MXPA97009245A - Endoperasitician agents - Google Patents

Abstract

The present invention relates to mixtures of avermectins, 22, 23-dihydroavermectins B1 (ivermectins) and milbemycins, of the class of compounds of the macrocyclic lactones, in combination with cyclic depsipeptides, optionally in the presence of Praziquantel or Epsiprantel, for the Increased endoparasiticidal activity in endoparasiticid agents

Description

ENDOPERASTICIDE AGENTS FIELD OF THE INVENTION The present invention relates to mixtures of avermectins, 22, 23-dihydrovermectins B, (ivermectins) and milbe icines, of the class of macrocyclic lactone compounds, in combination with cyclic depsipeptides, if appropriate in the presence of Praziquantel or Epsiprantel, for the increase of endoparasiticide activity in endoparasiticidal agents.

BACKGROUND OF THE INVENTION In most cases, gastrointestinal infections of dogs by nematodes are caused by species of the three families of nematodes: ascarids. apcuilcstotas and tr icuroideos. In cats, the two families of nematodes: ascarids and anquilcstomas are universally extended. After passing several stages of development in the different tissues of the host animal, a manifest infection of the gastro-intestinal tract is reached. In the course of the latency and patency of infection, the parasitosis of neonates, hookworms and whipworms causes considerable problems, especially in dogs, cats and even young, growing humans. Therefore, a therapeutic or pro-lactic treatment is urgently needed, both for the recovery of animals and REP: 26070 patients, as well, to preserve the state of health of animals not yet infected. For this reason, the protection of dogs and cats from infection is essential, as prophylaxis against infections in humans, especially in children. In the breeding of animals, a series of necidal substances are already used as anthelmintics. To achieve effective protection, combinations of several substances are also used more and more, together with the pure compound. In any case, the activity against parasites of these previously known combinations is not always completely satisfactory, especially at small doses. Along with the gastrointestinal diseases in dogs and cats caused by helminths mentioned above, there are other serious parasitosis, filiariosis for example, which are very specific to the host. The parasite Dirofilaria irnnitis - an endemic filaria in areas from North to South America, Africa, Asia, even Australia, originates the significant canine and feline cardiovascular heartworm. The severe physiopathological changes that occur within the cardiovascular system in the course of the infection of dogs and cats by Dirofilaria i itis. they can cause a dramatic disease course in the host animal.

Of the known anthelminthic active compounds, only a few possess an efficacy as prophylactics against Dirofilaria imitis. Anthelmintics such as, for example, diethylcarbamazine (DEC) are certainly active, but should be administered daily during a spread (mosquitoes) of the pathogen. With the introduction of the ivermectin / ilbe icine anthelmintics of the class of macrocyclic lactone compounds the prophylactic treatment of dogs and cats can be reduced to a monthly intake. There are certainly endoparasiticidal agents with high efficacy against gastro-intestinal nematodes and other agents with activity against Dirofilaria iTipi is in dogs and cats but, to date, none of the known compounds exhibits such an amplitude of the spectrum of activity to be able to use them. as therapeutic both against all gastrointestinal nematodes and, also, as a prophylactic against Dirofilaria immitis. for this reason, various combinations of active substances are used, which exhibit improved activity and, in addition, have decreased side effects and host toxicity. In most cases, the monthly prophylaxis against Dirofilaria immitis is carried out with an avermectin, such as ivermectin, of the class of macrocyclic lactone compounds in combination with an anthelmintic such as Pyrantel or a benzimidazole, for example Albendazole (see WC Campbell, Ann. Rev. Microbiol. 45 (1991), pages 445-474; J.N. Clark et al. Am. J. Vet. Res. 53 (4), (1992), pages 517-520). A combination composed of 6.0 μg / kg ivermectin and 5.0 mg / kg Pyrantel-pamoate is to be mentioned by way of example. While this combination guarantees a treatment and control of the roundworms (T. canis and T. leonina) as well as the hookworms (A. canis and U. steneocephala), it is not usable against whipworms (T. vulpis). Even milbemycin at 500 μg / kg also shows a clear decrease in activity against hookworm Uncinaria stenocephala, a gastrointestinal nematode, which causes a severe parasitemia in young dogs (see DD Bo man et al., Am. J. Vet. Res. 51 (1990) page 487; R. Grieve J. Am. Vet. Assoc. 194 (1939), page 1815). In addition, ivermectin was successfully tested in human medicine, as an agent against filarial infections and against various gastrointestinal infections by nematodes. But these studies have also shown that ivermectin, despite the high dosage for several successive days, has no activity in hookworm-infected patients (see Ottesen &Campbell, J. Antimicrob, Chemother, 2A &1994; 195-203). These facts make clear that, to date, avermectins, 22, 23-dihydroavermectins B, (ivermectin) and milbemycins of the class of macrocyclic lactone compounds, either alone or also in combination with an anthelmintic can not act simultaneously at small doses against pematelminths, hookworms as well as against whipworms in the gastrointestinal tract of dogs and cats.

DESCRIPTION OF THE INVENTION The present invention relates to endoparasiticidal agents that contain at least one avermectin, 22, 23-dihydroavermectin B, (ivermectin) or nilbemycin, of the class of macrocyclic lactone compounds, with cyclic depsipeptides composed of amino acids and hydroxycarboxylic acids as ring links and 6 to 30 atoms in the ring, optionally in the presence of Praziquantel or Epsiprantel. The agents according to the invention, a combination of at least one avermectin, 22, 23-dihydroavermectin B, (ivermectin) or milbemycin, of the class of macrocyclic lactone compounds, with cyclic depsipeptides composed of amino acids and hydroxycarboxylic acids as ring links and 6 to 30 atoms in the ring, they exhibit an unexpected synergistic effect. This synergistic effect in the endoparasiticidal agents according to the invention, originated by the combination of at least one avermectin, 22, 23-dihydroavermectin B, (ivermectin) or milbemycin, of the class of macrocyclic lactone compounds, with depsipeptides cyclics composed of amino acids and hydroxycarboxylic acids as ring links and 6 to 30 atoms in the ring, also remains in the presence of Praziquantel or Epsiprantel. The avermectins were isolated as microbial metabolites of the microorganism Streptomyces aver itilis (Patent US 4 310 519) and can be presented essentially in the form of a mixture composed of the eight components AIa, A | ", A2a / A:", B, B, ", B, a and B: "(I. Putter et al., Experientia 37 (1931) page 963, Birkháuser Verlag (Switzerland)). Along with these are also the synthetic derivatives, especially 22, 23-dihydroavermectin B, (ivermectin) (US Patent 4 199569). Milbemycin B-41 D was also isolated fermentatively from Streptomyces hygroscopicus (see: Milbemycin: Discovery and Development) ("Milbemycin: discovery and development") I. Junya et al., Annu, Rep. Sankyo Res. Lab. 45 (1993), pages 1-98, JP Patent 8 378 549, GB 1 390 336) The use as endoparasiticides of avermectins, 22, 23-dihydroavermectins B, (ivermectins) and milbemycins of the class of compounds of macrocyclic lactopas , has been known for a long time and is the subject of numerous patent applications as well as review articles (for example: biological activities in "Ivermectin and Abamectin" WC Campbell, Ed. Springer Verlag, New York, NY, 1989; "Aver ectins and Milbemycins Part II "HG Davies et al., Chem. Soc. Rev. 20 (1991) pages 271-339; chemical modifications in: G. Lukacs et al. (Eds.), Springer-Verlag, New York, (1990) , Chapter 3; Cydectin ™ (Moxidectin und Derivate) ("Moxidectin and derivatives"): GT Cárter et al., J. Chem. Soc. Co mun. (1937), pages 402-404); EP 423 445-A1). It is also known the use of Dora ectin (Pfizer) as endoparasiticide (see: "Doramectin - a potent novel endectozide" ("Doramectin, a potent new endectocide") AC Goudie et al., Vet. Parasitol 49 (1993), pages 5 -fifteen). In addition, combinations of avermectins, 22,23-dihydroaver ectinas B, (ivermectins) or milbemycins with certain classes of anthelmintics such as, for example, benzimidazoles, salicylamides, Leva isol, Pyrantel or Praziquantel are the subject of numerous patent applications (eg : GB 2 252 730; GB 2 224 933; GB 2 21 3 722; EP-OS 59 074). A cyclic depsipeptide, PF 1022 A, and its activity against endoparasites is known from EP-OS documents 382 173 and EP-OS 503 538 (Total synthesis of PF 1022 A: Patent JP 05 229 997; Makoto Ohya a et al., Biosci. Biotech Biochem. 58 (6), 1994, pages 1193-1194; Makio Kobayshi et al., Annu. Rep. Sankyo Res. Lab. 46, 1994, pages 67-75; Stephen J. Nelson et al., J. Antibiotics 47, (11), 1994, pages 1322-1327). Other cyclic depsipeptides and their endoparasiticidal activity are subject to the following patent applications, of cyclooctadepsipeptides: WO 93/19053; EP 0 634 408 Al; WO 94/19334; WO 95/07272; EP 626 375; EP 626 376; of cyclohexadepsipeptides: DE-OS 4342 907; WO 93/25543, German patent applications P 4 437 198.5; P 4 440 193.0, as well as cyclootetradepsipeptides: EP-OS 664 297. Praziquantel, 2- (cyclohexylcarbonyl) -1,2,3,6,7, llb-hexahydro-4H-pyrazino [2,1-a] isoquinoline- 4-one and its activity against endoparasites are known from DE-P 2 362 539. Epsiprantel, 2- (cyclohexylcarbonyl) -2, 3, 6, 7, 8, 12b-hexahydro-pyrazino (2, 1-a) ] benzazepin-4 (1H) -one and its activity against endoparasites, are known from EP-OS 13 4 934, EP-OS 185 012. The use of Praziquantel and Epsiprantel for the increase of the endoparasiticide activity of cyclic compound depsipeptides for amino acids and hydroxycarboxylic acids as ring links and 6 to 30 ring atoms are the subject of a previously published patent application (EP-OS 662 326). Therefore, the present invention relates to endoparasiticidal agents containing, for example, at least one avermectin, 22, 23-dihydroavermectin B, (ivermectin) or milbemycin, from the class of compounds of the s macrocyclic lactones, in combination with cyclic depsipeptides composed of amino acids and hydroxycarboxylic acids as ring links and 6 to 30 ring atoms, optionally in the presence of Praziquantel or Epsiprantel.

The object of the present invention is also the use of avermectins, 22, 23-dihydroavermectins B, (iver ectins) and milbemycins of the class of macrocyclic lactone compounds in combination with cyclic depsipeptides composed of amino acids and hydroxycarboxylic acids as linkages of the ring and 6 to 30 atoms in the ring, optionally in the presence of Praziquantel or Epsiprantel, for the production of endoparasiticidal agents. In the combination, components of the microbial meta-group group, for example, avermectin and its derivatives, are to be mentioned. These compounds are a mixture of acrylic acid lactones, of the general formula (I) wherein the residues R1 to R4 have the meaning indicated in the table 1 below and X may represent a single or double bond between the position of C ,, and the C :, (-C ,, R'-XC, 3R2 -).

In the case of a double bond, no substituent (R1, R2) is found at the C ,: and C ,, positions.

Table l 22, 23-dihydroavermectin B, represents ivermectin B,; sec-Bu = secondary butyl; iso-Pr = isopropyl; Chx = cyclohexyl; -Me = methyl.

The avermectins and 22, 23-dihydroavermectins B, (ivermectins) of the general formula (I) are generally used as a mixture. In this, the product abamectin, which contains essentially avermectin B, and its hydrogenation product 22,23-dihydroavermectin B, (ivermectin) is of special interest. The macrocyclic lactone compounds designated by "b", which possess an iso-propyl moiety in the C < , must not necessarily be separated from the compounds "a", which have a sec-butyl group in the C, position. The mixture of both substances composed of > 80% sec-butyl derivative (B, and <20% iso-propyl derivative (B ",) and can be used according to the invention In addition, in stereoisomers, substituents at positions C ,, and C, can be arranged with respect to the ring in both a and b, this is above or below the plane of the molecule In all cases, all stereoisomers are contemplated with respect to the invention Milbemycins have the same structure of acrylic ring that the avermectins or 22,23-dihydroavermectins B, (ivermectins), but do not carry any substituents (that is, missing the disaccharide fragment of oleandrose) in position 13 (R '= hydrogen.) As milbemycins of the class of compounds of the macrolide lactones are to mention the compounds with the general formula (II) wherein the residues R1 to R * have the meaning indicated in table 2 below: Table 2 iso-Pr = isopropyl.

Of the components of the combination for the compounds of formula (I) and (II), the following macrocyclic lactones are of special interest: Avermectin B,., / B | b 22, 23-dihydroavermectin B ,. / B, b (ivermectin Bla / B, b) Dora ectin Moxidectin According to the invention, cyclic depsipeptides with 24 ring atoms are to be mentioned as preferred components of the combination with the macrocyclic lactones above, of formulas (I) and (II). The compounds of general formula (III) belong to the depsipeptides with 24 atoms in the ring: wherein R1 represents benzyl, optionally substituted, hydrogen, C, -C4-alkyl, especially methyl, hydroxyl, halogen, especially fluorine, C | -, -alkoxy, especially methoxy or t-butyloxy, nitro, are mentioned as substituents. amino, dialkylamino, especially dimethylamino or diethylamino, N-orpholinyl, N-pyrrolidinyl or N-piperidinyl, R 2 represents hydrogen, C, -C 4 -alkyl, especially methyl, hydroxyl, halogen, especially fluorine, C, -C-alkoxy , especially methoxy or t-butyloxy, nitro, amino, dialkylamino, especially dimethylamino or diethylamino, N-morpholinyl, N-pyrrolidinyl or N-piperidinyl, wherein a) in the case where R1 represents benzyl, R2 represents hydrogen, hydroxyl, C, -C 4 -alkoxy, especially methoxy, halogen, especially fluorine, alkenyloxy, especially allyloxy, b) in the case where R 1 represents methyl, R 2 represents hydrogen, hydroxyl, C, -C 6 -alkoxy, especially methoxy, nitro, amino , dialkylamino, especially d imethylamino, N-morpholinyl.

For the purposes of the present invention, all compounds of general formula (III) can be used, which may be present in optically active, stereoisomeric forms, or as racemic mixtures. According to the invention, however, the optically active, stereoisomeric forms of the compounds of general formula (III) are preferably used. Particular preference is given to cyclic depsipeptides which are composed of amino acids of L configuration and hydroxycarboxylic acids of configuration D, as ring members. By way of example, the compound PF 1022A, known from EP-OS 382 173 and EP-OS 503 538, of the following formula (Illa), in which R 1 represents bepcyl and R 2 hydrogen, can be mentioned as the cyclic depsipeptide: In addition, the compounds known from PCT patent application WO 93/19053 and EP 0 634 408 A1 are to be mentioned as depsipeptides. From PCT patent application WO 93/19053 and EP 0 634 408 A1, they are especially to be mentioned the compounds of the following formula (Illb), wherein R 1 represents substituted benzyl (R 3): wherein R2 and R3 represent N-morpholinyl, nitro, amino, mono- or dimethylamino. In addition, the compounds known from PCT patent application WO 94/19334 are to be mentioned as depsipeptides. From the PCT patent application WO 94/19334, mention may be made especially of the compounds of the following formula (lile), in which R 'represents benzyl: wherein R2 represents hydroxyl, methoxy or t-butoxy. Finally, the compounds known from the PCT patent application WO 95/07272 are to be mentioned as depsipeptides. From the PCT patent application WO 95/07272, mention may be made especially of the compounds of the following formula (Illd), in which R 1 represents methyl: wherein R2 represents methoxy, dimethylamino or N-morpholinyl. According to the composition of the most preferred endoparasiticidal agent according to the invention, 22, 23-dihydroavermectins B / B, b (ivermectins B / Blb) of the class of macrocyclic lactone compounds of the general formula are combined in the present invention. ) (la) in which R represents methyl and ethyl, with the cyclic depsipeptide PF 1022A, of formula (Illa) as components of the combination, optionally in the presence of Praziquantel or Epsiprantel, in a synergistic proportion of action. According to another especially preferred composition of the endoparasiticidal agent according to the invention, the 22,23-dihydroaver ectinas B / B, (ivermectins B ,, / B | b) of the class of macrocyclic lactone compounds are combined in the present invention. general formula gives) wherein R5 represents methyl and ethyl, with the cyclic depsipeptide of formula (Illb) wherein R2 and R- 'represent N-morpholinyl as components of the combination, optionally in the presence of Praziquantel or Epsiprantel, in a proportion of synergistic action. According to the invention, the compounds of formula (I) or (II) and (III) can also be combined with two or more of the active substances listed, optionally in the presence of Praziquantel or Epsiprantel. The endoparasiticidal activity of the combinations of active substances according to the invention is clearly higher than would be expected from the activities of the individual components. Therefore, by using these combinations the amounts of use of the individual components can be reduced. As a consequence of this, its application entails economic and ecological advantages. The agents according to the invention are suitable for their favorable toxicity in warm-blooded animals, to fight against pathogenic endoparasithat occur in humans and in the exploitation and breeding of animals, in useful animals, breeding animals, zoo animals, animals of laboratory, research animals and recreational animals. In these, they are active against all stages of development of the harmful animals, as well as against resistant species and of normal sensitivity. By fighting against pathogenic endoparasites, the disease should be avoided, cases of mortality and diminution of yields (in the production of meat, milk, wool, skins, eggs, honey, and others, for example), so that through the use of the active substances it is possible to more economic and simple animal husbandry. Among the pathogenic endoparasites are cestodes, trematodes, nematodes, acanthocephalic, especially: From the order of the Pseudophyllidea, for example: Diphyllobothriu species, Spiro etra species, Schistocephalus species, Ligule species, Bothridium species, Diphlogonoporus species. From the order of Cyclophyllidea, for example: Mesocestoid species, Anoplocephala species, Paranoplocephala species, Moniezia species, Thysanosomsa species, Thysaniezia species, Avitellina species, Stilesia species, Cittotaenia species, Andyra species, Bertiella species, Taenia species, Echinococcus species, Hydatigera species , Davainea species, Raillietina species, Hy enolepsis species, Echinolepsis species, Echinocotyle species, Diorchis species, Dipylidium species, Joyeuxiella species, Diplopylidium species. From the subclass of the Monogenea, for example: Gyrodactylus species, Dactilogyrus species, Polystoma species. From the Digenea subclass, for example: Diplostomum species, Posthodiplostomum species, Schistosoma species, Trichobilharzia species, Ornithobilharzia species, Austrobilharzia species, Gigantobilharzia species, Leucochloridium species, Brachylaima species, Echinostoma species, Echinoparyphium species, Echinochasmus species, Hypoderaeum species, Fasciola, Fasciolides species, Fasciolopsis species, Cyclocoelum species, Typhlocoelum species, Paramphistomum species, Calicophoron species, Cotylophoron species, Gigantocotyle species, Fischoederius species, Gastrothylacus species, Notocotylus species, Catatropis species, Plagiorchis species, Prosthogonimus species, Dicrocoelium species, Eurytrema species, Troglotrema species, Paragoni us species, Collyriclu species, Nanophyetus species, Cpisthorchis species, Clonorchis species, Metorchis species, Heterophyes species, Metagoni us species. From the order of Enoplida, for example: Trichuris species, Capillaria species, Trichomosoides species, Trichinella species. From the order of the Rhabditia, for example: Micronema species, Strongyloides species. From the order of the Strongylida, for example: Stronylus species, Triodontophorus species, species Oesophagodontus, Trichonema species, Gyalocephalus species, Cylindropharinx species, Poteriostomum species, Cyclococercus species, Cylicostephanus species, Oesophagostomum species, Chabertia species, Stephanurus species, Ancylostoma species, Uncinaria species, Bunostomum species. Species Globocephalus, Syngamus species, Cyathostoma species, Metastrongylus species, Dictyocaulus species, Muellerius species, Protostrongylus species, Neostrongylus species, Cystocaulus species, Pneumostrongylus species, Spicocaulus species, Elaphostrongylus species, Parelaphostrongylus species, Crenosoma species, Paracrenosome species, Angiostrongylus species, Aelurostrongyulus species , Filaroides species, Paraphylaroid species, Trichostrongylus species, Haemonchus species, Ostertagia species, Marshallagia species, Cooperia species, Ne atodirus species, Hyostrongylus species, Obeliscoides species, Amidostomum species, Ollulanus species. From the order of the Oxyurida, for example: Oxyuris species, Enterobius species, Passalurus species, Syphacia species, Aspiculuris species, Heterakis species. From the order of Ascaridia, for example: Ascaris species, Toxascaris species, Toxocara species, Parascaris species, Anisakis species, Ascaridia species. From the order of the Spirurida, for example: Gnathostoma species, Physaloptera species, Thelazia species, Gongylonema species, Habronema species, Parabronema species, Draschia species, Dracunculus species. From the order of the Filariida, for example: Stephanofilaria species, Parafilaria species, Setaria species, Loa species, Dirofilaria species, Litomosoides species, Brugia species, Wuchereria species, Onchocerca species. From the order of the Gigantorhynchida, for example: species Filicollis, species Moniliformis, species Macracanthorhynchus, species Prosthenorchis. Useful mammals such as cows, horses, sheep, pigs, goats, camels, buffaloes, donkeys, rabbits, deer, reindeer, thin-skinned animals such as, for example, mink, chinchillas, apaches, belong to breeding animals. , birds such as chickens, geese, turkeys, ducks, ostriches, freshwater fish and saltwater such as trout, carps, eels, reptiles, insects such as, for example, honey bees and silk worms. To the laboratory and research animals belong mice, rats, guinea pigs, golden hamsters, dogs and cats. To the animals of recreation belong dogs and cats.

The administration can be carried out both for prophylactic and therapeutic purposes. The administration of the active substance is carried out directly or in the form of suitable preparations, intercranial, parenteral, dermal, nasal, by treatment of the environment or with the aid of molded objects containing active substance, such as girdles, plates, ribbons, necklaces , earmuffs, bracelets, signaling devices.

The enteral administration of the active substance takes place, for example, orally, in the form of powders, tablets, capsules, pastes, beverages, granules, solutions, suspensions and emulsions that can be administered orally, boluses, medicated feed or drinking water. The dermal administration takes place, for example, in the form of immersion (baths), spraying (spraying) or pouring (pour-on and spot-on). Parenteral administration takes place, for example, in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants. Suitable preparations are: Solutions, such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pouring formulations, gels; Emulsions and suspensions for oral or dermal administration as well as for injection; semi-solid preparations; Formulations in which the active substance is processed in an ointment base or in an oil-in-water or water-in-oil emulsion base; Solid preparations such as powders, pre-ezclas or concentrates, granulates, agglomerates, tablets, boluses, capsules; aerosols and inhalations, solid tablets containing active substance.

The solutions for injection are administered intravenously, intramuscularly and subcutaneously. The solutions for injection are obtained by dissolving the active substance in a suitable solvent and adding any additives, such as dissolving aids, acids, bases, tartar salts, antioxidants, preservatives. The solutions are sterilized by filtration and packaged. Mention may be made as solvents: physiologically tolerable solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone and mixtures thereof. The active substances can also be dissolved, if appropriate, in physiologically tolerable vegetable or synthetic oils which are suitable for injection. As dissolving aids, mention may be made of: solvents which promote the dissolution of the active substance in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters. They are preservatives: benzyl alcohol, trichlorobutanol, esters of p-hydroxybenzoic acid, n-butanol. The oral solutions are administered directly. The concentrates are administered orally, after dilution prior to the administration concentration. The oral and concentrated solutions are obtained as described above in the solutions for injection, being able to renounce a sterile processing. Solutions for use on the skin are applied by instillation, spreading, scrubbing, spraying or spraying. These solutions are obtained as described above in the solutions for injection. In obtaining it, it may be advantageous to add thickeners. They are thickeners: inorganic thickeners such as bentonite, colloidal silicic acid, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohol alcohols and their copolymers, acrylates and methacrylates.

The gels are applied or spread on the skin or are introduced into body cavities. The gels are obtained by mixing solutions that have been obtained as described in the solutions for injection with as much thickening agent as necessary so that a clear mass with ointment consistency is formed. The thickeners mentioned above are used as the thickening agent. The formulations for pouring are poured or sprayed over limited areas of the skin, whereby the active substance either passes through the skin and acts systemically or is distributed over the body surface. The formulations for pouring are obtained by dissolving, suspending or emulsifying the active substance in solvents or suitable solvent mixtures tolerable by the skin. If necessary, other coadjuvant substances are added such as dyes, resorption promoting substances, antioxidants, sunscreens, adhesives. Mention may be made as solvents: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol-onomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2,2-dimethyl-4-oxy-methylene-l, 3-dioxolane. Dyes are all dyes authorized for administration to animals, which may be dissolved or suspended. Resorption-promoting substances are, for example, DMSO, dispersant oils such as isopropyl mtate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols. Antioxidants are sulphites or metabisulfites such as potassium carbonate, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, tocopherol.

Photoprotective agents are, for example, novantisol acids. Adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin. The emulsions can be administered orally, dermally or as injections. The emulsions are either of the water in oil type or the oil in water type. They are obtained by dissolving the active substance, either in the hydrophobic phase or in the hydrophilic phase, and to homogenize it with the solvent of the other phase with the help of suitable emulsifiers and, if necessary, other coadjuvant agents such as dyes, promoter substances of the resorption, preservatives, antioxidants, photoprotective agents, viscosity-increasing substances. As the hydrophobic phase (oils), mention should be made of: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid diglycerides, mixtures of triglycerides with fatty acids plants of chain length C, or other specially chosen natural fatty acids, mixtures of partial glycerides of saturated or unsaturated fatty acids, optionally also containing hydroxyl groups, mono- and diglycerides of fatty acids C (/ C?,. fatty acids such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of intermediate chain length with saturated fatty alcohols of chain length C, 6-C (1, myristate of isopropyl, isopropyl palmitate, caprylic / caprine esters of saturated fatty alcohols of chain length C, 2-C-stearate isopropyl, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, esters of fatty acids of waxy consistency such as artificial fat of the uropigial gland of ducks, dibutyl phthalate, diisopropyl adipate, mixtures of esters related to the latter , among others, Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol. Fatty acids, such as, for example, oleic acid and mixtures thereof. As the hydrophilic phase, mention may be made of: Water, alcohols such as, for example, propylene glycol, glycerol, sorbitol and their mixtures. As emulsifiers, mention may be made of: non-ionogenic surfactants, for example polyoxyethylated castor oil, polyoxyethylated sorbitan mono-oleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether; Ampholytic surfactants such as disodium N-lauryl-β-iminodipropionate or lecithin; Surfactants with anionic activity, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether esters of orthophosphoric acid, monoethanolamine salt; Surfactants with cationic activity such as cetyltrimethylammonium chloride. Examples of additional auxiliary substances are: viscosity stabilizing substances and emulsion stabilizers such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and anhydride maleic, polyethylene glycols, waxes, colloidal silicic acid or mixtures of the indicated substances. The suspensions can be administered orally, dermally or as an injection. They are obtained by suspending the active substance in a liquid excipient, optionally with the addition of other auxiliary substances such as wetting agents, dyes, resorption promoting substances, preservatives, antioxidants and photoprotective agents. Suitable liquid excipients are all homogeneous solvents and solvent mixtures. As the wetting agent (dispersant), mention may be made of the surfactants already indicated above. Additional coadjuvants are those mentioned above. Semi-solid preparations can be administered orally or dermally. They differ only from the suspensions and emulsions described above because of their higher viscosity. In order to obtain the solid preparations, the active substance is mixed with suitable excipients, optionally with the addition of adjuvants, and brought to the desired shape. Suitable excipients are all physiologically tolerated inert solid substances. As such they serve inorganic and organic substances. The inorganic substances are, for example, sodium chloride, carbonates such as calcium carbonate, bicarbonates, aluminum oxides, silicic acids, clays, precipitated or colloidal silicon dioxide, phosphates. The organic substances are, for example, sugar, cellulose, nutritional products and feed such as milk powder, animal meals, flour and cereal grindings, starches. The adjuvants are preservatives, antioxidants, dyes, which have already been indicated above. Other substances Suitable adjuvants are lubricants and glidants, such as, for example, magnesium stearate, stearic acid, talc, bentonite, disintegration-promoting substances such as starches or crosslinked polyvinylpyrrolidone, binders such as, for example, starch, gelatin or linear polyvinylpyrrolidone, as well as dry binders such as microcrystalline cellulose. The active substances can also be present in the mixed preparations with synergistic agents or with other active substances that act against pathogenic endoparasites. Such active substances are, for example, L-2,3,5,6-tetrahydro-6-phenyl-imidazothiazole, benzyl-idazol-carbatolate, Pyrantel. Ready-to-use preparations contain the active substance in concentrations of 10 ppm - 20 weight percent, preferably 0.1-10 weight percent. Preparations that are diluted before administration contain the active substance in concentrations of 0.5-90% by weight, preferably 5 to 50 percent by weight. In the endoparasiticidal agents according to the invention, in the case of an application in the dog recreational animal, a weight ratio of acrocyclic lactone to depsipeptide is generally observed from 1 to 500 to 1,000, preferably from 1 to 500 to 850 , with very special preference from 1 to 500.

Furthermore, in the endoparasiticidal agents according to the invention, in the case of an application in the cat recreational animal, a weight ratio of macrocyclic lactone to depsipeptide of 1 to 150 to 500, preferably 1 to 150, is generally observed. up to 350, with very special preference from 1 to 150 to 200. Finally, in the endoparasiticidal agents according to the invention, in the case of an application in useful animals, a weight ratio of macrocyclic lactone to depsipeptide is generally observed. 1 to 20 to 400, preferably 1 to 20 to 250, very particularly preferably 1 to 20 to 50. For the purposes of the present invention, the endoparasiticidal agents may also contain, together with a macrocyclic lactone, at least and depsipeptides, Praziquantel or Epsiprantel. In these cases, in the combination according to the invention, a weight ratio of macrocyclic lactone to Praziquantel or Epsiprantel corresponding to that of the depsipeptide is generally used.

EXPERIMENTAL EXAMPLE A In-vivo nematode assay Neosatiroides dubius in the mouse [0118] Mice are experimentally infected with nematodes of the species Nematospiroides dubius. For the infection, Nematospiroides dubius is administered orally. in the form of 60 filiform larvae. After the latency has elapsed, suspended active substances are orally administered 12 days after infection. Determination of the activity: The selection of the mice takes place on the 20th day after infection. The account of adult parasites in the duodenum is carried out by Kompressorium. The result of the treatment in the dose groups is expressed in the relation to the untreated control group. The activity of the combination against Nematospiroides dubius in the mouse is indicated in the following tables A and B.

Table A Activity of the combination of PF 1022 A and ivermectin B, JBib against Nematosoiroides dubius in the mouse, after oral administration.

Table B Activity of the combination of PF 1022 A and ivermectin B | a / Blb, in the presence of Praziquantel, against Nematospiroides dubius in the mouse, after oral administration.

EXAMPLE B In-vivo nematode assay Heterakis spumosa in the mouse Mice with nematodes are experimentally infected of the species Heterakis spumosa. For the infection, Heterakis spumosa is administered orally. in the form of 90 embryonated eggs. After the latency time has elapsed, the 46th day after the infection, orally administered active substances suspended. Determination of the activity: The selection of the mice is carried out 5 a day after infection. The account of adult parasites in the colon and Caecu is carried out microscopically. He The result of the treatment in the dose groups is expressed in relation to the untreated control group. The activity of the combination against Heterakis spumosa in the mouse is indicated in the following tables C and D. twenty Table C Activity of the combination of PF 1022 A and ivermectin B,., / B ", against Heterakis spumosa in the mouse, after oral administration.

Table D Activity of the combination of PF 1022 A and ivermectin B,. / B | h, in the presence of Praziquantel, against Heterakis spumosa in the mouse, after oral administration.

Example C In-vivo nematode assay Ancylostoma caninum in the dog Beagle pups are experimentally infected with hookworms of the species Ancylostoma caninum. For infection, dogs are administered orally A. caninum, in the form of 250 larvae L ,. After the latency time has elapsed (or when an activity of the larvae is checked during the latency period), the active substances are administered orally (p.o.), in the form of a pure substance in gelatin capsules. The activity is determined by 2 methods. 1. Count the worm eggs expelled in the excrement before and after the treatment. 2. Percent activity in the critical test, according to the formula: Worms expelled after treatment% activity - • 100 worms expelled after treatment and remaining worms The activity of the combination against Ancylostoma caninum in the table is indicated dog.

Table E Activity of the combination of PF 1022 A and ivermectin B,., / B, h against Ancylostoma caninum in the dog, after oral administration.

It is noted that, in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that it is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (1)

R E I V I N D I C A C I O N

1. Endoparasiticidal agents, characterized in that they contain, at least one avermectin, 22,23-dihydroavermectin B (ivermectin) or milbamycin, of the class of macrocyclic lactone compounds, in combination with cyclic depsipeptides composed of amino acids and hydrocarboxylic acids as linkages of the ring and 6 to 30 atoms in the ring, optionally in the presence of Praziquantel or Epsiprantel. BBRTlM-a. DB T TMVB-IglQM The present invention relates to mixtures of avermectins, 22,23-dihydroavermectins B, (ivermectins) and milbemycins, of the class of compounds of the macrocyclic molecules, in combination with cyclic depsipeptides, optionally in the presence of Praziquantel or Epsiprantel, for the increase of endoparasiticide activity in endoparasiticidal agents.