Palatable ductile chewable veterinary composition

European).

Z-5466/08

EP 1 675 474 B1

Tasty, ductile compressive composition

Description

The present invention relates to an easy-to-use, safe, effective and stable veterinary product consisting of a very palatable ductile chewable veterinary composition comprising an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases, an additive with the taste of meat, partially gelatinized starch, softener and amount of water not more than 9%. The present invention also resides in the use of a method of controlling said animal pests, pathogens and treating or preventing said animal diseases by feeding the animal with a very palatable, ductile, opaque veterinary composition. Further, the invention consists in applying a method of producing said very palatable, malleable, chewable veterinary compositions by cold extrusion. In a preferred embodiment, very palatable ductile and chewable veterinary compositions control animal pests such as endo-parasites, e.g. roundworms and simultaneously ecto-parasites such as biting insects, e.g. fleas in domestic animals. The active agent against pests is effectively released when the animal chews the product.

The scope and background of the present invention.

Veterinary products can be administered to warm-blooded animals in very different ways depending on their mode of action and their ability to be treated by the treated animals or target pests. Therefore, the veterinary products can be administered e.g. for topical use as pouring or spraying preparations, in the form of shampoos, showers, as a dip bath, or as a spray liquid, in the form of a collar and in many variants of these forms of application. They can also be administered systemically, e.g. orally, parenterally and in some cases even through the skin. Examples of forms of systemic administration are: by injection, as a tablet, capsule, pill, beverage, food additive, etc. Each of these forms of administration has advantages and disadvantages, depending on the current situation and the type of animal in need of such treatment.

One very convenient and easy-to-implement form of administering drugs to human patients is to take the medicine orally. It would also be desirable in veterinary medicine, but in this case the animal keeper or veterinarian is confronted with the natural behavior of animals and oral treatment can be a real challenge.

Much effort has been put into designing an ideal oral application form that can actually be accepted and voluntarily accepted by an animal, but most of these forms of application still need refinement.

For example, EP-A-1247456 describes a tasty pharmaceutical composition for oral administration to animals comprising a pharmaceutically effective amount of a pharmaceutically active agent in combination with a taste improving agent and a pharmaceutically acceptable carrier, wherein the taste improving factor does not originate from either meat or fish and is present in amounts sufficient to improve the palatability of the pharmaceutical composition. The claimed content of the present invention differs from that disclosed in the reference above, that partially gelatinized starch is used in the present invention. The effect of this difference is the fact that the product can be obtained by the cold extrusion method.

Document GB-A-2300103 describes tasty biscuits for dogs and their production by extrusion. The final product contains partially gelatinized starch and creatine. However, as far as the problem of destruction of the active ingredient is concerned, this document does not provide cold extrusion methods. Extrusion occurs rather at relatively high temperatures, up to 130^aboutC.

The present inventors have found that in the field of animal health, the dosage form and especially the palatability of the dosage form, e.g. the natural acceptability of the drug plays a fundamental role. Appropriate problems related to this are presented below.

As in humans, medications can be dosed in a wide range of application forms such as tablets, coated tablets, emulsions, injection solutions, suppositories, etc., because discipline and the desire to improve human health can be trusted, in the case of animals encountering quickly practical problems, because few forms of application, such as the use of suppositories, can be made and administered by everyone, or in the case of other forms such as injections, it must be carried out only by the veterinarian.

Generally speaking, people do not like visiting a doctor. The same applies to animal keepers who need the advice of a veterinarian. In general, animal keepers prefer to use treatments that can be carried out alone, without the help of a veterinarian. Among the preferred methods of treatment, which the animal keeper oral oral administration of drugs. Treatment of people with medication generally is not problematic, because a patient follows a doctor's instructions or reads the instructions provided with the medicine and applies to them because it is in his own interest and because the manufacturer usually prepares a tablet, capsule or coated tablet in the form which is suitable for oral consumption and is adapted for people.

However, if the pharmaceutically active ingredient has a taste that is unpleasant to the animal because it is bitter or has a different unpleasant taste or is simply disgusting to the animal, it refuses to take this medicine orally. This innate behavior occurs to varying degrees among different animal species and essentially depends on their conventional eating habits. Unfortunately, only a few active ingredients have a neutral taste, so the problem discussed here is almost always present.

In the case of a human patient, the unpleasant taste ingredient may be masked relatively easily e.g. by covering it with a neutral flavor or a sweet layer. Everyone once met, once or twice, gelatin capsules or tablets covered with sugar or varnish. It is easy to instruct a human patient to take the preparation without chewing.

The animal must have a natural desire to take the medicinal preparation orally, which means that the medical preparation must taste good and be tasty. Of course, an individual animal or several animals may also be forced to take the drug by ingestion or injection. However, these strength methods are not only unacceptable for large numbers of animals, but also for individual dogs and cats that tend to bite and scratch if they do not want to be treated. Therefore, treatment of animals is very labor-intensive and requires veterinary intervention, which in turn leads to increased costs.

Thus for pets as well as for animals kept on a larger scale, simple and safe forms of oral application are required, which can be easily administered by an animal caretaker that leads to certain results and are useful.

The chewable composition of the present invention is not only suitable for replacing treatment with a tablet or capsule. These chewable compositions can also be mixed with conventional non-medicated feed portions if the animal herds are to be treated.

Due to their excellent palatability, the chewable compositions of the present invention are adopted by the animals without causing acceptance problems. Their use is easy and safe and can be adapted for the needs of an individual pet like a cat or dog, as well as for livestock like sheep and cows.

In summary, the use of capsules and coated tablets for animals showed that these forms of administration are not convenient for treating animals, because in the case of livestock they can be used only in a controlled manner with daily intense effort and in the case of pets such as dogs or cats, they lead to specific acceptance problems. As mentioned above, when using oral medications, eating habits of animals generally play a decisive role. Therefore, the most important are attractive taste and deliciousness.

In the case of dogs, it was observed that they bite on solid food, e.g. bone, and swallowed other foods prepared in the form of large pieces or in a liquid state almost unchained. If the tablet or coated tablet is mixed with food prepared in a liquid state, different results are obtained. In a few cases, the dog did not notice the tablet at all and just swallowed it and in other cases it remained intact in the dog's bowl. Unlike dogs, cats are much more demanding when it comes to eating habits. Only in the rarest cases the tablet or coated tablet can be mixed with the prepared food without being immediately noticed and discarded. Although cats also do not chew their food thoroughly, they generally crush it into small pieces. Thus, they damage the protective layer of the tablet or capsule and release the unpleasantly-tasting active ingredient. Similarly, attempts to mix the active ingredient with food failed, either because the degree of dilution was insufficient to neutralize the unpleasant taste or the active ingredient broke down very quickly in contact with food. For the same reasons, a mixture of food, active ingredients and pharmaceutical excipients that can stimulate the appetite of dogs and cats did not give a satisfactory result in cats. Given that the test animals hurriedly thrown on a placebo that has a suitable appetite stimulant, i.e. a tablet containing food, fragrance and other drug excipients, but no active ingredient, test animals reject this combination immediately after the active ingredient has been added. That it was clear

Of course, any active ingredient that is suitable for animals can be administered in accordance with the present invention, but especially those active ingredients that have the previously mentioned unfavorable taste, and are therefore not readily taken orally by animals.

In principle, the diversity of individual active ingredients can be taken into account, for example those that act against the external (ecto) and internal (endo) parasites or active ingredients acting against animal diseases including viral or bacterial infections, behavioral disorders such as hypolubs hyper-recovery, inflammatory and autoimmune diseases. In this way, the active ingredient can be a pesticide or a drug or a mixture of both.

It should be borne in mind that the present invention relates to an optimized use of the veterinary composition form rather than to the treatment of animals with a specific class of active ingredients. Conversely, the present invention is an easy-to-use, safe, potent and stable veterinary product consisting of a very palatable ductile chewable veterinary composition that allows oral administration to a warm-blooded animal of almost any and any active ingredient, provided that the active ingredient or mixture of active ingredients is administered animal in a physiologically acceptable dose, does not give unpredictable side effects and, most importantly, shows systemic activity after oral administration. This means that the main precondition for the active ingredient is that that after oral administration it is carried by body fluids, including blood and lymph, and transported to an animal pest, a pathogenic agent or a diseased organ where it can show its activity. Thus, each active ingredient or class of active ingredients mentioned below is nothing but a non-limiting example of suitable active ingredients. The form of use of the present invention is not currently limited to existing active ingredients, but also convenient for each and any of the active ingredients discovered in the future, provided that the future active ingredient meets the main characteristics explained above. where he can show his activity. Thus, each active ingredient or class of active ingredients mentioned below is nothing but a non-limiting example of suitable active ingredients. The form of use of the present invention is not currently limited to existing active ingredients, but also convenient for each and any of the active ingredients discovered in the future, provided that the future active ingredient meets the main characteristics explained above. where he can show his activity. Thus, each active ingredient or class of active ingredients mentioned below is nothing but a non-limiting example of suitable active ingredients. The form of use of the present invention is not currently limited to existing active ingredients, but also convenient for each and any of the active ingredients discovered in the future, provided that the future active ingredient meets the main characteristics explained above.

The very palatable, ductile, chewable veterinary composition of the present invention is in principle a medical nutritional product and anyone working in the field is aware of the technical problems that arise in the context of producing a medical nutritional product. For example, the stability of the active ingredient is decisive. It is a fact that many effective active compounds are sometimes unstable (sensitive to temperature), primarily in contact with nutritional materials, particularly close contact with plant and animal materials during conventional extrusion of nutritional pills causes significant losses of the active ingredient.

For example, when dietary pills are prepared by extrusion, the dried organic starting material of plant or animal origin is ground and thoroughly mixed with the active ingredient, i.e. solidly homogenized and then moistened with water or steam and compressed into tablets at moderate temperature and pressure 100 kbar. . However, these high pressures and permanently high temperatures of 60-100 ° C are unfavorable and not only dramatically reduce the viscosity of the tablets, but lead to a significant loss of the active agent.

Whereas most active ingredients in pure form or in contact with carriers that are routinely used in the production of tablets or capsules withstand such relatively high temperatures per se very well and can be stored in pure form or as tablets or capsules at room temperature for months or years without a clear loss of active agent, they decompose relatively quickly under pressure and in

Ί close contact with animal or vegetable fibers in food at generally elevated temperatures. It seems that contact with fibers significantly catalyzes the degradation process. Even when the elevated temperature and elevated pressure phase is maintained as short as technically possible and the finished tablets are immediately cooled to room temperature immediately after the process, one fourth to one third of the active ingredient is still lost. Even in rare cases, where degradation products do not have adverse effects on the test animals, the unavoidable loss of active ingredient inevitably causes a significant increase in the cost of the final product. The extrusion process can lead to undesirable effects.

Hence, for reasons mentioned, a lot of effort has been put into stabilizing temperature-sensitive active ingredients so that they withstand elevated temperature and pressure during the preparation of the granules without loss of active substance and also, when in the form of final granules, have the long-term stabilization period needed for practical purposes.

Unfavorable attempts of such stabilization include, for example, (1) reducing the surface of the active ingredient by compression (compression) to granules in which a large variety of granule sizes has been tried; (2) sealing said active ingredient granules with a large variety of protective layers, e.g. gelatin or various sugars and coatings; (3) closure of active ingredients with porous materials such as e.g. various celluloses, starches, silicic acids or zeolites with or without additional protective layers; and (4) chemical modification of the substantial, macrocyclic structure of the active ingredient. Although in some cases the chemical modification led to increased stabilization of the compound as such, it also led to loss of activity.

However, none of these attempts resulted in significantly less loss of active ingredient during compression into granulated feed or measurable improved storage stability.

Moreover, at present, surprisingly, success has been achieved by providing the user with a friendly, easy-to-use, safe, strong, stable and particularly very palatable, chewable veterinary composition according to the present invention.

Unexpectedly, it is now possible to provide a product that not only withstands the extrusion process undamaged, but also is able to survive a long storage life.

It is highly surprising and absolutely unpredictable that even if the chewable veterinary composition of the present invention contains a high amount of meat, naturally, if it is combined with a sufficient amount of partially gelatinized starch, there is no adverse effect on the stability of the active ingredient. It has now been found that the chewable veterinary food of the present invention is a very stable product that can be stored at room temperature for many months without significant loss or degradation of the active ingredient. Tests made on the stored material indicate that the palatability is not reduced and the effectiveness of the active ingredient remains high.

In addition, studies of kinetic behavior show another amazing effect. It was unpredictable that the administration of the chewable veterinary composition of the present invention would lead to absolutely the same level of bioavailability as when tablets or capsules were administered. In this way, the present invention provides a convenient, easy-to-use and stable product that is at least as efficient as conventional forms of oral administration e.g. tablets or capsules.

Many biocides and veterinary drugs that can now be included in the chewable veterinary compositions and that can be used in the present invention have been known to those skilled in the art for a long time, but conventional oral dosage forms are not satisfactory because they are not attractive to animals and exhibit the disadvantages described above .

The porous veterinary composition of the present invention can be used to control all types of parasites. External parasites also called ecto-parasites are understood as parasites that normally live on an animal, i.e. on the skin of an animal or on its fur. Biting insects such as mosquito, meat flies, fleas or lice or members of the order Acarina, e.g. mites or ticks, are included here. Suitable products used against external parasites include insecticides and acaricides. It is not important what their current way of operation is. These may be, for example, chitin synthesis inhibitors, growth regulators, juvenile hormones or agents that act to kill adults. These may be broad-spectrum insecticides, broad-spectrum acaricides. The active ingredient can be the agent that causes death, deterrent or deterrent. It can only work on insects in adult form, only on insects in juvenile form or insects in any form. The only condition is that the active ingredient reacts systemically. This means that it does not decompose after oral intake, but is transferred by means of liquids to the skin or the organ, where the parasite usually lives.

If the active agent is a miticide, hereinafter referred to as shortly acaricide, a systemically active acaricide may be selected from one of the following well-known classes of acaricides, including: antibiotic acaricides such as abamectin, doramectin, eprinomecitin, ivermecithin, milbemecytin, nikkomycin, selamecytin, tetranactin and thuringiensin; bridged diphenyl acaricides such as azobenzene, benzoxate, benzyl benzoate, bromopropylene, chlorobizide, chlorfenetol, chlorphenone, chlorphenesulfide, chlorobenzyl, chloropropylate, dicofol, diphenylsulfone, dofenapine, fensone, fentrifanil, fluorocidide, proclofenol, tetradifon and tetrasul; carbamate acaricides such as benomyl, carbanolate, carbaryl, carbofuran, phenothiocarb, methiocarb, metolcarb, promacil and propoxur; oxymo carbamate acaricides such as aldicarb, butocarboxym, oxamyl, thiocaboxime and thiofanox; dinitrophenol acaricides such as binapacryl, dinex, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinopentone, dinosulfone, dinoterbon and DNOC; formamidine acaricides such as amitraz, chlordimeform, chloromebuform, formetanate, mite growth regulators such as clofentazine, dofenapin, fluazuron, flubenzimine, flucycloxuron, flufenoxuron and hexytiazox; organochlorine acaricides such as bromocyclene, camfechlor, dienochlor and endosulfan; organotin acaricides such as azocyclotin, cyhexatin and fenbutatin oxide; pyrazole acaricides such as acetoprol, Fipronil and analogs, and dinopentone, dinosulfone, dinoterbon and DNOC; formamidine acaricides such as amitraz, chlordimeform, chloromebuform, formetanate, mite growth regulators such as clofentazine, dofenapin, fluazuron, flubenzimine, flucycloxuron, flufenoxuron and hexytiazox; organochlorine acaricides such as bromocyclene, camfechlor, dienochlor and endosulfan; organotin acaricides such as azocyclotin, cyhexatin and fenbutatin oxide; pyrazole acaricides such as acetoprol, Fipronil and analogs, and dinopentone, dinosulfone, dinoterbon and DNOC; formamidine acaricides such as amitraz, chlordimeform, chloromebuform, formetanate, mite growth regulators such as clofentazine, dofenapin, fluazuron, flubenzimine, flucycloxuron, flufenoxuron and hexytiazox; organochlorine acaricides such as bromocyclene, camfechlor, dienochlor and endosulfan; organotin acaricides such as azocyclotin, cyhexatin and fenbutatin oxide; pyrazole acaricides such as acetoprol, Fipronil and analogs, and organotin acaricides such as azocyclotin, cyhexatin and fenbutatin oxide; pyrazole acaricides such as acetoprol, Fipronil and analogs, and organotin acaricides such as azocyclotin, cyhexatin and fenbutatin oxide; pyrazole acaricides such as acetoprol, Fipronil and analogs, andderivatives, tebufenpyrad and vaniliprol; Pyrethroid acaricides including: pyrethroid ester acaricides like acrinatrin, bifentrin, cyhalotrin, cypermetrin, alpha-cypermetrin, fenpropatrin, fenvalerate, flucytryrate, flumetrin, fluvalinate, tau-fluvalinate and permetrin, and pyrethroid ether acaricides like halfenprox; quinoxaline acaricides such as quinomethionate and thiokvinox; sulfur-ester acaricides such as propargite; tetronic acid based acaricides such as spirodiclofen; and unacclyed acaricides such as acequinocyl, amidoflumet, arsenic oxide, chloromethiuron, closantel, crotamiton, diafenthiuron, dichlofluanid, disulfiram, fenazaflor, fenazakwin, fenpirixymat, fluacripyrim, fluenetil, mesulfene, MNAF, nilfluride, piridaben, pyrimidifen, sulfiram, sulfuramide, sulfur and tiaraten.

Suitable insecticides acting either as insecticides for adult forms or insect growth regulators (IGR) can be selected from a variety of well-known different classes of chemical compounds such as chlorinated hydrocarbons, organic phosphates, carbamates, pyrethroids, formamidines, borates, phenylpyrazoles and macro-cyclic lactones ( previously known as avermectin). Prominent representatives of insecticides for adult forms / insecticides are imidacloprid, fention, fipronil, allethrin, resmetrin, fenvalerat, permethrin, malathion and their derivatives. Insecticides for adult forms kill insects in almost every state of development by contact or as a stomach poison. Widely used representatives of insect growth regulators (IGR) are e.g. benzoylphenyl ureas such as diflubenzuron, lufenuron, niviflumuron, hexaflumuron, triflumuron and teflubenzuron or substances such as fenoxycarb, pyriproxyfen, metoprene, kinoprene, hydroprene, cyromazine, buprofezin, pymetrozine and their derivatives. Insect growth inhibitors or insect growth regulators (all of which are commonly referred to as IRGs) are products or materials that inhibit or interrupt the life cycle of pests.

It seems evident that the very palatable, ductile, chewable veterinary composition of the present invention is also very suitable for the administration of active ingredients that fight against internal parasites (endo-parasites) such as worms living in the blood or other organs of the animal. In this case, the active ingredient may be the anti-flatfish drug (anti-worm drug).

Anti-flatulence drugs (anti-worm drugs) are a heterogeneous group of drugs, but are selectively toxic to worms. Drugs can achieve this either by inhibiting metabolic processes of viable importance for the parasite, or by causing the parasite to be exposed to a higher drug concentration than the host cells, which means that a beneficial therapeutic window can be used. Anti-flatulent drugs can affect the target parasite during treatment by affecting the integrity of the parasite's cells, inhibiting neuromuscular transmission and coordination or mechanisms that protect against host immunity, ultimately leading to hunger, neuromuscular paralysis, death and expulsion of the parasite. Anti-flatulent medications are commonly given by soaking, in the form of a paste, orally or via injections. The medications are absorbed into the blood stream and widely spread. They are metabolized in the liver and excreted in the faeces and urine. In the field of animal health, anti-flatfish medications are widely used against the nematodes, nematodes, tapeworms, intestinal villi, trichomonas, hookworms, pinworms, trichinellates (trichinellosis) and other less common organisms such as hepatic fascioli and other less-common organisms in a wide range of animals such as steers, cattle, pigs, goats, horses and pets like dogs and cats. The spectrum of activity of medicaments against fetuses for dogs and cats includes butterflyflies such as Alaria alata and Opisthorchis tenuicollis; tapeworms such as Taenia hydatigena, Taenia pisiformis, Taenia ovis, Hydatigena Taenia taeniaeformis, Echinoccocus granulosus, Echinoccocus multilocularis, Dipylidium caninum, Diphyliobothrium latum, Multiceps multiceps, Multiceps serialis, Mesocestoides lineatus and Mesocestoides corti; and nematodes such as Ancylostoma caninum, Uncinaria stenocephaia, Toxocara canis, Toxocara cati, Toxascaris leonina, Strongyloides stercoralis, Filaroides perier, Capillaria aerophila, Capillaria plica, Capillaria hepatica, Trichinella spiralis, Angiostrongylus vasorum, Trichuris vulpis, Spirocerca lupi, Dirofilaria immitis, Ancylostoma tubaeforme and Aelurostrongyius abstrusus.

Internal parasites, according to the present invention, are all types of infection with worms (bats) but also with bacteria and viruses causing bacterial and viral infections, in particular those that infect organs or parts of the body such as the lungs, heart, digestive tract, limbs or spread on the whole body.

The parasite control agents may be selected from agents for controlling parasites, exteriors and agents for combating both of these parasite groups, comprising one of the following well-known anthelmintic groups such as macrocyclic lactones (sometimes referred to simply as macrolides), benzimidazoles, pro-drugs. -benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organic phosphates and piperazines.

The most favorable group of parasite agents contains more modern natural or chemically modified macrocyclic lactones (macrolides) such as avermectins, milbemycins and their derivatives containing their key representatives such as Ivermectin, Doromecytin, Moxidecitin, Selamecytin,

Emamecytin, Eprinomecytin, Milbermecithin, Abamecytin, Milbermecithin oxime,

Nemadecitin and its derivatives in free form or in the form of a physiologically acceptable salt.

Macrocyclic lactones are most preferred because they exhibit a broad spectrum of activities. Many of them show ecto- and parallel endo-parasiticidal activity. So they are called endo-occipants. Macrocyclic lactones bind to the chloroglutamic acid channel causing first paralysis and subsequent death of the parasite.

In the context of the invention, preferably a group of macrocyclic lactones is represented

<img file="PL1675474T3_D0001.tif" />

where X is -C (H) (OH) -; -WHAT)-; or -C (= N-OH) -; Y is -C (H₂) -; = C (H) -; -C (H) (OH) -; or C (N-OCH₃) -; Ri is hydrogen or one of the radicals

<img file="PL1675474T3_D0002.tif" />

R4 is hydroxyl, -NH-CH3 or -NH-OCH3; R₂ is hydrogen, -CH3, -C₂H₅, -CH (CH 3) CH₃ , -C12 E11 (C12): 3) C2₂^ 5, -C '(CHfi) CHICHICHi22 or cyclohexyl; and if and ties between atoms 22 and 23 represents a double bond, the carbon atom in position 23 is unsubstituted, so Y is = C (H) -, or if the bond between atoms 22 and 23 is a single bond, the carbon atom in position 23 is unsubstituted or substituted by hydroxy or by a group = NO-CH3 so Y is -C (H2) -; -C (H) (OH) -; or C (= N-OCH3) -; as a free compound or as a physiologically acceptable salt.

Typical and particularly preferred representatives of the compounds of formula (I) are:

1) Ivermectin is 22, 23-Dihydroabamectin; 22,23-dihydroavermectin B 1; or 22, 23 dihydro C-076B 1, wherein X is C (H) (OH) -; Y is -C (H₂) -; Ri is a radical

<img file="PL1675474T3_D0003.tif" />

R2 is either Cl I ('C.I.₃) -CI I3 or -CH (CH₃) -C₂H₅ and the bond between atoms 22 and 23 is a single bond. Ivermectin is known from US-4,199,569

2) Doramectin is 25-cyclohexyl-5-demethyl-25-de (1-methylpropyl) avermectin A 1a, wherein X is C (H) (OH) -; Y is = C (H) -; R1 is a radical

<img file="PL1675474T3_D0004.tif" />

R2 is cyclohexyl and the bond between atoms 22 and 23 is a double bond. Doramectin is known from US 5,089,480.

3) Moxidectin is [6 R, 23 E, 25 S (E)] - 5- O- Demethyl-28-deoxy-25- (1,3-dimethyl-1-butenyl) -6,28-epoxy-23- (methoxyimino) ) mibermycin B, where X is ClHllOH) -: Y is C (= N-OCH₃) -; R1 is hydrogen; R₂ is -C (CH₃) = CH-CH (CH3)₂; and the bond between atoms 22 and 23 is a single bond. Moxidectin is known from EP-0,237,339 and US4,916,154.

4) Selamectin is a 25-cyclohexyl-25-de (1-methylpropyl) -5-deoxy-22,23 dihydro-5- (hydroimino) avermectin B1 monosilicate and thus a compound of formula (I) where X is C (NOH) - ; Y is -C (H2) -; R1 is a radical

<img file="PL1675474T3_D0005.tif" />

R₂ is cyclohexyl; and the bond between atoms and 22 and 23 is a single bond.

Selamectin is known e.g. from ECTOPARASITE ACTIVITY OF SELAMECTIN; New endectocides for dogs and cats. Pfizer Symposium, conducted in conjunction with the 17th International Conference of the World Association for the Advancement of Veterinary Parasitology, August 19, 1999. Copenhagen, Denmark.

5) Emamectin is (4 "R) -5- O -demetyl-4" deoxy-4 "((methlamino) avermectin A 1a and (4" R) -5-O-dimethyl-25-de (1-methylpropyl) -4 "-deoxy-4" ((methylamino) -25- (1-methylethyl) avermectin A 1a (9: 1), wherein X is C (H 1) (OH) - Y is -C (H 2) -; is

<img file="PL1675474T3_D0006.tif" />

R2 is -CH (CH3) -CH3 or -CH (CH3) -C2H₅ and the bond between atoms 22 and 23 is a double bond. Emamectin is known from US-4,874,749.

6) Eprinomectin is (4 "R) -4" -epi- (acetylamino) -4 "-deoxyavermectin B 1, wherein X is C (H 1) (OH) -; Y is = C (H) - · R1 is a radical

<img file="PL1675474T3_D0007.tif" />

R2 is -CH (CH3) -CH3 or -CH (CH3) -C2H₅ and the bond between atoms 22 and 23 is a double bond. Eprinomectin is known from US-4,427,663.

7) Milbermectin is (6R, 25R) -5-O-demethyl-28-deoxy-6,28-epoxy-25-methylmilbermycin, where X is C (H) (OH) -; Y is -C (H₂) -; Ri is hydrogen; R2 is CH3 or -C2H5; and the bond between atoms 22 and 223 is a single bond. Milbermectin is known from US-3,950,360.

8) Abamectin is Avermectin B i, which is also referred to as 5-OdemeSylavermekSyn Ala and 5-O-demethyl-25-de (1-methylpropyl) -25- (1-methylethyl) avermectin Aia (4: i), where X is C (H) (OH) -; Y is = C (H) - · Ri is a radical

<img file="PL1675474T3_D0008.tif" />

R2 is -CH (CH3) -CH3 or -CH (CH3) -C2H5 and the bond between atoms 22 and 23 is a double bond. Abamectin is known from US-4.310,5 and 9.

9) Milbemycin Oxime is Milbemycin A-5-oxime; Milbemycin 5-oxime A 3, 15 where X is C (II) (OI I) -; Y is -C (H2) -; Ri is hydrogen; R2 is -CH (CH3) -CH3 or CH (CH3) -C2H5 and the bond between atoms 22 and 23 is a single bond. Milbemycin oxime is known from US-4,547,520.

10) A compound of formula (I) wherein X is C (II) (OII) -; Y is -C (H2) -; Ri is a radical

<img file="PL1675474T3_D0009.tif" />

R2 is CH; or -C2H5; and the bond between atoms 22 and 23 is a single bond. This compound is known from WO 0383500.

11) Nemadectin is an antibiotic S-541A, also called [6R, 23S, 25S, (E)] - 5-Odemetyl-28-deoxy-25- (1,3-dimethyl-1-butenyl) -6,28-epoxy -23-hydroksymilbermycyną

B; where X is = CH-OH; Y is -C (H₂) -; Ri is hydrogen; IR is -C (CH₃) = CH-CH (CH₃) 2, and the bond between atoms 22 and 23 is a single bond. Nemadektyna is known for

US-4,869,90E

The compounds mentioned in items i-ii are preferred embodiments of the present invention and can be used alone or in combination with other agents for controlling the parasites, external and internal agents for combating these two groups of parasites.

Benzimidazoles, benzimidazole carbamates and pro-benzimidazoles interact with energy metabolism by inhibiting microtubule polymerization and contain very strong compounds such as thiabendazole, mebendazole, fenbendazole, oxfendazole, oxybendazole, albendazole, luxabendazole, netobimin, parbendazole, flubendazole, cyclobendazole, febantel, thiophanate and their derivatives.

Imisadothiazoles are cholinesterase inhibitors and contain highly active compounds such as tetramisole, levamisole and their derivatives.

Tetrahydropyrimidines also act as cholinesterase inhibitors and contain highly active compounds such as morantel, pirantel and their derivatives.

Organic phosphates are cholinesterase inhibitors. This class contains effective compounds such as dichlorvos, haloxone, trichlorfone and their derivatives.

Piperazines exhibit anticholinergic activity and block the neuromuscular transmission. This class contains effective compounds such as piperazine and its derivatives.

Salicylanilide selected from closantel, tribromsalan, dibromsalan, oxychlozanid, clioxanid, rafoxanide, brothianid, bromoxanide and derivatives thereof.

In the present invention, the preferred embodiment of the anti-healing drug (anthelmintic drug) is a combination of macrocyclic lactone and anti-flatfish drug selected from the group consisting of Albendazole, Clorsulon, Cydectin, Dietharbamazine, Febantel, Fenbendazole, Haloxone, Levimasol, Mebendazole, Morantel, Oxyclozanide, Oxybendazole , Oxfendazole, Oxamatin, Pyrantel, Piperazin, Prazaquantel, Thiabendazole,

Tetramisol, Trichlorfon and their derivatives. The most preferred is Prazykwantel. In order to broaden the spectrum of activity towards ecto-parasites, said anti-amphibian drug combination may contain in addition to anti-worm drugs, a parasiticidal effective amount of an insecticide, acaricide or insecticide and acaricide. Of course, you can also add an antibiotic to treat a bacterial disease.

All of the parasiticides mentioned above are known. Most of them are described in THE MERCK INDEX 1999 by Merck &amp; Co Inc, Whitehouse Station, NJ, USA; published on CD-ROM by Chapman &amp; Hill / CRC, 1999, Hampden Data Service, Ltd. and specialist literature mentioned in THE MERCK INDEX 1999.

Suitable bactericidal active agents are e.g. various penicillins, tetracyclines, sulfonamides, cephalosporins, cephamycins, aminoglucosides, trimethoprims, dimetridazoles, erythromycins, framycetes, frazazolidones, various pleuromutilins such as tiamulin, valnemulin, various macrolides, streptomycin and anti-protozoan active ingredients, e.g. clopidol, salinomycin, monensin, halofuginone, narasin, robenidine, etc.

Behavioral disorders include sadness of separation or motion sickness of dogs and cats. A suitable compound that acts against behavioral disorders is, e.g., clomipramine.

The chewable combination of the present invention may also contain an active ingredient for the treatment of dysfunction or hypoactivity.

Dysfunction or hypo-activity is understood as an autoimmune disorder, which has a deviation from the norm, whether by inborn or acquired damage to individual organs or tissues. This syndrome also contains rheumatic diseases, pathological changes in the joints, bones or internal organs and much more. An outstanding representative of compounds that can be used in this complex field is cyclosporine and its derivatives. The term "animal disease" even includes various types of cancer and progressive metastases in connective tissue that are common in animals. Bisphosphates such as corndronate, clodronate, etidronate, pamidronate and alendronate play an important role in this field. These bisphosphates may also be used to treat or prevent ulcers, rheumatoid arthritis and other inflammations and periodontitis. Another suitable class of active ingredients includes anti-inflammatory agents such as benzenesulfonamides, e.g. Deracoxib, which is most suitable for the control of pain and inflammation associated with osteomyelitis. Further anti-inflammatory agents are diclofenac and its derivatives.

In the present invention, the problems of administering drugs presented in connection with a conventional oral dosage form, such as tablets and capsules, can be very easily solved and the chewable products can be prepared so that the animals can take them orally without any problem. The animals are currently eagerly chewable veterinary compositions.

Summary of the invention.

The present invention overcomes the disadvantages and drawbacks of the prior art by providing an easy-to-use, safe, potent and stable veterinary product consisting of a very palatable ductile compostable composition (or about room temperature) and wherein the extruder is cooled below room temperature, preferably up to 5 hours. -10 ° C. A tasty, ductile, chewable composition is a veterinary composition and is administered orally. This composition is capable of killing endo-parasites and ectoparasites and / or can be used for the prophylaxis or treatment of animal diseases and is useful for the treatment of any warm-blooded non-human animal, including animal livestock consisting of horses, cattle, sheep, poultry and individual dogs and cats.

The very palatable, ductile, chewable veterinary composition of the invention consists of a mixture of organic compounds that contains an effective amount of one or more active ingredients, preferably an effective amount of a single, double or triple mixture of active organic compounds capable of controlling ectoparasites, endo-parasites, bacterial or viral pathogens or a combination of ecto-parasites, endo-parasites, bacterial or viral pathogens. Depending on the method, a very palatable, ductile, chewable veterinary composition according to the invention comprises an effective parasiticidal or anti-pathogenic amount of one or more active ingredients. The expression "effective parasiticidal amount" refers to that amount of active ingredient in the composition, which will fully control the target parasites, which means that 95-100%, preferably 98-100% or nearly 100% of these parasites will die and the active ingredient will be well tolerated. The expression "effective anti-pathogenic amount" refers to that amount of active ingredient in a composition that will efficiently cure a bacterial, viral or behavioral disease, or in prophylactic use will completely remove the possibility of an outbreak of such disease. The very palatable, ductile, chewable veterinary composition of the invention comprises an effective amount of one or more ingredients that are active against animal parasites, pathogens or animal diseases; moreover, it contains a meat flavoring and partially gelatinized starch and contains a plasticizer; and at most 9% (w / w), preferably 3-7% (w / w), most preferably 4-6% (w / w) of water. It is essential that during the extrusion process the extruder is cooled below room temperature. The ideal temperature range j^est 5^-10^aboutC.

Each of the following paragraphs defines a preferred embodiment of the present invention.

A very palatable, ductile, chewable veterinary composition that contains (A) an effective amount of one or more components that are active against animal parasites, pathogens or animal diseases; (B) meat flavored addition; (C) partially gelatinized starch; (D) plasticizer; and (E) optional, at most 9% (w / w) of water.

Very tasty, ductile, chewable veterinary composition as defined above, controlling non-human endo-parasites and at the same time ectoparasites of animals.

A very palatable, ductile, chewable veterinary composition as defined above, wherein the animal disease relies on bacterial infections, viral infections, behavioral diseases, inflammatory diseases and immune diseases.

A very palatable, ductile, chewable veterinary composition as defined above, containing 20 to 30% (w / w) of a natural meat flavoring.

Very tasty, ductile, chewable veterinary composition as defined above, where the natural meat flavored addition contains 20 to 55% (w / w) of fat.

A very palatable, ductile, chewable veterinary composition as defined above, containing 25 to 70% (w / w) of partially gelatinized starch.

A very palatable, ductile, chewable veterinary composition as defined above, wherein the partially gelatinized starch contains 12 to 17% (w / w) of gelled starch.

A very palatable, ductile, chewable veterinary composition as defined above, containing 10 to 20% (w / w), preferably 11 to 15% (w / w) plasticizer calculated on the weight of the partially gelatinized starch.

A very palatable, ductile, chewable veterinary composition as defined above wherein the softener is selected from the group consisting of glycerol, polyethylene glycol and polypropylene glycol.

Very tasty, ductile, chewable veterinary composition as defined above, containing at most 9% (w / w), preferably 3 to 7% (w / w), most preferably 4 to 6% (w / w) of water.

Very tasty, ductile, chewable veterinary composition as defined above, containing 1 to 10% (w / w), preferably 3 to 7% (w / w) of the sweetener.

A very palatable, ductile, chewable veterinary composition as defined above, containing 0 to 3.5% (w / w), preferably 0.01 to 0.5% (w / w) of the antioxidant.

Very tasty, ductile, chewable veterinary composition as defined above, containing 0 to 5% (w / w), preferably 0.05 to 2% (w / w) coloring agent.

Very tasty, ductile, chewable veterinary composition as defined above, containing 0 to 4% (w / w) of sodium chloride.

Very tasty, ductile, chewable veterinary composition as defined above, containing an effective parasiticidal amount of ecto-parasiticide, endoparasiticide, endocardicide or a combination of parasiticides selected from the group consisting of ecto-parasiticide, endo-parasiticide and endocardicide.

A very palatable, ductile, chewable veterinary composition as defined above, wherein the ecto-parasiticide is active against insects, members of the order Acarina or insects and members of the order Acarina.

A very palatable, ductile, chewable veterinary composition as defined above, wherein the ecto-parasiticide is an insecticide that either kills adult forms or regulates the growth of these forms.

A very palatable, ductile, chewable veterinary composition as defined above, comprising a parasiticidal amount of an endo-parasitic or endo-parasiticide agent selected from the group consisting of macrocyclic lactones, benzimidazoles, pro-benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organic phosphates and piperazines.

Very tasty, ductile, chewable veterinary composition as defined

<img file="PL1675474T3_D0010.tif" />

where X is -C (H) (OH) -; -WHAT)-; or -C (= N-OH) -; Y is -C (H₂) -; = C (H) -; -C (H) (OH) -; or C (\ -OCH₃) -; Ri is hydrogen or one of the radicals

<img file="PL1675474T3_D0011.tif" />

R4 is hydroxyl, -NH-CH3 or -H-OCH₃; R₂ is hydrogen, -CH3, -C₂H₅, -CH (CH₃) CH3, -CH (CH3) -C2H₅, -C (CH 3) = CH-CH (CH 3) 2 or cyclohexyl; and if the bond between atoms 22 and 23 represents a double bond, the carbon atom at position 23 is unsubstituted, so Y is = C (H) -, or if the bond between atoms 22 and 23 is a single bond, the carbon at position 23 is unsubstituted or substituted by a hydroxy group or a group = NO-CH3 so Y is -C (H2) -; -C (H) (OH) -; or C (= N-OCH3) -; as a free compound or as a physiologically acceptable salt.

A very palatable, ductile, chewable veterinary composition as defined above, comprising an effective amount of a natural or chemically modified macrocyclic lactone of formula (I) wherein X is -C (ff) (OH) -; Y is -C (H₂) -; Ri is a radical

<img file="PL1675474T3_D0012.tif" />

R2 is CH3 or C2H5, and the bond between atoms 22 and 23 is a single bond. Very tasty, ductile, chewable veterinary composition as defined above, where animal pests are external and parasitic and animal and / or internal animal parasites or both.

A very palatable, ductile, chewable veterinary composition as defined above, wherein the macrocyclic lactone is selected from the group consisting of avermectins, milbemecithins and their derivatives in free form or in the form of a physiologically acceptable salt.

A very palatable, ductile, chewable veterinary composition as defined above, wherein the macrocyclic lactone is selected from the group comprising Ivermecithin, Doromecytin, Moxidecitin, Selamecytin, Emamecytin, Eprinomecytin, Milbermecithin, Abamecytin, Milbermectyin oxime, Nemadecytin and their derivatives in free form or in the form physiologically acceptable salt.

A very palatable, ductile, chewable veterinary composition as defined above, comprising an effective amount of a macrocyclic lactone in combination with an effective amount of an anti-worm drug selected from the group comprising Albendazole, Clorsulon, Cydectin, Diethylcarbomazine, Febantel, Fenbedazole, Haloxon, Levamisol, Mebendazole,

Morantel, Oxyclozanide, Oxbenendazole, Oxfendazole, Oxfendazole, Oxamniquin, Pyrantel, Piperazine, Prazaquantel, Thiabendazole, Tetramisol, Trichlorfon, Thiabendazole and their derivatives.

A very palatable, ductile, chewable veterinary composition as defined above, further comprising an effective amount of an insecticide, a mite destroying agent or an insecticide and a mites destroying agent.

A very palatable, ductile, chewable veterinary composition as defined above, containing an effective amount of milbemycin oxime and praziquantel.

A very palatable, ductile, chewable veterinary composition as defined above, containing an effective amount of lufenuron, praziquantel and milbemycin oxime.

Very tasty, ductile, chewable veterinary composition as defined above, containing an effective amount of cyclosporin

Very palatable, ductile, chewable veterinary composition as defined above, containing an effective amount of antibacterial agents selected from the group consisting of penicillin, tetracycline, sulfonamide, cephalosporin, cephamycin, aminoglucoside, trimethoprim, dimetridazole, erythromycin, framycetin, frualizodine, pieuromutiline, streptomycin and a compound that he is active against protozoa.

A very palatable, ductile, chewable veterinary composition as defined above, comprising an effective amount of a compound that is active against behavior including separation sadness or motion sickness of dogs and cats.

A very palatable, ductile, chewable veterinary composition as defined above, wherein the active ingredient or other chemical class is an insecticide or acaricide.

A very palatable, ductile, chewable veterinary composition as defined above, wherein the insecticide is selected from the group of agents that kill adult forms or regulate the growth of these forms.

Another preferred embodiment of the present invention is a method of controlling the animal pests or pathogens contemplated and treating or preventing the animal diseases contemplated by providing the animal with a very palatable ductile oral chewable composition discussed herein.

Yet another preferred embodiment of the present invention is a method of controlling said animal pests or pathogens and treating or preventing said animal diseases by providing said very palatable ductile animal with an animal subject to this veterinary composition.

Yet another preferred embodiment of the present invention is a method of producing a very palatable ductile chewable veterinary food as defined above, comprising (i) filling the extruder hopper with an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases; meat-flavored addition; partially gelatinized starch; a plasticizer and up to 9% (w / w) of water, (ii) a constant cooling of the mixture of active ingredients and carriers so that the temperature of the extruder leaving the outlet does not exceed 40 ° C throughout the extrusion time, (iii) compression of the extruder extruded through the extruder a die that is responsible for the shape of the chewable product, and (iv) cutting the extruder extruded into the same parts.

Yet another preferred embodiment of the present invention is a method as defined above, wherein the extruder is fed continuously and simultaneously with pre-mixture (1) and pre-mixture (2), wherein the pre-mixture (1) consists of a homogeneous mixture of one or more active ingredients and partially gelatinized starch, and the pre-mixture (2) consists of a homogeneous mixture of meat flavors, a softener and alternatively a carrier selected from the group consisting of a sweetener, a plasticizer, an antioxidant, a coloring agent and sodium chloride.

Yet another preferred embodiment of the present invention is a method as defined above, wherein the extruder is cooled below room temperature.

A further preferred method of the present invention is a method of controlling non-human animal or non-human animal pathogens or treating or preventing non-human animal diseases by using the very palatable ductile chewable veterinary food as defined above.

A further preferred method of the present invention is a method as defined above, wherein the highly palatable ductile chewable veterinary food consists of one chewable portion containing an effective amount of a compound or mixture of compounds capable of controlling non-human animal poultry or non-human animal pathogens. human or treating or preventing non-human animal diseases.

A further preferred embodiment of the present invention is a method as defined above, wherein the amount of active ingredient is adapted to the weight of the animal that needs treatment.

Another preferred embodiment of the present invention is the use of (A) an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases; (B) meat flavored additions; (C) partially gelatinized starch; (D) plasticizer; (E) up to 9% (w / w) of water; and an active ingredient suitable for combating animal pests, pathogens or animal diseases for obtaining a very palatable ductile chewable veterinary composition.

Another preferred embodiment of the present invention is the use as defined above, comprising 20 to 30% (w / w) of a natural meat flavoring.

Another preferred embodiment of the present invention is the use as defined above, wherein the natural meat flavoring includes 20 to 55% (w / w) fat.

Another preferred embodiment of the invention is the use as defined above, comprising 25 to 70% (w / w) of partially gelatinized starch.

Another preferred embodiment of the present invention is the use as defined above, wherein the partially gelatinized starch comprises 12 to 17% (w / w) of gelatinized starch.

Another preferred embodiment of the present invention is the use as defined above, comprising 10 to 20% (w / w) of a plasticizer with respect to the weight of the partially gelatinized starch.

Another preferred embodiment of the present invention is the use as defined above, wherein the softener is selected from the group consisting of glycerol, polyethylene glycol and polypropylene glycol.

Another preferred embodiment of the present invention is the use as defined above, comprising 3 to 7% (w / w) of water.

Another preferred embodiment of the present invention is the use as defined above, wherein the animal pests are external animal parasitic factors or internal animal parasitic factors or both animal parasitic factors.

Another preferred embodiment of the present invention is the use as defined above, comprising 1 to 10% (w / w) of the sweetener.

Another preferred embodiment of the present invention is the use as defined above, including 0 to 3.5% (w / w) of the antioxidant.

Another preferred embodiment of the present invention is the use as defined above, comprising 0 to 5% (w / w) of the coloring agent.

Another preferred embodiment of the present invention is the use as defined above, comprising 0 to 4% (w / w) sodium chloride.

Another preferred embodiment of the present invention is the use as defined above, comprising an effective parasiticidal amount of an ecto-parasiticide, endo-parasiticide, endoecto-parasiticide or a combination of parasiticides selected from the group consisting of an ecto-parasiticide, endo-parasiticide and endocardicide.

Another preferred embodiment of the present invention is the use as defined above, wherein the ecto-parasiticide is active against insects, members of the order Acarina or insects and members of the order Acarina.

Another preferred embodiment of the present invention is the use as defined above, wherein the ecto-parasiticide is an insecticide that either kills adult forms or regulates the growth of these forms.

Another preferred embodiment of the present invention is the use as defined above, comprising a parasiticidal amount of endoparasicide or endo-parasiticide selected from the group comprising macrocyclic lactones, benzimidazoles, pro-benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organic phosphates and piperazines.

Another preferred embodiment of the present invention is the use of as

<img file="PL1675474T3_D0013.tif" />

wherein X is -C (H) (OH) -; -WHAT)-; or C '(N-OH) -; Y is -C (H₂) -; = C (H) -; -C (H) (OH) -;

or C (N-OCH₃) -; Ri is hydrogen or one of the radicals

<img file="PL1675474T3_D0014.tif" />

R4 is hydroxyl, -NH-CH3 or -NH-OCH3; R₂ is hydrogen, -CH3, -C₂H₅, -CH (CH3) CH3, -CH (CH3) -C2H₅, -C (CH 3) = CH-CH (CH 3) 2 or cyclohexyl; and if the bond between atoms 22 and 23 represents a double bond, the carbon atom at position 23 is unsubstituted, so Y is = C (H) -, or if the bond between atoms 22 and 23 is a single bond, the carbon at position 23 is unsubstituted or substituted by a hydroxyl group or by a group = NO-CH3 so Y is -CfHty-; -C (H) (OH) -; or C (= N-OCH3) -; as a free compound or as a physiologically acceptable salt.

Another preferred embodiment of the present invention is the use as defined above, wherein the macrocyclic lactone is a compound of formula (I) wherein X is -C (H) (OH) -; Y is -C (H₂) -; R1 is a radical

<img file="PL1675474T3_D0015.tif" />

R₂ is -CH3 or -C₂H₅, and the bond between atoms 22 and 23 is a single bond. Another preferred embodiment of the present invention is the use as defined above, wherein the endoekto-parasiticide agent is a macrocyclic lactone selected from the group consisting of avermectin, milbemycin and derivatives in free form or in the form of a physiologically acceptable salt.

Another preferred embodiment of the present invention is the use as defined above, wherein the macrocyclic lactone is selected from the group consisting of Ivermecithin, Doramecytin, Moksydecytin, Selamecytin, Emamecytin,

Eprinomecitin, Milbermecithin, Abamecytin, Milbermecithin oxime, Nemadecithin and their derivatives in free form or in the form of a physiologically acceptable salt.

Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of a macrocyclic lactone in combination with an effective amount of an anti-worm drug selected from the group comprising Albendazole,

Clorsulon, Cydectin, Diethylcarbomazine, Febantel, Fenbedazole, Haloxon, Levamisol, Mebendazole, Morantel, Oxyclycanid, Oxbenendazole, Oxfendazole, Oxfendazole, Oxamniquin, Pyrantel, Piperazine, Prazaquantel, Thiabendazole, Tetramisol, Trichlorfon, Thiabendazole and their derivatives.

Another preferred embodiment of the present invention is the use as defined above, comprising in combination with an endo-parasiticidal or endo-parasiticidal, an effective amount of insecticide, acaricide or insecticide and acaricide.

Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of milbemycin oxime and praziquantel.

Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of lufenuron, praziquantel and milbemycin oxime.

Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of cyclosporin.

Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of an antibacterial agent selected from the group consisting of penicillin, tetracycline, sulfonamide, cephalosporin, cephamycin, aminoglucoside, trimethroprim, dimetridazole, erythromycin, framycetin, frualizodine, pleuromutilin, streptomycin and a compound which he is active against protozoa.

Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of a compound that is active against behavioral disorders including separation, sadness or motion sickness of dogs and cats.

An additional preferred embodiment of the present invention is the use of a highly palatable ductile chewable veterinary composition as defined above in the process for controlling non-human animal pests or non-human animal pathogens or treating or preventing non-human animal diseases.

Detailed description of the present invention

Even if the meat flavoring additive is not the main ingredient of a very palatable ductile chewable veterinary composition, it plays a large role in the present invention. Surprisingly, it has been found that the desired palatability that is necessary to obtain reliable and reproducible results is closely dependent on the amount of meat flavoring in the final composition. This meat flavor supplement is a natural product consisting of dried powdered meat originating, for example, from domestic animals and productive livestock, such as pigs, horses, cattle, sheep, goats and poultry, including chickens, ducks, geese and turkeys. Unexpectedly turned out, that the natural fat content of said natural pulverized meat of 20-55% (w / w) is important not only to achieve the desired flavor and excellent taste for animals, but also to achieve the desired softness of the final chewable product. In the context of the present invention, the term "meat flavoring" will mean both natural dried and powdered meat as well as artificial meat taste, which is well known in the food industry. It has been found that these meat-flavored artificial additives match the present invention if they already contain 2055% (w / w) fat or if this amount of fat is added to the meat-flavored artificial addition. The fat which can be added to the artificial meat flavoring can be selected from animal fats or preferably, from vegetable fats containing vegetable oil. When using vegetable oils, it is preferable to use hardened / saturated oils. Unsaturated oils are usually liquids at room temperature and as a result the product does not show toughness / softness. They are usually too soft. Preference is given to using hardened / saturated oils / fats, which are usually solid at room temperature, which leads to chewable compositions exhibiting the desired ductility.

Fats and oils contain a variety of fatty acids that have different effects on the body. The easiest way is to classify them as saturated or unsaturated. Saturated fats are sometimes also called hardened fats. Saturated fats are found in many animal products. Saturated fats are usually solid at room temperature. They are mainly of animal origin, but they can also be isolated from plants. Typical examples derived from plants are cocoa butter, coconut oil or palm oil. These products are often used in baked cakes bought in shops, non-dairy whipped toppings, cream substitutes, many types of peanut butter and some margarines. Typical sources of saturated fat are animal fat, coconut oil, meat fat,

The natural and artificial meat-flavored addition is commercially available from various manufacturers.

A natural meat-flavored addition is available, for example, at:

IDF (International Dehydrated Food) INTERNATIONAL DEHYDRATED FOODS, INC.

PO Box 10347 Springfield, Missouri 65808, USA 800 / 641-6509 or 417 / 881-7820

ADF (American Dehydrated Food), American Dehydrated Foods, Inc., PO Box 4087

3801 East Sunshine, Springfield, Missouri 65809

IFF (International Flavor and Fragrance), IFF Global Headquarters, 521 West 57¹¹'Street New York, NY 10019, United States

Proliant, Proliant Inc. - US Office, 2325 North Loop Drive, Ames, IA 50010 USA

The artificial meat flavor is available from sample producers:

Kemin, Worldwide Headquarters, 2100 Maury Street, Box 70, Des Moines, Iowa 50301-0070

USA

McCormick, 226 Schilling Circle, Hunt Valley, MD 21031

Givaudan, Givaudan Flavors Corp. (Flavors creation, sales &amp; production) 1199 Edison Drive Cincinatti, Ohio 45216

Haarman und Reimer

Within the scope of the present invention, the term "soft" is used to characterize a product that is not as hard and crunchy as, for example, roasted corn, and on the other hand is not as malleable as for example toffee candy. The desired ductility / hardness is somewhere in the middle. If the hardness measurements are made with a commercially available Texture Analyzer, which is commercially available in Stable Micro Systems (TA-XT2 and HR / 25), the texture (softness / hardness) of the chewable food is ideally between 6-12 N.

Hard and crunchy products are particularly harmful if someone intends to treat old dogs and cats, because most of these old animals suffer from periodontitis (Pyorrhea). This disease involves inflammation and degeneration of the cells that surround and support the teeth.

This disease affects the gums, alveolar bone, periodontal ligaments and corymbs. Inflammation of the periodontal tissue or loss of the supporting bone is the last stage of progressive discomfort and is the main cause of tooth loss in old dogs and cats.

Animals suffering from periodontitis avoid eating hard and crunchy products that cause them pain.

A second important distinguishing feature of the present invention is the use of partially gelatinized starch. The starch contains 10-20% (w / w), preferably about 13-17% (w / w), most preferably 13-17% (w / w) pre-gelatinized starch. It is important that the non-gelatinized and completely pre-gelatinized starch does not affect the chewiness of the final product.

Starch exhibits thermal stability to about 121 ° C. Starch is a carbohydrate with the general formula (C 6 H 10 O₅) ni originating from maize, cereals, oats, rice, potatoes, yucca and similar plants and vegetables. They consist of about 27% linear polymer (amylose) and about 73% branched polymer (amylopectin). These two polymers are interlaced with starch granules. The granules are insoluble in cold water, but soaking in hot water or under the pressure of water vapor causes their surfaces to burst and the polymers hydrate into a colloidal suspension. The product is a pre-gelatinized starch and has been used as a slurry for many years. In this way, the pre-gelatinized starch is a water-soluble starch that is irreversible when heated in water or steamed. Many suitable pre-gelatinized starch is commercially available. For example, Naster® Instant, which is a pre-gelatinized peanut starch with a high gelling force. Due to its high level of amylose it has several special properties. It exhibits excellent stability at high temperatures, shear and pH changes and is ideal for use in cold processes.

Another important factor is the plasticizer that maintains the moisture in the mixture and allows the final product to be stored for weeks and months.

If the meat flavor additive, partially gelatinized starch and the base compound containing the active ingredient does not contain moisture, water should be added during the extrusion process. This affects the flexibility of the chewable veterinary composition of the present invention. It has been found advantageous to adjust the moisture content of the product so that the final product contains water at a concentration equal to or lower than 9% (w / w), preferably about 3 to 7% (w / w), more preferably 4 to 6% ( w / w).

Not only the proportion between the meat-flavored addition and partially pre-gelatinized starch is of great importance for the present invention, but also the production process that affects the final product. The very palatable, ductile, chewable veterinary composition of the present invention is the result of a special extrusion process. As such, extrusion is a very common method of thermoforming widely used in the food industry to obtain ordinary nutritional pills. However, to achieve the chewable materials of the present invention, it is a very palatable, ductile, chewy product, the method can be modified and the extrudate can be protected so that it is not heated throughout the extrusion process, because it leads to a hard and crunchy product, loss of the active ingredient and in particular to reduce the palatability. Currently, production can be easily achieved in a desirable manner. A very palatable, ductile, chewable veterinary composition according to the present invention is conveniently produced in an injection molding machine or in an extruder. A mixture containing an effective amount of one or more ingredients that are active against animal parasites, pathogens or animal diseases, meat flavoring, partially gelatinized starch, plasticizer and up to 9% (w / w) of water is fed through a funnel to a rotating, moving reciprocating screw. The material moves along the screw towards the outlet. During this process, its temperature is constantly lowered using external coolers placed around the pipe and through the shearing action of the screw. The cooling process is controlled such that the temperature of the expeller leaving the extruder during the entire extrusion process does not exceed the upper limit of 40 ° C. Starting from the feed zone and continuing through the compression zone, the expeller temperature during the entire extrusion process should not reach a temperature higher than said 40 ° C. It has been found that the product is ideally extruded at room temperature or around room temperature and the extruder is cooled below room temperature, preferably to 5-10 ° C. It is then conveyed through the metering zone, where homogenization takes place, to the end of the screw. The homogenised material at the outlet is forced through the press to obtain shaped objects of the required size. The simplest method is to cut the expeller leaving the extruder to equal parts with the required size. "Required" means that each part contains the correct amount of active ingredient. In this way, for example, larger pieces are produced for large dogs than for small cats. The amount of active ingredient is adapted to the body weight of the animal to be treated.

Said cooling during the extrusion process is very important because extruding this type of material without cooling can easily bring the temperature inside the extruder to about 100-200^aboutC. High extrusion temperatures convert the extruded mold in an undesirable manner. The reason for this transformation is that the starch is heated above the melting point and the vitrification of its constituents, so that they undergo endothermic transformation. As a consequence, melting and disruption of the molecular structure of the starch granules takes place, so that essentially damaged starch is obtained. Instead of a ductile and rather soft product, a hard or crunchy product is obtained that is not only rejected by the animals but does not contain a repetitive amount of active ingredients. Many of the active ingredients are not even quite stable at these relatively high temperatures and they are at least partially degraded. As a result, the biological activity of the product is reduced and undesired degradation of the product takes place that may cause undesirable side effects or lead to allergic reactions. Cooling the extruder to temperatures close to room temperatures, preferably 5-10 ° C, suppresses all these undesirable effects and leads to a perfect product that is not only very palatable, but can unexpectedly be stored for months without degradation.

A very palatable, ductile, chewable veterinary composition according to the present invention may contain a sweetener to further improve the palatability. Any natural sugar can be used, including confectioner's sugar, maltitol, xylitol, sorbitol, mannitol, lactose, dextrose, sucrose, glucose or fructose, or any mixture thereof. In addition, artificial sweeteners known to those skilled in the art, including saccharin, aspartame and Acesulfame-K, may also be used. The sweetener is preferably used in amounts of 1 to 10% (w / w), preferably between 3 to about 7% (w / w) based on the sweetening power of the sugar.

The sweetener serves as a flavor enhancer due to its organoleptic properties. Enhancement of palatability can be particularly achieved in those cases where the active ingredient is extremely bitter or has a taste that is absolutely unacceptable to the animal.

The veterinary compositions of the present invention may also contain an antioxidant even when it has been found that in most cases this is not necessary. However, in some instances, the antioxidant serves as a safety feature that increases the stability of ingredients exhibiting instability when in contact with oxygen for a longer period of time. The term "antioxidant" represents three groups of antioxidants, true antioxidants such as Tenox 2, Tenox PG, Tenox s-1, BHA (2-t-butyl-4-methoxyphenol) and BHT (2,6-di-t-butyl-4 methylphenol), sodium bisulfite as reducing agents and synergic antioxidants, such as tocopherols (alpha, beta or delta tocopherols, tocopherol esters, alpha-tocopherol acetate), alkyl galloates, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, edetal acid and its salts, lecithin and tartaric acid. Further preferred antioxidants are resveratrol, quercetin, benzoic acid, Trolox (N-acetylcysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), dimethyl thiourea (DMTU), hesperetin, tetrahydrocurcumin, tetrahydrodemetoxycurcumin and monothioglycerol. Said antioxidants have been added at concentrations ranging from 0 to 3.5% (w / w), preferably 0.01 to 0.5% (w / w). Preferred antioxidants are Tenox 2 and BHA (2-t-butyl-4-methoxyphenol). Said antioxidants have been added at concentrations ranging from 0 to 3.5% (w / w), preferably 0.01 to 0.5% (w / w). Preferred antioxidants are Tenox 2 and BHA (2-t-butyl-4-methoxyphenol). Said antioxidants have been added at concentrations ranging from 0 to 3.5% (w / w), preferably 0.01 to 0.5% (w / w). Preferred antioxidants are Tenox 2 and BHA (2-t-butyl-4-methoxyphenol).

Sodium chloride may also be added up to about 4% (w / w) to further improve the palatability of the product and bind moisture. For some animals, sodium chloride serves as a taste improvement.

The very palatable, ductile, chewable animal composition of the present invention may further comprise a softener. The plasticizer for use in the invention serves as a softening agent that increases the flexibility of the pet food so that the pet food structure is maintained at ambient temperature.

Typically, the softener is present in a very palatable, ductile, chewable veterinary product of the present invention at a concentration of about 10-20% (w / w), and preferably about 11-15% (w / w) with respect to the weight of the partially gelatinized starch. Suitable softeners are alcohols such as sorbitol, mannitol, hexanol, pentanol and polyalcohols (such as glycerol, propylene glycol, polyethylene glycol and polypropylene glycol).

The very palatable, malleable, chewable veterinary compositions of the present invention may further contain a coloring agent that results in a better-looking product. The colorant may be selected from the group of azo dyes, organic or inorganic pigments or coloring agents of natural origin, preferably from iron or titanium oxides. Said coloring agents are added in concentrations from 0 to 5% (w / w), preferably from 0.05 to 2% (w / w).

The preferred colorant is iron oxide, which is normally used in amounts of about 0.1% (w / w).

Technical equipment.

The extruder used to make the chewable materials produced according to the present invention is a co-rotating BCTG-62 / 28D twin screw extruder with a screw diameter D = 62 mm and a screw length with an L / D ratio of L = 28D with a granulating machine from Buhler AG; Industriestrasse; CH-9240 Uzwil; Switzerland. Feeder (supplying dry food to the extruder) can be obtained from K-Tron, Switzerland. It is a feeder operating on the basis of weight loss: a twin screw type feeder K2-ML-T-35 equipped with an AC screw (twin drills). In addition, two pumps were used to supply water and separately glycerine. In addition, two refrigerators were used to keep the temperature of the extruder below 10 ° C.

Measurement of softness / hardness of chewable materials.

The texture (softness / hardness) of a chewy material is measured using a TEXTURE ANALYZEER of the type: TA-XT2 iHR / 25 which is available from Stable Micro Systems Ltd. (Seat: Stable Micro Systems Ltd., Vienna Court, Lammas Road, UK). The maximum force (in N) necessary to push the ball at a speed of 1mm / sec to a depth of 2mm into the interior of the chewable material is measured. The ball has a diameter of 8mm. The texture of the chewable materials is measured to determine when the chewable materials are hard enough to be packed into the containers before they are packed into the blisters. Texture after 24h: typical values ​​are between 8 and 20N. Examples

Example 1: Product with two active ingredients containing Milbermycin oxime and Pseudquezel <a name="caption1"></a>Ingredients Quantity Percentage [w / w]

Active ingredient nr. 1

Oxygene Milbermycin 1,975 kg 0.395%

Active ingredient nr. 2 Prazykwantel. Excipients (excipients)

19,000 kg

3.800%

<td>Pre-gelatinized starch</td><td>255.525 kg</td><td>41.555%</td>

<td>The natural taste of chicken</td><td>155.555 kg</td><td>15.555%</td>

<td>Sugar</td><td>25,555 kg</td><td>5.555%</td>

<td>Sodium chloride powder</td><td>7.555 kg</td><td>1.555%</td>

<td>Iron oxide</td><td>5.555 kg</td><td>5.155%</td>

<td>Total solids</td><td>409,000 kg</td><td>81.800%</td>

<td>Water</td><td>25,555 kg</td><td>4.555%</td>

<td>Glycerine</td><td>75.555 kg</td><td>14.555%</td>

<td>Tenox 2</td><td>1.555 kg</td><td>5.255%</td>

<td>Total liquid bodies</td><td>91.000 kg</td><td>18.200%</td>

<td>The entire set of ingredients</td><td>500,000 kg</td><td>100.000%</td>

The product with two active ingredients containing Milbermycin oxime and Prazykwantel is obtained as follows:

1. Mabbemnycin (19975 kg) and oxideeelzaa (0.500 kg) pre-oxime with 13 kg of pre-gelatinized starch using a V-shaped mixer for 5 min.

2. The pre-mixture is transferred in a vacuum through a 15 mesh screen into the mixing chamber

1. Wheat and si) beer, 1 \ θηίο1 \ θίοικην; · ιην αιΤη '. hhloreksodu, chicken flavor dodttkk and the rest of the pre-gelatinized starch through a 15 mesh screen into the mixing chamber and mixed for 25 min.

4. Refreshing the water to the polemorum and water and holding back the ½ ^ ΐ) hemiresin to the polycarbonate with glycerol and mixes with the tenox.

5. Własaasiz dnyłtaškaekę.

6. Temperstutzlednostki chSodzenla ustdwlasiz on 5⁰C.

7. The dry mix (mix from step 3) is added to the ICT'G thermocouple with the K-tron dosing device.

8. Miesaeninzgiieeneny / Tenoxu 2 zip to the boring machine.

9. Water pompalzsiz to the breaker

10. The speed of the extruder (rpm) is set in accordance with the speed of dispensing of the dry mix

11. The extruder cutting tool is set to obtain the right masses of the chewable products

12. After extrusion, the chewable products are transported by the conveyor to the conveying hopper of the conveyor and finally

13. Packaged for boxes no larger than 3 inches

14. The treatment of chewable products takes about 24 hours. at room temperature and relative humidity &lt;60%

15. After conditioning, the chewable products are packaged in blister packs.

Extruder settings for different product masses of 0.6 g, 1.5 g, 3.0 g and 6.0 g

<td>weight [G]</td><td>Speed administration dry mix^[kg^/him^dwith^]</td><td>Speed adding glycerine^[kg^/him^dwith^]</td><td>Speed adding water^[kg^/him^dwith^]</td><td>extruder [R / min]</td><td>Speed cuts</td>

<td>0.6</td><td>120</td><td>20.72</td><td>7.96</td><td>87</td><td>2200</td>

<td>1.7</td><td>140</td><td>23.94</td><td>6.92</td><td>100</td><td>2000</td>

<td>3.0</td><td>190</td><td>29.09</td><td>8.16</td><td>120</td><td>1270</td>

<td>6.0</td><td>200</td><td>34.2</td><td>9.6</td><td>140</td><td>900</td>

Example 2: Product with three active ingredients containing Milbermycin oxime, Prazykwantel and Lufenuron

Components

Active ingredient nr. 1 Oxymom Milbermycin. Active ingredient no. 2 Prazykwantel

Quantity Procnntowość [w / w]

1.975 gg

19,000 kg

0.395%

3.800%

Active ingredient nr. 3

<td colspan="2">lufenuron</td><td rowspan="2">38,340 kg</td><td rowspan="2">7.667%</td>

<td></td><td>Excipients (excipients)</td>

<td></td><td>Pre-gelatinized starch</td><td>159,690 kg</td><td>31.938%</td>

<td>5</td><td>Boiled beef powder</td><td>142,000 kg</td><td>30.000%</td>

<td></td><td>The taste of bacon</td><td>25,000 kg</td><td>5.000%</td>

<td></td><td>Sugar</td><td>25,000 kg</td><td>5.000%</td>

<td></td><td>Sodium chloride powder</td><td>7.500 kg</td><td>1.500%</td>

<td></td><td>Iron oxide</td><td>0.500 kg</td><td>0.100%</td>

<td>10</td><td>Total solids</td><td>419,000 kg</td><td>83.8 00%</td>

<td></td><td>Water</td><td>20,000 kg</td><td>4.000%</td>

<td></td><td>Glycerine</td><td>60,000 kg</td><td>12,000%</td>

<td></td><td>Tenox 2</td><td>1,000 kg</td><td>0.200%</td>

<td>15</td><td>Total liquid bodies</td><td>81.000 kg</td><td>16.200%</td>

<td></td><td>The entire set of ingredients</td><td>500,000 kg</td><td>100.000%</td>

The three-part product containing Milbermycin oxime, Prazykquantel and Lufenuron is produced on the same lines as the two-part composition in Example 1.

Example 3: Product with one active ingredient containing Ciclosporin

<td>20</td><td>Components Active ingredient</td><td>Quantity</td><td>Percentity [w / w]</td>

<td></td><td>cyclosporine</td><td>43.40 g</td><td>8.7%</td>

<td></td><td>Pre-gelatinized starch</td><td>183.60 g</td><td>36.7%</td>

<td></td><td>The natural taste of chicken</td><td>150.00 g</td><td>30.0%</td>

<td>25</td><td>Sugar</td><td>25.0 ^g</td><td>5.0%</td>

<td></td><td>Iron oxide</td><td>0.50 ^g</td><td>0.10%</td>

<td></td><td>Total solids</td><td>410.00 g</td><td>82.0%</td>

<td></td><td>Water</td><td>20.00 g</td><td>4.0%</td>

<td>thirty</td><td>Glycerine</td><td>70.00 g</td><td>14.0%</td>

<td></td><td>Total liquid bodies</td><td>90.00 g</td><td>18.0%</td>

<td></td><td>The entire set of ingredients</td><td>500.00 g</td><td>100.00%</td>

The one-piece composition containing Ciclosporin is produced on the same lines as the two-part product in Example 1.

Example 4: Tastability test (acceptance) of various palatable chewable products with a 3-part recipe carried out on 100 dogs and 100 cats.

100 males and females of different breeds and at different ages were tested. The dogs were divided into 4 groups of 25 dogs with the same body weight. The test person offered one meal once a day of the chewable product, which was adapted to the dog's body weight. In the first case, the chewable product was given to the dog by hand in 60 seconds. If the dog did not take the product, it was offered to the dog in an empty bowl. The dog had another 60 seconds. to take the product, if not, the product was placed in the dog's mouth. If the dog / cat spit it out, the product was considered unacceptable. Generally, no more than 5 to 6 different products were tested in the following days. Each product was packaged separately and labeled to be easily identifiable. An analogous test was carried out on 100 cats.

<td>The product to be tested</td><td>Taste</td><td>Total acceptability (dogs) [% 1</td>

<td>2-part product containing Milbermycin oxime and Prazykwantel</td><td>Natural bacon</td><td>96</td>

<td>3-part product containing Milbermycin oxime, Prazsquantel and Lufenuron</td><td>Natural bacon</td><td>93</td>

<td>3-part product containing Milbermycin oxime, Prazsquantel and Lufenuron</td><td>Natural beef</td><td>94</td>

<td>3-part product containing Milbermycin oxime, Prazsquantel and Lufenuron</td><td>Natural chicken</td><td>95</td>

<td>3-part product containing Milbermycin oxime, Prazsquantel and Lufenuron</td><td>Artificial bacon</td><td>94</td>

<td>3-part product containing oxime</td><td>artificial</td><td>95</td>

<td>Milbermycin, Prazykwantel and Lufenuron</td><td>beef</td><td></td>

An analogous test on cats shows results in the same range.

Example 5: Stabilization tests

Samples of the very palatable, ductile, chewable veterinary composition of the present invention were tested for stability under stressful conditions to simulate different temperature and humidity conditions. Samples were tested at 25 ° C / 60% rh, 30 ° C / 60% r^{hi 40oc /}7⁵% y^h. B^vein they three^smane wm^kat^batorac^hi anabzowane ^pat 3^. 6 9 ^and l²months in terms of the content of the active ingredient. Analysis of the active ingredient content in all samples tested at 25 ° / 60% ± and 30 "('/ 60⁽⁾όιΊι for 12 months showed no difference when compared to identical samples kept in the freezer at -25 ° C for the same period of time. Chewable tablets held for 12 months at 40 ° / 75% ^ also show good stabilization results, which indicate that they can be stored on the shelf for at least 12 months and remain fresh if stored under normal conditions, e.g. 25 ° C or 30 ° C and 40-70% rh. No significant change was seen in relation to the stability of the 2-part products containing Milbermycin oxime and Praziquantel and 3-part products containing Milbermycin oxime, Prazykquantel and Lufenuron.

Novartis AG, Switzerland

Proxy:

Z-5466/08

EP 1 675 474: