cats often prefer to lick liquids out of a bowl instead of digesting solids.
- a veterinary drug product which is based on a liquid animal food and still has a shelf life sufficient, for example, for a prescription drug.
- the present invention therefore concerns a veterinary drug administration system comprising
- a first container comprising a liquid animal food that is based on meat, water and optionally further excipients, wherein the water contents is ⁇ 80% (w/w), based on the entire animal food, and
- a second container comprising one or more veterinary drugs in solid form
- the term meat comprises all kinds of animal meat, for example, from domestic animals and productive livestock, e.g. pigs, horses, cattle, sheep, goats and poultry including chicken, duck, goose and turkey, or from fish, or mixtures thereof, as well as artificial meat flavors which are well-known from the food industry.
- domestic animals and productive livestock e.g. pigs, horses, cattle, sheep, goats and poultry including chicken, duck, goose and turkey, or from fish, or mixtures thereof, as well as artificial meat flavors which are well-known from the food industry.
- the liquid animal food is based on animal meat, in particular on animal meat, for example, from pig, cattle, chicken or fish.
- animal meat may be based on human food- grade meat or on animal by-products such as slaughterhouse waste containing all kinds of animal tissue, such as skin, sinews, bowels and meat.
- the meat preferably after having been chopped and/or homogenized, is mixed with water and optionally further excipients, and the mixture is then filled in a plurality of first containers which are closed or sealed afterwards.
- the mixture within the first containers is sterilized, preferably by application of heat and/or pressure.
- the first containers are autoclaved at a temperature of about 80 to 140°C for about 5 to 30 minutes, in particular 10-25 minutes.
- the liquid animal food according to the present invention contains ⁇ 80% (w/w) and preferably ⁇ 85% (w/w) water, based on the entire formulation.
- Overall meat contents may vary, for example, between 1 and 20% (w/w), preferably 1 .5 and 15% (w/w), more preferably 2 to 10% (w/w), and in particular 4 and 8 % (w/w), based on the entire formulation.
- Main components of said meat are proteins and fat, besides minerals and vitamins.
- liquid animal food or gravy may be, for example: (i) thickeners, for example carrageen, xanthan gum, locust bean gum, guar gum, cornstarch, oat meal flour, microcrystalline cellulose, hydroxyethyl cellulose, carboxymethyl cellulose;
- thickeners for example carrageen, xanthan gum, locust bean gum, guar gum, cornstarch, oat meal flour, microcrystalline cellulose, hydroxyethyl cellulose, carboxymethyl cellulose;
- antioxidants for example propyl 3,4,5-trihydroxybenzoate, BHA (2-t-butyl-4- methoxyphenol), BHT (2,6-di-t-butyl-4-methylphenol), tocopherols (alpha, beta, or delta- tocopherol, tocopherol esters, alpha-tocopherol acetate), alkyl gallates such as propyl gallate, tert. butyl hydroquinone, butylated hydroxyanisole or butylated hydroxytoluene.
- the liquid animal food is devoid of an antioxidant.
- preservatives for example sorbic acid and its salts, benzoic acid and its salts, ascorbic acid and its salts, for example sodium ascorbate, citric acid and its salts, or EDTA salts, for example disodium EDTA.
- the liquid animal food is devoid of a preservative.
- additional aromas or flavors for example sweeteners such as sugar, fructose or xylose; amino acids such as glycine, lysine, methionine or cystein.
- (v) colors such as iron oxide or gravy browning.
- Preferred excipients of the liquid animal food are one or more thickeners, mainly for consistency adjustment.
- the further excipients most preferably comprise one or more thickeners and one or more additional aromas or flavors.
- excipients if contained in the liquid animal food, are present in an amount of, for example, from 0.1 to 19% (w/w), preferably from 0.5 to 10% (w/w), more preferably from 1 to 7% (w/w), and in particular from 1 to 5% (w/w), based on the entire formulation.
- Preferred formulations of the liquid animal food comprise:
- the energy contents of a liquid animal food according to the invention is in general low, for example, ⁇ 1 kcal/g and preferably ⁇ 0.5 kcal/g. Therefore, the liquid animal food according to the invention is in general not a complete meal but, for example, a snack which may be provided to the animal as a treat. Moreover, the animal food according to the invention may be applied as a complementary food additive which is provided to the animal before, concurrently with, or after its main meal.
- the liquid animal food within the first container has preferably a low viscosity, for example ⁇ 1000 mPa-s, advantageously below about 500 mPa-s, for example from about 0.1 to 250 mPa-s, and preferably from 0.5 to 100 mPa-s, in order to facilitate a smooth mixing with the veterinary drug contained in the second container.
- the overall volume of liquid animal food contained in the first container may vary within wide limits but is, for example, from 1 to 100 ml, preferably from 2.5 to 50 ml, more preferably from 2.5 to 25 ml, and in particular from 4 to 10 ml. A particularly preferred volume is about 5 ml.
- the veterinary drug or mixture of veterinary drugs contained in the second container is in general present in form of a powder, granules or pellets, preferably in form of granules or pellets.
- the particle size is in general not critical, as long as it does not prevent the food uptake of the medicated food after mixing the first and second container.
- a particle size of ⁇ 1 .6 mm for example from 0.01 to 1 .6 mm, and preferably ⁇ 1 .0 mm, especially from 0.1 to 1 .0 mm, has proven as valuable.
- Granulation of the drugs is performed in a manner known per se, for example by granulation, which may be performed dry or more commonly wet, by extrusion or spheronization. Suitable processes are known to the person skilled in the art.
- (meth)acrylates and a cationic (meth)acrylate or with a lipid such as glycerol distearate, or coating inert carrier particles first with a drug layer and then with a layer of protective polymer or lipid, for example as described above, are known to the person skilled in the art.
- veterinary drug(s) is (are) mixed with the liquid animal food only shortly before use; therefore, virtually any solid veterinary drug may be employed.
- veterinary drug(s) is (are) mixed with the liquid animal food only shortly before use; therefore, virtually any solid veterinary drug may be employed.
- the following classes of compounds may be mentioned:
- Endoparasiticides for example abamectin, doramectin, eprinomectin, ivermectin, milbemectin, selamectin, milbemycin, milbemycin oxime, moxidectin, emamectin, derquantel, monepantel, praziquantel, albendazole, clorsulon, cydectin, diethylcarbamazine, febantel, fenbendazole, haloxon, levamisole, mebendazole, morantel, oxyclozanide, oxibendazole, oxfendazole, oxamniquine, pyrantel, thiabendazole, tetramisole, trichlorfon, emodepside or mixtures or derivatives thereof.
- Endoparasiticides for example abamectin, doramectin,
- a preferred group of endoparasiticides comprises abamectin, doramectin, ivermectin, milbemycin oxime, moxidectin, emodepside, derquantel, monepantel, praziquantel or mixtures thereof.
- endoparasiticide according to the present invention is a combination of milbemycin oxime and praziquantel or emodepside and praziquantel.
- Ectoparasiticides for example a neonicotinoid, in particular imidacloprid, thiamethoxam, nitenpyram, indoxacarb or dinotefuran; an insect growth regulator, for example cyromazine, methoprene, kinoprene or hydroprene; a benzoylurea, for example diflubenzuron, lufenuron, noviflumuron, hexaflumuron, triflumuron, teflubenzuron; a phenylpyrazole, in particular fipronil or pyriprole; a pyrethroid, for example permetrin allethrin, resmethrin; a carbamate, in particular fenoxycarb; a spinosyn, in particular spinosad; or an arylisoxazoline as mentioned below, or mixtures or derivatives thereof.
- an insect growth regulator for example cyromazin
- a suitable arylisoxazoline compound is, for example, of formula
- R', R" and R'" are each independently hydrogen, halogen, cyano, CrC 2 -alkyl, halo-CrC 2 -alkyl, CrC 2 -alkoxy or CrC 2 -haloalkoxy, subject to the proviso that at least one of R', R" and R'" is not hydrogen;
- *-Y- ** is a radical of formula
- Ai is O, S or NRi', A 2 is CH 2 , O or S, and A 3 is O, S or NR-i';
- Ri' independently is as defined as Ri below;
- R 2 is H , methyl, halogen, hydroxy or methylsulfonyl
- R 5 is H, CrC 2 -alkyl, Ci-C 2 -haloalkyl, halogen, nitro or cyano and Q is
- a 5- or 6-membered heteroaromatic ring comprising 1 to 3 same or different heteroatoms selected from the group consisting of O, S and N which is further unsubstituted or substituted; or is
- R- ⁇ is H, CrC 4 -alkyl, C 2 -C 4 -alkylcarbonyl or C 2 -C 4 - alkoxycarbonyl and T is CrC 6 -alkyl which is unsubstituted or substituted by C 3 -C 6 -cycloalkyl, halogen, cyano, nitro, amino, hydroxy, CrC 6 -alkoxy, CrC 6 -haloalkoxy, CrC 6 -alkylthio, d- C 6 -haloalkylthio, CrC 6 -alkylsulfinyl, CrC 6 -haloalkylsulfinyl, CrC 6 -alkylsulfonyl, CrC 6 - haloalkylsulfonyl, carboxy, carbamoyl, Ci-C 6 -alkylcarbonylamino,
- R 5 is H, Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, halogen, nitro or cyano, and Q is as defined above;
- n 1 or 2 and Q' is a group -N(R 4 )-C(0)-T 2 , wherein T 2 independently has the meaning of T above and R 4 is as defined above; or
- milbemycin oxime and spinosad milbemycin oxime and spinosad
- milbemycin oxime, praziquantel and lufenuron milbemycin oxime, praziquantel and spinosad
- ivermectin and spinosad an arylisoxazoline as mentioned above and an endoparasiticide as mentioned above, for example afoxolaner or fluralaner each with milbemycin oxime or moxidectin; and the like.
- cardiovascular drugs such as benazepril, amlodipine or pimobendan
- pain relief, anti-inflammatory or arthritis agents for example deracoxib, meloxicam or robenacoxib
- skin disease agents for example ciclosporin A or oclacitinib
- agents for treating metabolic disorders, oncology drugs and the like for example cardiovascular drugs, such as benazepril, amlodipine or pimobendan; pain relief, anti-inflammatory or arthritis agents, for example deracoxib, meloxicam or robenacoxib
- skin disease agents for example ciclosporin A or oclacitinib
- agents for treating metabolic disorders, oncology drugs and the like for example cardiovascular drugs, such as benazepril, amlodipine or pimobendan
- pain relief, anti-inflammatory or arthritis agents for example deracoxib, meloxicam or robenacoxib
- skin disease agents for example ciclosporin A or oclacitinib
- a suitable first container for the liquid animal food may be, for example, a pouch or stick pack, a blister, a bottle, a tube or a syringe.
- a suitable second container for the veterinary drug(s) likewise may be a pouch or stick pack, blister, bottle, tube or syringe.
- Combination of the contents of the first and second container may take place in a manner known per se, for example by opening a first and second container each, filling their contents in a suitable bin such as a bowl, and, if necessary, admixing both.
- both the first and second container are in form of a stick pack or pouch, which are opened prior to use, and the contents thereof are each filled in a suitable bin such as a bowl and, if necessary, admixed.
- the first and second containers are capable of being assembled and are closed prior to assembly.
- the first container comprises a first reservoir for holding the liquid animal food
- the second container comprises a second reservoir for holding the one or more veterinary drugs.
- the first and second reservoirs of the first and second containers are set in communication with one another to allow mixing of the liquid contained in the first reservoir of the first container with the veterinary drug(s) contained in the second reservoir of the second container to form a liquid-substance mixture.
- the liquid-substance mixture may then be provided to the animal, and due to the liquid animal food is attractive to the animal, so that the liquid-substance mixture is easily accepted by the animal.
- the liquid animal food may be stored in a bottle which is provided with a cap comprising a separate capsule in the cap that contains the veterinary drug(s) in powder, granule or pellet form.
- the cap Upon use, the cap is screwed downwards further onto the bottle thereby rupturing the capsule and mixes with the liquid animal food contained in the bottle. Thereafter the animal food-drug mixture is ready for use.
- a kit of parts comprising one first container comprising one portion of liquid animal food, where the above given meanings and preferences apply, and one second container comprising a single dosage unit of one or more veterinary drugs, wherein the above given meanings and preferences apply.
- kit of parts comprising
- the plurality of first containers may contain liquid animal food of 2 or more different flavors, for example 2 to 5, or in particular 2 or 3 different flavors.
- Examples of typical flavors are chicken, pork, beef or fish flavor.
- the palatability of a drug may be further enhanced by providing different choices of taste to the animal in need of medication.
- a veterinary drug administration system according to this embodiment is especially suited for drugs which have to be administered to the animal on a regular basis, for example on a weekly or daily basis.
- mixing of the contents of the first and second container and offering the mixture to the animal takes place in a standardized container in order to provide control of the uptake.
- Said container for mixing and offering may be the above first or second container or a separate third container.
- a suitable container for mixing and offering the mixture to the animal is, for example a standardized bowl; in case of a cat product it is preferred to employ a small bowl being adapted to receive volumns of, for example, from 0.5 to 25 ml and preferably from 1 to 10 ml.
- Control of the uptake by the animal may be performed, for example, by visual inspection of the container after uptake, or by measuring the weight difference of the container before and after uptake.
- the veterinary drug administration systems of the present invention are in principle useful for all kinds of non-human animals. Preference is given to companion animals, for example horses, donkeys, mules, dogs, cats or birds, preferably dogs and cats, in particular cats.
- a unique system of administering veterinary drugs of all kinds to an animal is provided by means of a standardized liquid animal food with a high shelf life of, for example 1 year or more, to which is added a single dose unit of desired veterinary drug(s) in solid form only shortly before use.
- the uptake by the animal may be controlled and adjusted, if necessary.
- the palatability, meaning the voluntary acceptance or ingestion by the animal, of the liquid animal food alone is in general above 70%, preferably ⁇ 90%, even in fed condition.
- a suitable palatability test on cats may be performed as follows.
- a plurality of cats, males and females, are treated with a single dose of liquid medicated food according to the present invention; the medicated food is presented once to each cat alone in a bowl.
- Palatability scoring is established from the spontaneous complete test item consumption ratio (total consumed versus total offered).
- Example 1 illustrates the present invention.
- A1 Veterinary drug: 16 mg Milbemycin Oxime granules mixed with 40 mg Praziquantel granules that are coated with Kollicoat Smartseal ® 30D Coating (copolymer of one or more (meth)acrylates and a cationic (meth)acrylate); Liquid animal food: 5 ml of chicken chunk liquid gravy, water contents >85%.
- A2 Veterinary drug: 16 mg Milbemycin Oxime granules mixed with 40 mg of inert pellets coated with a first layer containing Praziquantel and with a second protective layer of Eudragit ® EPO (copolymer of one or more (meth)acrylates and a cationic (meth)acrylate); Liquid animal food: 5 ml ofchicken chunk liquid gravy, water contents >85%.
- B Veterinary drug: 16 mg Milbemycin Oxime granules mixed with 40 mg Praziquantel granules that are coated with Precirol® AT05 (glycerol distearate); Liquid animal food: 5 ml of chicken chunk liquid gravy, water contents >85%.
- a commercially available tablet containing the same active ingredients and same amounts thereof yields a palatability score of only ⁇ 50%.
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Description
Veterinary Drug System
The present invention relates to a new veterinary drug administration system imparting an improved palatability to a given drug which is especially useful for administration to non- human animals, in particular cats.
Oral administration of a drug to a non-human animal can be a real challenge depending on the nature of the drug and animal. For example, cats are known to be delicate with respect to any kind of oral medication, and administration thereof often requires special measures. In addition, many veterinary drugs have an unpleasant taste and therefore have to be made attractive, for example, by adding suitable flavors. Various solutions to increase the palatability of veterinary drugs have been proposed, such as the addition of suitable aromas or flavors, coating drugs with one or more protective layers, creation of a specific drug consistency like a soft chewable or a more crunchy formulation. However, said known solutions often don't provide a satisfactory palatability, especially in cases of drugs which have to be taken on a regular basis, such as endoparasiticides, ectoparasiticides or drugs for treating chronic diseases.
A further approach would be to include the drug into a suitable animal food which is, however, problematic from a regulatory perspective. First of all, the food must have a constant, reproducible quality. In addition, the drug must be stable within the animal food, and the veterinary drug product as a whole has to have a sufficient shelf life, for example, of at least one year or more. While solid products, such as coated drug pellets incorporated in yeast or a drug incorporated in a chewable formulation with high meat contents, are known, for example, from WO2003/075895 or WO2005/013714, no products of a veterinary drug in a liquid animal food have been contemplated yet, most likely for stability reasons. A liquid consistency, however, would be very beneficial , as animals such as cats often prefer to lick liquids out of a bowl instead of digesting solids.
Accordingly, it is an object of the present invention to provide a veterinary drug product which is based on a liquid animal food and still has a shelf life sufficient, for example, for a prescription drug.
The present invention, according to one aspect, therefore concerns a veterinary drug administration system comprising
a first container comprising a liquid animal food that is based on meat, water and optionally further excipients, wherein the water contents is≥80% (w/w), based on the entire animal food, and
a second container comprising one or more veterinary drugs in solid form,
wherein the contents of the first and second container are combined prior to use.
According to the present invention, the term meat comprises all kinds of animal meat, for example, from domestic animals and productive livestock, e.g. pigs, horses, cattle, sheep, goats and poultry including chicken, duck, goose and turkey, or from fish, or mixtures thereof, as well as artificial meat flavors which are well-known from the food industry.
Preferably, the liquid animal food is based on animal meat, in particular on animal meat, for example, from pig, cattle, chicken or fish. The animal meat may be based on human food- grade meat or on animal by-products such as slaughterhouse waste containing all kinds of animal tissue, such as skin, sinews, bowels and meat.
In order to prepare the liquid animal food, the meat, preferably after having been chopped and/or homogenized, is mixed with water and optionally further excipients, and the mixture is then filled in a plurality of first containers which are closed or sealed afterwards. Finally, the mixture within the first containers is sterilized, preferably by application of heat and/or pressure. For example the first containers are autoclaved at a temperature of about 80 to 140°C for about 5 to 30 minutes, in particular 10-25 minutes.
The liquid animal food according to the present invention contains≥80% (w/w) and preferably≥85% (w/w) water, based on the entire formulation. Overall meat contents may vary, for example, between 1 and 20% (w/w), preferably 1 .5 and 15% (w/w), more preferably 2 to 10% (w/w), and in particular 4 and 8 % (w/w), based on the entire formulation. Main components of said meat are proteins and fat, besides minerals and vitamins.
Further excipients contained in the liquid animal food or gravy may be, for example:
(i) thickeners, for example carrageen, xanthan gum, locust bean gum, guar gum, cornstarch, oat meal flour, microcrystalline cellulose, hydroxyethyl cellulose, carboxymethyl cellulose;
(ii) antioxidants, for example propyl 3,4,5-trihydroxybenzoate, BHA (2-t-butyl-4- methoxyphenol), BHT (2,6-di-t-butyl-4-methylphenol), tocopherols (alpha, beta, or delta- tocopherol, tocopherol esters, alpha-tocopherol acetate), alkyl gallates such as propyl gallate, tert. butyl hydroquinone, butylated hydroxyanisole or butylated hydroxytoluene. According to a preferred embodiment of the invention, the liquid animal food is devoid of an antioxidant.
(iii) preservatives, for example sorbic acid and its salts, benzoic acid and its salts, ascorbic acid and its salts, for example sodium ascorbate, citric acid and its salts, or EDTA salts, for example disodium EDTA. According to a preferred embodiment of the invention, the liquid animal food is devoid of a preservative.
(iv) additional aromas or flavors, for example sweeteners such as sugar, fructose or xylose; amino acids such as glycine, lysine, methionine or cystein.
(v) colors such as iron oxide or gravy browning.
Preferred excipients of the liquid animal food are one or more thickeners, mainly for consistency adjustment. The further excipients most preferably comprise one or more thickeners and one or more additional aromas or flavors.
Further excipients, if contained in the liquid animal food, are present in an amount of, for example, from 0.1 to 19% (w/w), preferably from 0.5 to 10% (w/w), more preferably from 1 to 7% (w/w), and in particular from 1 to 5% (w/w), based on the entire formulation.
Preferred formulations of the liquid animal food comprise:
(i) 1 to 10 % (w/w) animal meat, 0.1 to 19 % (w/w) further excipients and water ad 100 % (w/w).
(ii) 2 to 10% animal meat, 0.5 to 10% further excipients and water ad 100% (all (w/w);
(iii) 4 to 8 % animal meat, 0.5 to 10% further excipients, and water ad 100% (all (w/w);
The energy contents of a liquid animal food according to the invention is in general low, for example, <1 kcal/g and preferably <0.5 kcal/g. Therefore, the liquid animal food according to the invention is in general not a complete meal but, for example, a snack which may be
provided to the animal as a treat. Moreover, the animal food according to the invention may be applied as a complementary food additive which is provided to the animal before, concurrently with, or after its main meal.
The liquid animal food within the first container has preferably a low viscosity, for example < 1000 mPa-s, advantageously below about 500 mPa-s, for example from about 0.1 to 250 mPa-s, and preferably from 0.5 to 100 mPa-s, in order to facilitate a smooth mixing with the veterinary drug contained in the second container. The overall volume of liquid animal food contained in the first container may vary within wide limits but is, for example, from 1 to 100 ml, preferably from 2.5 to 50 ml, more preferably from 2.5 to 25 ml, and in particular from 4 to 10 ml. A particularly preferred volume is about 5 ml.
The veterinary drug or mixture of veterinary drugs contained in the second container is in general present in form of a powder, granules or pellets, preferably in form of granules or pellets. The particle size is in general not critical, as long as it does not prevent the food uptake of the medicated food after mixing the first and second container. In general, a particle size of < 1 .6 mm, for example from 0.01 to 1 .6 mm, and preferably < 1 .0 mm, especially from 0.1 to 1 .0 mm, has proven as valuable. Granulation of the drugs is performed in a manner known per se, for example by granulation, which may be performed dry or more commonly wet, by extrusion or spheronization. Suitable processes are known to the person skilled in the art.
In general, no additional steps of taste masking the active ingredients need to be taken, as the liquid animal food in the final drug formulation sufficiently compensates unpleasant tastes. However, in case of veterinary drugs with an extremely bad taste, it may be advisable to previously coat the drug particles with a protective layer in order to further enhance the palatability. Suitable techniques, such as coating the drug granules with a layer of protective polymer or lipid, for example with a copolymer of one or more
(meth)acrylates and a cationic (meth)acrylate or with a lipid such as glycerol distearate, or coating inert carrier particles first with a drug layer and then with a layer of protective polymer or lipid, for example as described above, are known to the person skilled in the art.
It is an important feature of the veterinary drug administration system of the present invention, that the veterinary drug(s) is (are) mixed with the liquid animal food only shortly
before use; therefore, virtually any solid veterinary drug may be employed. Just by way of examples the following classes of compounds may be mentioned:
(A) Endoparasiticides, for example abamectin, doramectin, eprinomectin, ivermectin, milbemectin, selamectin, milbemycin, milbemycin oxime, moxidectin, emamectin, derquantel, monepantel, praziquantel, albendazole, clorsulon, cydectin, diethylcarbamazine, febantel, fenbendazole, haloxon, levamisole, mebendazole, morantel, oxyclozanide, oxibendazole, oxfendazole, oxamniquine, pyrantel, thiabendazole, tetramisole, trichlorfon, emodepside or mixtures or derivatives thereof. A preferred group of endoparasiticides comprises abamectin, doramectin, ivermectin, milbemycin oxime, moxidectin, emodepside, derquantel, monepantel, praziquantel or mixtures thereof. A particularly preferred
endoparasiticide according to the present invention is a combination of milbemycin oxime and praziquantel or emodepside and praziquantel.
(B) Ectoparasiticides, for example a neonicotinoid, in particular imidacloprid, thiamethoxam, nitenpyram, indoxacarb or dinotefuran; an insect growth regulator, for example cyromazine, methoprene, kinoprene or hydroprene; a benzoylurea, for example diflubenzuron, lufenuron, noviflumuron, hexaflumuron, triflumuron, teflubenzuron; a phenylpyrazole, in particular fipronil or pyriprole; a pyrethroid, for example permetrin allethrin, resmethrin; a carbamate, in particular fenoxycarb; a spinosyn, in particular spinosad; or an arylisoxazoline as mentioned below, or mixtures or derivatives thereof.
A suitable arylisoxazoline compound is, for example, of formula
including all geometric and stereoisomers, N-oxides, S-oxides and salts thereof,
wherein, R', R" and R'" are each independently hydrogen, halogen, cyano, CrC2-alkyl, halo-CrC2-alkyl, CrC2-alkoxy or CrC2-haloalkoxy, subject to the proviso that at least one of R', R" and R'" is not hydrogen;
Ai is O, S or NRi', A2 is CH2, O or S, and A3 is O, S or NR-i';
Ri' independently is as defined as Ri below;
R2 is H , methyl, halogen, hydroxy or methylsulfonyl;
and X is
(a) a radical of formula
wherein R5 is H, CrC2-alkyl, Ci-C2-haloalkyl, halogen, nitro or cyano and Q is
(i) a 5- or 6-membered heteroaromatic ring comprising 1 to 3 same or different heteroatoms selected from the group consisting of O, S and N which is further unsubstituted or substituted; or is
(ii) a group -C(0)N(R1)-T, wherein R-\ is H, CrC4-alkyl, C2-C4-alkylcarbonyl or C2-C4- alkoxycarbonyl and T is CrC6-alkyl which is unsubstituted or substituted by C3-C6-cycloalkyl, halogen, cyano, nitro, amino, hydroxy, CrC6-alkoxy, CrC6-haloalkoxy, CrC6-alkylthio, d- C6-haloalkylthio, CrC6-alkylsulfinyl, CrC6-haloalkylsulfinyl, CrC6-alkylsulfonyl, CrC6- haloalkylsulfonyl, carboxy, carbamoyl, Ci-C6-alkylcarbonylamino, CrC6-haloalkyl- carbonylamino, CrC6-alkoxycarbonyl, sulfonamido, N-mono- or N,N, di-CrC4-alkylsulfon- amido, C2-C6-alkanoyl, unsubstituted or in the alkyl portion by halogen, cyano, ethenyl or ethynyl substituted N-Ci-C6-alkylaminocarbonyl, or unsubstituted or halogen-, Ci-C2-alkyl-, CrC2-haloalkyl or cyano-substituted 4- to 6-membered heterocyclyl; or T is C3-C6-cycloalkyl or 4- to 6-membered heterocyclyl, which is each unsubstituted or substituted by halogen, Ci-C2-alkyl, Ci-C2-haloalkyl or cyano; or is
(iii) a radical -C(0)NH-C=N-0-C C2-alkyl, a radical -C(0)N=C-N-di-C C2-alkyl or a radical -C(0)N=C(NH2)-0-CrC2-alkyl; or is
(iv) a group -CH(R3)-N(R4)-C(0)-T1 , wherein R3 is H, C C6-alkyl, CrC6-haloalkyl, halogen or cyano, R4 is H; CrC4-alkyl C2-C4-alkylcarbonyl or C2-C4-alkoxycarbonyl, and ΤΊ is
independently defined as T above;
wherein R5 is H, Ci-C2-alkyl, Ci-C2-haloalkyl, halogen, nitro or cyano, and Q is as defined above;
(c) a radical of formula
wherein Q is as defined
(d) a radical of formula
wherein n is 1 or 2 and Q' is a group -N(R4)-C(0)-T2, wherein T2 independently has the meaning of T above and R4 is as defined above; or
wherein 4 is O or S and Q and R5 are each as defined above, and wherein one of Q and R5 is located in the 2-position and the other one in the 3-position.
Examples of preferred arylisoxazoline compounds are
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2- carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide; or
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2- carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide; or
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2- carboxylic acid ethylcarbamoylmethyl-amide; or
5-[5-(3,5-dichloro-phenyl)-5-trifluorom
carboxylic acid prop-2-ynylcarbamoylmethyl-amide; or
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thioph carboxylic acid [(cyanomethyl-carbamoyl)-methyl]-amide; or
5-[5-(3,5-bis-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl^ thiophene-2-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide; or
5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thioph 2-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide;
5-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl- thiophene-2-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide;
4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N{-2-oxo-2- [(2,2,2-trifluoroethyl)amino]ethyl}-benzamide (fluralaner);
4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]^ oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1 -naphthalenecarboxamide (afoxolaner);
4-[5-[3!5-dichlorophenyl]-4!5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2!2,2- trifluoroethyl)amino]ethyl]-1 -naphthalenecarboxamide.
(C) Endectoparasiticidal combinations, for example milbemycin oxime and lufenuron;
milbemycin oxime and spinosad; milbemycin oxime, praziquantel and lufenuron; milbemycin oxime, praziquantel and spinosad; ivermectin and spinosad; an arylisoxazoline as mentioned above and an endoparasiticide as mentioned above, for example afoxolaner or fluralaner each with milbemycin oxime or moxidectin; and the like.
(D) Further veterinary products for companion animals, for example cardiovascular drugs, such as benazepril, amlodipine or pimobendan; pain relief, anti-inflammatory or arthritis agents, for example deracoxib, meloxicam or robenacoxib; skin disease agents, for example ciclosporin A or oclacitinib; agents for treating metabolic disorders, oncology drugs and the like.
A suitable first container for the liquid animal food may be, for example, a pouch or stick pack, a blister, a bottle, a tube or a syringe. A suitable second container for the veterinary drug(s) likewise may be a pouch or stick pack, blister, bottle, tube or syringe.
Combination of the contents of the first and second container may take place in a manner known per se, for example by opening a first and second container each, filling their contents in a suitable bin such as a bowl, and, if necessary, admixing both. According to a preferred variant of this embodiment, both the first and second container are in form of a stick pack or pouch, which are opened prior to use, and the contents thereof are each filled in a suitable bin such as a bowl and, if necessary, admixed.
According to a further embodiment of the invention, the first and second containers are capable of being assembled and are closed prior to assembly. The first container comprises a first reservoir for holding the liquid animal food, and the second container comprises a second reservoir for holding the one or more veterinary drugs. Upon assembly the first and second reservoirs of the first and second containers are set in communication with one another to allow mixing of the liquid contained in the first reservoir of the first container with the veterinary drug(s) contained in the second reservoir of the second container to form a liquid-substance mixture. The liquid-substance mixture may then be provided to the animal, and due to the liquid animal food is attractive to the animal, so that the liquid-substance mixture is easily accepted by the animal. As an example, the liquid animal food may be stored in a bottle which is provided with a cap comprising a separate capsule in the cap that contains the veterinary drug(s) in powder, granule or pellet form. Upon use, the cap is screwed downwards further onto the bottle thereby rupturing the capsule and mixes with the liquid animal food contained in the bottle. Thereafter the animal food-drug mixture is ready for use.
According to still another embodiment of the invention, a kit of parts is provided comprising one first container comprising one portion of liquid animal food, where the above given meanings and preferences apply, and one second container comprising a single dosage unit of one or more veterinary drugs, wherein the above given meanings and preferences apply.
According to still another embodiment of the invention, a kit of parts is provided comprising
(i) a plurality of first containers with liquid animal food of different flavors, where the above given meanings and preferences apply, and
(ii) a plurality of second containers comprising each a single dosage unit of one drug or drug combination, or one second container comprising a plurality of single dosage units of
one drug or drug combination, wherein each the above given meanings and preferences apply.
For example, the plurality of first containers may contain liquid animal food of 2 or more different flavors, for example 2 to 5, or in particular 2 or 3 different flavors. Examples of typical flavors are chicken, pork, beef or fish flavor.
According to this embodiment the palatability of a drug may be further enhanced by providing different choices of taste to the animal in need of medication. A veterinary drug administration system according to this embodiment is especially suited for drugs which have to be administered to the animal on a regular basis, for example on a weekly or daily basis.
According to still another preferred embodiment, mixing of the contents of the first and second container and offering the mixture to the animal takes place in a standardized container in order to provide control of the uptake. Said container for mixing and offering may be the above first or second container or a separate third container. A suitable container for mixing and offering the mixture to the animal is, for example a standardized bowl; in case of a cat product it is preferred to employ a small bowl being adapted to receive volumns of, for example, from 0.5 to 25 ml and preferably from 1 to 10 ml. Control of the uptake by the animal may be performed, for example, by visual inspection of the container after uptake, or by measuring the weight difference of the container before and after uptake.
The veterinary drug administration systems of the present invention are in principle useful for all kinds of non-human animals. Preference is given to companion animals, for example horses, donkeys, mules, dogs, cats or birds, preferably dogs and cats, in particular cats.
A unique system of administering veterinary drugs of all kinds to an animal is provided by means of a standardized liquid animal food with a high shelf life of, for example 1 year or more, to which is added a single dose unit of desired veterinary drug(s) in solid form only shortly before use. In addition, if the combination of the liquid animal food and veterinary drug(s) is offered to the animal in a standardized container as mentioned above, the uptake by the animal may be controlled and adjusted, if necessary.
The palatability, meaning the voluntary acceptance or ingestion by the animal, of the liquid animal food alone is in general above 70%, preferably≥90%, even in fed condition. Also with veterinary drug(s) incorporated into the liquid animal food, the attractiveness of the resulting veterinary drug product for the animal is still very high; accordingly, the palatability of the veterinary drug products according to the present invention clearly exceeds that of classical veterinary drug products, such as tablets or capsules.
A suitable palatability test on cats may be performed as follows.
A plurality of cats, males and females, are treated with a single dose of liquid medicated food according to the present invention; the medicated food is presented once to each cat alone in a bowl.
The following parameters are measured and calculated:
A: Acceptance: spontaneous (less than 10s), late (after at least 10s) or refusal;
B: Consumption: total, partial (<95%) or refusal.
Palatability scoring is established from the spontaneous complete test item consumption ratio (total consumed versus total offered).
The following examples illustrate the present invention. Example 1 :
A study was performed to evaluate the acceptance of three different Milbemycin Oxime and Praziquantel gravy formulations in cats.
Formulations A1 , A2 and B as tested were as follows:
A1 : Veterinary drug: 16 mg Milbemycin Oxime granules mixed with 40 mg Praziquantel granules that are coated with Kollicoat Smartseal® 30D Coating (copolymer of one or more (meth)acrylates and a cationic (meth)acrylate); Liquid animal food: 5 ml of chicken chunk liquid gravy, water contents >85%.
A2: Veterinary drug: 16 mg Milbemycin Oxime granules mixed with 40 mg of inert pellets coated with a first layer containing Praziquantel and with a second protective layer of Eudragit® EPO (copolymer of one or more (meth)acrylates and a cationic (meth)acrylate); Liquid animal food: 5 ml ofchicken chunk liquid gravy, water contents >85%.
B: Veterinary drug: 16 mg Milbemycin Oxime granules mixed with 40 mg Praziquantel granules that are coated with Precirol® AT05 (glycerol distearate); Liquid animal food: 5 ml of chicken chunk liquid gravy, water contents >85%.
In addition, a positive and negative control were incorporated in the study.
C (positive control): Chicken chunk liquid gravy as in A and B, but without veterinary drug.
D (negative control): Coffee.
30 (17 males + 17 females) European shorthair cats were selected for the acclimation phase (bodyweight: 2.2 - 6.5 kg). Cats were fed daily a maintenance dry food around 1 to 2 hours after offering except on weekends during which food were distributed in the morning. Each formulation was tested once to overnight fasted animals.
Acceptance type or denial for each administration of any treatment was recorded as follows:
- (I) when the cat fully ate the test item from the bowl.
- (II) when the item was ignored or partially consumed after being put in the bowl.
Palatability score was calculated for each tested item according to the following formula: % Palatability =∑(!) /∑ offerings
Palatability of tested formulations A, B, C and D resulted in the following scores:
Test Item Palatability [%]
Formulation A1 70
Formulation A2 100
Formulation B 60
Positive Control C 96.7
Negative Control D 0
By contrast, a commercially available tablet containing the same active ingredients and same amounts thereof (Milbemax® film-coated tablet) yields a palatability score of only <50%.
Claims
1 . Veterinary drug administration system comprising
a first container comprising a liquid animal food that is based on meat, water and optionally further excipients, wherein the water contents is≥80% (w/w), based on the entire animal food, and
a second container comprising one or more veterinary drugs in solid form,
wherein the contents of the first and second container are combined prior to use.
2. Veterinary drug administration system according to claim 1 , wherein the liquid animal food comprises 2 to 10 % (w/w) meat, based on the entire animal food.
3. Veterinary drug administration system according to claim 1 or 2, wherein the meat is animal meat selected from the group of pig, horse, cattle, sheep, goat, chicken, duck, goose, turkey, fish, or mixtures thereof.
4. Veterinary drug administration system according to any of claims 1 to 3, wherein the liquid animal food comprises excipients selected from the group consisting of one or more thickeners, antioxidants, preservatives, flavors and colors.
5. Veterinary drug administration system according to any of claims 1 to 4, wherein the liquid animal food consists essentially of 2 to 10% (w/w) meat, 0.1 to 19% (w/w) further excipients, and water ad 100%.
6. Veterinary drug administration system according to any of claims 1 to 5, wherein the liquid animal food inside the first container is sterilized by autoclaving.
7. Veterinary drug administration system according to any of claims 1 to 6, wherein the one or more veterinary drugs are in form of granules or pellets.
8. Veterinary drug administration system according to any of claims 1 to 7, wherein the one or more veterinary drugs are selected from the group consisting of abamectin, doramectin, ivermectin, milbemycin oxime, moxidectin, emodepside, derquantel, monepantel, praziquantel, imidacloprid, thiamethoxam, nitenpyram, indoxacarb, dinotefuran, cyromazine,
methoprene, kinoprene, hydroprene, diflubenzuron, lufenuron, noviflumuron, hexaflumuron, triflumuron, teflubenzuron, fipronil, pyriprole, permetrin, allethrin, resmethrin, fenoxycarb, spinosad and an arylisoxazoline.
9. Veterinary drug administration system according to any of claims 1 to 7, wherein the one or more veterinary drugs are selected from the group consisting of ivermectin, milbemycin oxime, moxidectin, emodepside, praziquantel, lufenuron, spinosad, fluralaner, afoxolaner and 5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl- thiophene-2-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide.
10. Veterinary drug administration system according to any of claims 1 to 9, wherein the first and second containers are each in form of a pouch or stick pack.
1 1 . Veterinary drug administration system according to any of claims 1 to 9, wherein the first and second containers are capable of being assembled, are closed prior to assembly, and upon assembly are set in communication with one another to allow mixing of the liquid contained in the first container with the veterinary drug(s) contained in the second container.
12. Veterinary drug administration system according to any of claims 1 to 1 1 , comprising
(i) a plurality of first containers with liquid animal food of different flavors, and
(ii) a plurality of second containers comprising each a single dosage unit of one drug or drug combination, or one second container comprising a plurality of single dosage units of one drug or drug combination.
13. Veterinary drug administration system according to any of claims 1 to 1 1 , wherein mixing of the contents of the first and second container and offering the mixture to the animal takes place in a standardized container.
14. A method of controlling endoparasites and/or ectoparasites in a dog or a cat, which comprises applying a veterinary drug administration system according to any of claims 1 to 13 to the animal.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12187156 | 2012-10-04 | ||
| EP12187156.0 | 2012-10-04 |
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| WO2014053555A1 true WO2014053555A1 (en) | 2014-04-10 |
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ID=47115311
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2013/070561 Ceased WO2014053555A1 (en) | 2012-10-04 | 2013-10-02 | Veterinary drug system |
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| RU2657508C1 (en) * | 2017-07-04 | 2018-06-14 | Александр Анатольевич Хахалин | Combined antiparasitic agent for treatment and prevention of helminthiases and arachnoentomosis of carnivores |
| JP2023540312A (en) * | 2020-09-04 | 2023-09-22 | エランコ・ユーエス・インコーポレイテッド | palatable formulation |
| US12304903B2 (en) | 2020-07-24 | 2025-05-20 | Elanco Us Inc. | Process for making an isoxazoline compound and intermediate thereof |
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| US6174866B1 (en) * | 1999-10-20 | 2001-01-16 | Rosemary Smoter | Edible anti-parasite medication for domesticated animals |
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| RU2657508C1 (en) * | 2017-07-04 | 2018-06-14 | Александр Анатольевич Хахалин | Combined antiparasitic agent for treatment and prevention of helminthiases and arachnoentomosis of carnivores |
| US12304903B2 (en) | 2020-07-24 | 2025-05-20 | Elanco Us Inc. | Process for making an isoxazoline compound and intermediate thereof |
| JP2023540312A (en) * | 2020-09-04 | 2023-09-22 | エランコ・ユーエス・インコーポレイテッド | palatable formulation |
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