MXPA06010450A - Parasiticidal agents - Google Patents

Abstract

The invention relates to products containing macrocylic lactone and amidine,suitable for combating parasites, particularly ectoparasites in animals.

Description

PARASITICIDE AGENTS DESCRIPTION OF THE INVENTION The present invention relates to products that contain a macrocyclic lactone and an amidine that are suitable for combating parasites, in particular ectoparasites in animals. The macrocyclic lactones are known above all in veterinary medicine as agents having both an excellent endoparasiticidal effect and, to some extent, an ectoparasiticidal effect. Amidines, for example Amitraz or Cimiazol are also known as insecticides / acaricides. When used against ectoparasites, the active principles of these two groups of substances have certain disadvantages, such as insufficient effect or side effects when applied topically. A 100% effect with the minimum possible dose would be desirable to maintain the reduced side effects. It was surprisingly found that when macrocyclic lactones and amidines are applied in combination, the ectoparasiticidal effect with respect to the individual preparations increases unexpectedly. With this, a good ectoparasiticidal effect can be achieved with low dosages. Additionally, with the combined application Ref. 175610 the tolerance is clearly improved. The invention therefore relates to products containing a macrocyclic lactone and an amidine. The macrocyclic lactones in the sense of this invention are in particular avermictin, 22,23-dihydroavermycin Bi (ivermictine) or milbemycin. The avermictines were isolated from the microorganism Streptomyces avermirtilis as microbial metabolites (US Patent 4310519) and can appear essentially as a mixture composed of the eight components Ala, Alb, A2a, Antibody, Bla, Blb, B2a and B2b (I. Putter et al., Experentia 37 (1981) page 963, editorial Birkháuser (Switzerland). Also synthetic derivatives are interesting, especially 22, 23-dihydroavermictine Bi (Ivermictine) (US Patent 4199569). Milbemycin could also be isolated fermentatively from Streptomyces hygroscopicus (see "Milbemycin: DIscovery and Development" I. Junta et al Annu. Rep. Sankyo Res. Lab. 45 (1993), pages 1-98, Japanese Patent 8378549, GB 1390336). The use of avermictines, 22,23-dihydroavermictines Bi (iver ictins) and milbemycins of the macrocyclic lactone class as endoparasiticides has been known for a long time and is the subject of numerous patent applications as well as synthetic articles (eg Biologicals in "Ivermectin and Abamectin" WC Campbell, eds., Springer Publishing, New York, NY., 1989; "Avermictins and Milbe ycins 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 and derivatives]: GT Cárter et al., J. Chem. Soc Chem. Comm. (1987), pages 402-404); EP 423445-Al). The use of Doramectin (Pfizer) as an endoparasiticide is also known (see "Doramectin-a potent novel endectozide" A.C. Goudie et al., Vet. Parasitol, 49 (1993), pages 5-15). In the case of avermectins, they are substances or mixtures of substances of macrolide lactones of the general formula (I) wherein the residues R1 to R4 have the meaning mentioned in the following table and X may represent a single or double bond between positions C22 and C2 (-C2R1-X-C23-R2-). In case of a double bond, no substituent (R1, R2) is found at the C22 C23 position. Table 1 22, 23-dihydroavermectin Bi represents Iver ectin Bx; sec-Bu = secondary butyl; iso-Pr = isopropyl; Chx = cyclohexyl; Me = methyl The avermectins and 22, 23-dihydroavermectin Bi (Ivermectin) of the general formula (I) are generally used as mixtures. Of special interest in this regard is the product Abamectin, which generally contains Avermectin Bi, and its hydrogenation products 22,23-dihydroavermectin Ba (Ivermectin). The compounds indicated with "b" of the macrocyclic lactones having an isopropyl moiety in the C25 position must not necessarily be separated from the compounds "a" which possess a sec-butyl group in the C25 position. Generally the mixture of both substances that is composed of >is isolated80% m / m derived from sec-butyl (Bla) and < 20% m / m isopropyl derivative (B? B), and can be used according to the invention. Additionally, in the stereoisomers, the substituents at the C 3 and C 2 positions can be arranged both in situ and in the ring system, that is, they can be found above or below the molecular plane. In each case, all stereoisomers are taken into account according to the invention. Milbemycins have the same macrolide ring structure as Avermectin or 22, 23-dihydroavermectin Bi (Ivermectin), but they do not carry any substituent (ie, the oleandric disaccharide fragment is missing) at position 3 (R5 = hydrogen). By way of example, milbemycins of the class of macrocyclic lactones can be mentioned as compounds of general formula (II) in which the radicals R1 to R5 have the meaning indicated in the following table 2 Table 2 lso-Pr = Isopropyl Of the compounds of formulas (I) and (II), the following compounds are particularly interesting according to the invention; Aver ictine B? A / B? B (or Aba ectin) 22, 23-dihydroavermectin B? A / B? B (or Ivermectin B? A / B? B) Doramectin Moxidectin As abamectin, a 4-mixture is referred to in the literature: 1 of Avermectin Bla and Avermectin Bu ,. Abamectin is most preferably used according to the invention.

Amidines in the sense of this invention are understood to be amidine compounds having an arthropodicidal effect. It is a class well known to the expert. Typical amidines are the Cimiazol and Amitraz By "applicable", in the meaning of the invention, the pharmaceutically acceptable salts, hydrates and prodrugs thereof are also understood as active ingredients. The agents according to the invention are suitable for combating parasites, especially ectoparasites such as arthropods, especially insects and arachnids that appear in the maintenance and rearing of animals in farm animals, breeding animals and companion animals. In this sense they are effective against all stages of development or individual stages of development of the parasites as well as against resistant species and of normal sensitivity of the parasites. Combating animal parasites avoids diseases and their transmission, deaths and decreases in yield (for example in the production of meat, milk, skins, eggs), so that using the active ingredients facilitates easier and more cost-effective animal maintenance or in certain areas possible for the first time. To the parasites belong: From the order Anoplura, for example, Haematopinus spp., Linognathus spp, Solenopotes spp; of the order Diptera, for example Haematobia spp, of the order Metastigmata, for example Hyalo ma spp., Rhipicephalus spp., Boophilus spp., Amblyom a spp., Haemophysalis spp., Dermacentor spp., Ixodes spp., Argas spp. , Ornithodorus spp., Otobius spp. < of the order Mesostigmata, for example Dermanyssus spp., Ornithonyssus spp., Pneumonyssus spp., of the order Prostigmata, for example Demodex spp., of the order Astig ata for example Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp. , Knemidocoptes spp. , Neoknemidocoptes spp. , Preferably the products according to the invention are used against Boophilus spp. , especially Boophilus mi cropl us. To domestic and labor animals belong mammals such as cattle, sheep, goats, horses, pigs, dogs, cats, camels, water buffalo; birds such as chickens. Pet animals include dogs and cats. Application is preferred in dogs, horses, sheep, goats and in outdoor breeding, application in working animals, especially in bovines, is especially preferred.

The application can be carried out both prophylactically and therapeutically. The application of the active principles is carried out directly or in the form of suitable preparations, specifically by Genaro by topical application. The topical application is produced, for example, in the form of immersion (dip), spraying (spray), bathing, washing, pouring (spill dorsal or dorsal punctual, pour-on and spot-on), friction or powdered. Suitable preparations are: solutions, for example solutions for application on the skin or in body orifices, infusion formulations, gels; emulsions and suspensions, semi-solid preparations; solid preparations such as powders, premixes or concentrates, granulates. The solutions for application on the skin are supplied drop by drop, spread, rubbed, splashed, sprayed or applied by immersion (dipping, bathing or washing). These solutions are prepared by dissolving the active principle in a suitable solvent and optionally adding additives such as solubility mediators, acids, bases, buffer salts, antioxidants, preservatives; in this sense, one could give up working in sterile conditions. Solvents which may be mentioned are physiologically acceptable solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone and mixtures thereof. The active ingredients can also be dissolved, if appropriate, in physiologically acceptable vegetable or synthetic oils, which are pharmaceutically suitable. As solubility mediators there may be mentioned: solvents that promote the solubility of the active principle in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan ester.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol. It can be advantageous to add thickeners during the preparation. They are thickeners: inorganic thickeners such as bentonite, colloidal silicic acid, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their acrylate and methacrylate copolymers. The gels are applied or spread on the skin or are introduced into body orifices. The gels are prepared by adding to the solutions that are prepared as described above so much thickener that a transparent mass with a consistency similar to an ointment is produced. The thickeners mentioned above are used as thickeners. The infusion formulations are infused or splashed on delimited areas of the skin, in which the active ingredient penetrates the skin and acts systemically or is distributed on the body surface. Infusion formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable solvents or solvent mixtures acceptable to the skin. If necessary, other adjuvants are added such as dyes, substances that favor absorption, antioxidants, light protectors, adhesives.

As solvents there may be mentioned: water, alcohols such as ethanol, isopropanol, 2-hexyldecanol, octyldodecanol and tetrahydrofurfuryl alcohol, glycols such as glycerol, propylene glycol, polyethylene glycols, polypropylene glycols, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as acetic ester, butyl, benzyl benzoate, dibutyl adipate, dicapryl carbonate, diethylhexyl carbonate, propylene carbonate, ethers such as dicapryl ether, aliphatic ether of alicyclic glycol, dipropylene glycol monomethyl ether, diethylene glycol monomethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone , aromatic and / or aliphatic hydrocarbons, vegetable or synthetic fatty oils such as peanut oil, olive oil, rapeseed oil, sesame oil, soybean oil, sunflower oil, glyceryl ricinoleate, medium chain triglycerides, dicaprylate / dicaprate propylene glycol, propylene glycerol propylene glycol glycol and laurate; other esters of fatty acids such as 2-octyldodecyl myristate, cetearyl isononanoate, cetearyl octanoate, cetylethyl hexanoate, caprylate / coconut caprate, decyl cocoate, decyl oleate, ethyl oleate, isocetyl palmitate, isopropyl myristate, isopropyl palmitate, isostearyl isostearate, octyl palmitate, octyl stearate, oleyl lerucate; silicone oils such as cetyldimethicone, dimethicone and simethicone; dimethylformamide, dimethylacetamide, glycerol formal, glycofurol, 2-pyrrolidone, N-methylpyrrolidone, 2-dimethyl-4-hydroxy-methylene-1,3-diosolan, dioctylcyclohexane. Dyes are all dyes allowed for application in animals that can be dissolved or suspended. Substances that favor absorption are for example DMSO, extensible oils such as isopropyl myristirate, isopropyl palmitate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols. Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, tocopherol. They are protective agents against light, for example substances of the benzophenone class or novantisol acid. Adhesive agents are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin. The emulsions are of the water-in-oil type or the oil-in-water type. They are prepared by dissolving the active ingredient in the hydrophobic phase or in the hydrophilic phase, and this is homogenized with the solvent of the other phase with the help of suitable emulsifiers and optionally other adjuvants such as dyes, substances that favor absorption, preservatives, antioxidants , agents that protect against light, substances that increase viscosity. As the hydrophobic phase (oils) there may be mentioned: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as triglycerides of caprylic / capric acid, mixtures of triglycerides with fatty acids chain length vegetables Cs-? or other specially selected natural fatty acids, partial mixtures of saturated or unsaturated fatty acid glycerides, optionally containing also hydroxyl, mono and diglyceride groups of the Ca / Cio fatty acids. Esters of fatty acids such as ethyl stearate, di-n-butyl adipate, hexyl ester of lauric acid, dipropylene glycol pelargonate, esters of a branched fatty acid of half chain length with saturated fatty alcohols of chain length C? 6 -C? 8, isopropyl myristate, isopropyl palmitate, caprylic / caprinic acid esters of fatty alcohols of the chain length C? 2-C? 8, isopropyl stearate, oleic acid oleic ester, oleic acid decyl ester , ethyl oleate, lactic acid ethyl ester, wax type fatty acid ester such as duck uropygeal gland fat, dibutyl phthalate, isopropyl ester of adipic acid, mixtures of esters related to the latter, among others. Grade alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol. Fatty acids such as oleic acid and their mixtures. As the hydrophilic phase, there may be mentioned: Water, alcohols such as for example ethanol, isopropanol, propylene glycol, glycerol, sorbitol, and mixtures thereof. As emulsifiers there may be mentioned: nonionic surfactants such as, for example, polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monoestearate, glycerin monostearate, polyoxyethyl stearate, polyglycolic alkyphenyl ether.; amphoteric surfactants such as Di-Na-N-lauryl ß-imidpropionate or lecithin; anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfate, mono / dialkyl ether ester salt of orthophosphoric acid monoethanolamine; cationic surfactants such as cetyltrimethylammonium chloride As further adjuvants there may be mentioned: substances which increase the viscosity 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 maleic anhydride, polyethylene glycols, waxes, colloidal silicic acid or mixtures of the indicated substances. The suspensions are prepared by suspending the active ingredient in a carrier liquid with the addition of other adjuvants, such as humectants, dyes, substances that favor absorption, preservatives, stabilizers, antioxidants and light-protecting agents. All homogeneous solvents and solvent mixtures can be mentioned as carrier liquids. As humectants (dispersants), the abovementioned surfactants can be mentioned. As additional adjuvants, those mentioned above can be mentioned. The semisolid preparations differ from the suspensions and emulsions described above only because of their higher viscosity. For the preparation of more solid preparations, the active ingredient is mixed with suitable carriers, optionally with the addition of adjuvants and brought into the desired form. As carriers, all physiologically acceptable solid substances can be mentioned. They serve as such organic and inorganic substances. Inorganic substances are, for example, sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicic acids, clays, precipitated or colloidal silicon dioxide, phosphates. Organic substances are, for example, sugars, cellulose, food and feed, such as milk powder, animal meals, cereal flours and husks, starches. The preservatives, antioxidants, stabilizers, colorants that have been mentioned above are adjuvants. Other suitable adjuvants are lubricants and glidants such as for example magnesium stearate, stearic acid, talc, bentonite, substances that promote disintegration such as cross-linked starches or polyvinylpyrrolidone, binders such as starches, gelatin or linear polyvinylpyrrolidone as well as dry binders such as microcrystalline cellulose. . The active ingredients can also be present in the preparations in combination with synergists or with other active ingredients. Ready-to-use preparations contain the active ingredients respectively in concentrations of ppm to 25% m / m, the macrocyclic lactone is preferably used in concentrations of 0.01 to 5% m / m, particularly preferably 0.1 to 2% m / m; amidine is preferably used in concentrations of 1 to 20% m / m, particularly preferably 5 to 15% m / m. Preparations that are diluted before their application contain the active principles respectively in concentrations of 0.5 to 90% m / m, preferably 5 to 50% m / m. In general it has been found to be advantageous to administer amounts of about 0.01 to 100 mg of active ingredient per kg of body weight per day to achieve effective results, the preferred daily doses are found in the case of the macrocyclic lactone in the range of 0.05 to 5 mg / kg, particularly preferably 0.1 to 3 mg / kg, in the case of amidine the usual daily doses are preferably in the range of 1 to 30 mg / kg, with particular preference for 5 to 15 mg / kg. According to the invention, formulations of dorsal or punctual spill are especially preferred. Such formulations contain the macrocyclic lactone in amounts of 0.01 to 10% m / m, preferably 0.1 to 1% m / m. The amidine content is usually from 0.5 to 25% m / m, preferably from 5 to 15% m / m. As a solvent for the dorsal or dorsal spill formulations, the aforementioned solvents are suitable. In this regard, solvents having very good dissolubility properties for macrocyclic lactones and amidines such as ethanol, isopropanol, propylene glycol, 2-hexyldecanol, octyldodecanol, dibutyl adipate, medium chain triglycerides, propylene glycol dicaprylate / dicaprate, propylene glycol laurate are preferred. , isopropyl myristate, isopropyl palmitate, propylene carbonate, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether and ketones. Solvents having good extensibility properties such as 2-hexyldecanol, octyldodecanol, 2-octyldodecyl myristate, cetearyl isononanoate, cetearyl octanoate, cetylethyl hexanoate, caprylate / coconut caprate, decylke cocoate, decyl oleate, oleate are preferred. ethyl, isocetyl palmitate, isopropyl myristate, isopropyl palmitate, isostearyl isostearate, octyl palmitate, octyl stearate, oleyl lerucate; medium chain triglycerides, propylene glycol dicaprylate / dicaprate, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, cetyldimethicone, dimethicone and if ethicone. Especially preferred in this regard are solvents which have good dissolubility properties for macrocyclic lactones and amidines and good extensibility properties, such as 2-hexyldecanol, octyldodecanol, dibutyl adipate, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, chain triglycerides medium, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, isopropyl myristate and isopropyl palmitate. The solvents can be used alone or also in combination. Its total concentration is usually between 10 and 98% m / m, preferably between 30 and 95% m / m. Preferred spill or dorsal spill formulations may also contain additives and customary pharmaceutical adjuvants. Preferably basic reactive substances such as ammonia, sodium hydroxide or triethanolamine can be added for the stabilization of the active ingredients, and in a customary manner in concentrations of 0.1 to 3% m / m, preferably 0.1 to 2% by weight m / m. According to a preferred embodiment, mixtures of an alkanol with 1 to 4 carbon atoms, for example ethanol or especially isopropanol, with an aliphatic fatty acid ester, especially a fatty acid ester, are used as solvents for the agents according to the invention. of an aliphatic alcohol unit C? _ with a C? 2_? 8 fatty acid, such as for example ethyl oleate, isopropyl myristate or isopropyl palmitate and paraffin oil, especially fluid paraffin oil. These three components are particularly preferably contained in the mixtures in the same respective weight ratios. As already indicated above, it is advantageous to add a base such as triethanolamine to this mixture of solvents. Dorsal or dorsal spill formulations can be formulated as emulsion concentrates. In this sense, the active ingredients are dissolved at a higher concentration in a solvent together with a dispersing agent. The user adds a certain amount of this concentrate in water, after which an emulsion is formed spontaneously or after shaking. As solvents, the aforementioned substances can be used and the ionic and nonionic emulsifiers mentioned above can also be used as dispersants. The application in combination means that the macrocyclic amidines and lactones can be applied separately or stepwise in time. In this case the macrocyclic amidines and lactones are respectively formulated as individual drugs. Simultaneous application is also possible; according to the invention it is preferred that the amidine and the macrocyclic lactone be co-formulated in an agent. The following are suitable examples of formulations of the active compound combination which can be used according to the invention, without thereby limiting the invention in any way: Examples In the examples, the amounts used are indicated in grams per 100 milliliters of finished preparation. Example 1 0.5 g Abamectin 10 g Cymyzole 40 g Medium chain triglycerides (TCM, Miglyol 812) 40 g Isopropyl myristate The TCM and isopropyl myristate are mixed and heated to approximately 50aC. Abamectin and Cimiazol are dissolved consecutively in the mixture. A slightly cloudy, yellowish solution results. Example 2 0.5 g Abamectin 5 g Cymyzole 43 g Medium chain triglycerides (TCM, Miglyol 812) 43 g Isopropyl myristate Preparation, see Example 1. Example 3 0.5 g Abamectin 10 g Cymyzole 0.5 g Triethanolamine Se consecutively dissolve abamectin, triethanolamine, and chymosole in isopropanol. Next, isopropyl myristate and fluid paraffin are added. A yellowish solution appears. Example 4 0.5 g Abamectin 5 g Cymyzole 0.5 g Triethanolamine 26 g Isopropyl myristate 26 g Isopropanol 26 g Fluid paraffin Preparation, see Example 3. Example 5 0.5 g Abamectin 10 g Cymyzole 86 g Dibutyl adipate Se consecutively dissolve abamectin and cymyzole in dibutyl adipate with heating at 50 ° C. A yellowish solution appears. Example 6 0.5g Abamectin 10 g Cimiazol 082g Propylene Glycol Laurate (Lauroglycol FCC) Abamectin and cymycozole are consecutively dissolved in propylene glycol laurate with heating at 50 aC. A yellowish solution appears. Example 7 0.5 g Abamectin 10 g Cymyzole 25 g Isopropyl palmitate 25 g Isopropanol 25 g Fluid paraffin Abamectin and cymyzole are consecutively dissolved in isopropanol. Next, isopropyl palmitate and fluid paraffin are added. A yellowish solution appears. Example 8 0.5 g Abamectin 10 g Cimiazol 71 g Isopropanol Abamectin and cymyzole are consecutively dissolved in isopropnaol. It looks like a yellowish solution. Example 9 0.5 g Abamectin 10 g Cymyzole 0.5 g Cysteamine 40 g Isopropyl palmitate 40 g Isopropylene glycol laurate Abamectin, cysteamine and cymazole are dissolved consecutively in propylene glycol laurate with heating at 50 aC. Next, isopropyl palmitate is added. A yellowish solution appears. Example 10 0.5 g Abamectin 10 g Cymyzole 0.5 g Triethanolamine 0.05 g butylated hydroxytoluene (BHT) 40 g Isopropyl palmitate 40 g Propylene glycol urate Abamectin, cymyzole and BHT are consecutively dissolved in the mixture of isopropyl palmitate and propylene glycol laurate with heating at 502C. A yellowish solution appears. Example 11 0.5 g Abamectin 10 g Cymyzole 40 g Soybean oil 40 g Isopropyl palmitate Abamectin and cimiazole are consecutively dissolved in the mixture of soybean oil and isopropyl palmitate, with heating at 50 ° C. A yellowish-brownish turbid solution appears.

Example 12 l, 5g Abamectin 30 g Cimiazol 10 g Castor oil PEG-35 (CremophorEL) 56 g Propylene glycol laureth (Lauroglycol FCC) Abamectin and cymycozole are consecutively dissolved in propylene glycol laurate with heating at 50 ° C. PEG-35 castor oil is then added. A slightly cloudy, yellowish-brown solution appears. A part of this solution gives a dorsal spill emulsion with two parts of water for its application. Example 13 l, 5g Abamectin 30 g Cimiazol 10 g Hydrogenated castor oil-PEG-40 (Emulgin HRE40) 56 g Propylene glycol laureth (Lauroglycol FCC) Abamectin and cimiazole were consecutively dissolved in propylene glycol laurate with heating at 50 ° C. Next, hydrogenated castor oil-PEG-40 is added.

A slightly brownish-yellowish solution appears (emulsion concentrate). A part of this solution gives with two pairs of water a dorsal spill emulsion ready for its application.

Example 14 1.5 g Abamectin 30 g Cymyzole 10 g Polysorbate 80 (Tween 80) 25 g Methyl isobutyl ketone 25 g Isopropyl myristate Abamectin and cymyzole are consecutively dissolved in the mixture of methyl isobutyl ketone and isopropyl myristate with heating at 50 ° C. Then polysorbate 80 is added. A yellowish-brown turbid solution appears. A part of this solution gives with two parts of water a dorsal spill emulsion ready for its application. Example 15 1, 5 g Abamectin 30 g Cimiazol 10 g Polysorbate 60 (Crillet 3 Super) 25 g Methyl isobutyl ketone 25 g Isopropyl myristate Abamectin and cimiazole are consecutively dissolved in the mixture of methyl isobutyl ketone and isopropyl myristate with heating at 50 aC. Next, polysorbate 60 is added. A yellowish-brown turbid solution appears. A part of this solution with two parts of water gives a dorsal spill emulsion ready for application.

EXAMPLE 16 0.5 g Ivermectin 10 g Cymyzole 0.5 g Triethanolamine 25 g Isopropyl palmitate 25 g Isopropanol 25 g Fluid paraffin Ivermectin, triethanolamine and chyramzole are dissolved consecutively in isopropanol. Next, isopropyl palmitate and fluid paraffin are added. A yellowish solution appears. Example 17 0.5g Moxidectin 10 g Cymyzole 25 g Isopropyl palmitate 25 g Isopropanol 25 g Medium chain triglycerides (TCM, Miglyol 812) Moxidectin and cimiazole are dissolved consecutively in isopropanol. Next, isopropyl palmitate and medium chain triglycerides are added. A yellowish solution appears. Example 18 0.5 g Abamectin 10 g Amitraz 0.5 g Triethanolamine 25 g Isopropyl myristate Abamethine, triethanolamine and amitraz in isopropanol are consecutively dissolved. Next, isopropyl myristate and fluid paraffin are added. A yellowish solution appears. Example 19 0.33 g Abamectin 6.67 g Cymyzole 0.5 g Triethanolamine 25.7 g Isopropyl myristate 25.7 g Isopropanol 25.7 g Fluid paraffin Abamectin, triethanolamine and cymyzole are consecutively dissolved in isopropanol. Next, isopropyl myristate and fluid paraffin are added. A yellowish solution appears. Example 20 0.5 g Abamectin 10 g Cymyzole 0.5 g Triethanolamine 25 g Isopropyl palmetto 25 g Isopropanol 25 g Fluid paraffin Abamectin, triethanolamine and cimiazole are dissolved consecutively in isopropanol. Next, isopropyl palmitate and fluid paraffin are added. A yellowish solution appears Biological example Before the start of the experiment, calves are kept for two weeks in individual stables. After the adaptation phase, each calf was infected on days -24, -21, -19, -17, -14 ,. -12, -10, -7, -5, -3 and -1 with 5000 larvae (0.25 g) of Boophilus microplus (strain e), which were 7 to 21 days old. Day zero was the day of treatment. Fully swollen ticks were harvested on days -3 to 51. Based on the average number on days -3, -2, and -1 of collected Boophilus microplus females, the animals were ordered and divided into blocks, the corresponding figure to the number of experimental groups. Within the blogs the calves were assigned to the individual experimental groups in a random way: Experiment 1 Experiment 2 Composition of the comparative preparations of Cimiazol mono Cimiazol mono nsl Cymyzole 10.0% Triethanolamine 0.5% Isopropanol 24.8% Isopropyl myristate 24.8% Fluid paraffin 24.8% Cyniazole mono n? 2 Cymozole 10.0% Medium chain triglycerides 40.4% Isopropyl myristate 40.4% The percentage efficacy for each treatment was calculated using the following formula: Ef .i. caci a percentage, ^, 1 - TaxCb x 100 TbxCa Where Ta = average number of ticks that were collected from treated animals after treatment; Tb = average number of ticks that were collected from the animals treated during the three previous days before treatment; Ca = average number of ticks that were collected from the control animals in the post-treatment phase; Cb average number of ticks that were collected from the control animals in the three days prior to treatment. The results are represented in the figures: Fig. 1: Experiment 1: percentage efficacy of cyamizol / abamectin against Boophilus microplus in experimentally infected calves (arithmetic mean values for day 1 to day 36) Fig. 2a: Experiment 2: efficacy percentage of cyamizol / abamectin against Boophilus microplus in experimentally infected calves (mean values of sliding scale for day 3 to day 44) Fig. 2b: Experiment 2: percentage efficacy of cyamizol / abamectin against Boophilus microplus in experimentally infected calves (average values of sliding scale for day 3 to day 44). It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (13)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Products characterized in that they contain a macrocyclic lactone and an amidine in combination.
2. 2. Products according to claim 1, characterized in that they are for simultaneous, separate or stepwise application in time against parasites in animals.
3. 3. Products according to any of the preceding claims, characterized in that they contain abamectin as a macrocyclic lactone.
4. 4. Products according to any of the preceding claims, characterized in that they contain amitraz and / or cymyzole as amidine.
5. 5. Products according to any of the preceding claims, characterized in that they contain abamectin and cymyzole.
6. 6. Products according to any of the preceding claims, characterized in that they are for application in working animals.
7. 7. Products according to any of the preceding claims, characterized by being for their application in bovines.
8. 8. Products according to any of the preceding claims, characterized in that they are for application on the coat of the animals.
9. 9. Products according to any of the preceding claims, characterized in that they are for application as spill dorsal or dorsal punctual.
10. 10. Products according to any of the preceding claims, characterized in that they are for application as spill dorsal or dorsal point after diluting them with water.
11. 11. Use of macrocyclic lactones and amidines for the preparation of products to combat parasites in animals.
12. 12. Use according to claim 11, for the preparation of products for simultaneous application, separately or stepwise in time against parasites in animals.
13. 13. Procedure for combating parasites in animals, characterized in that an effective amount of macrocyclic lactone is applied in combination with an effective amount of amidine.