DK177441B1 - Composition for long-term protection against fleas in mammals, especially cats and dogs - Google Patents

Abstract

A method and composition in particular for controlling fleas in small mammals characterized in that the composition comprises at least one insecticide of the 1N-arylpyrazole type, especially fipronil, and on the other hand at least one compound of the insect growth regulating (IGR) type in doses and conditions which are parasitically effective against fleas in a liquid vehicle acceptable to the animal and convenient for local application to the skin, preferably located to a small surface area.

Description

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DK 177441 B1

The present invention relates to a composition for use for long-term protection against fleas on small mammals and especially fleas on cats and dogs. This invention relates to a novel composition based on the synergistic combination of parasiticides already known.

A novel class 1-N-arylpyrazole-based insecticide has been disclosed in EP Patent A-295,217 and A-352,944. The compounds of the classes defined in these patents are extremely active and one of these compounds 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2- pyrazole, whose common name is fipronil, has been found to be particularly effective against not only crop parasites but also against mammalian ectoparasites and in particular, but not exclusively, fleas, mites, flies and myiasis.

Compounds having an ovicidal and / or larvicidal effect on the 20 immature stages of various ectoparasites are already known from e.g. U.S. Patent A-5,439,924. Among these compounds are insect growth regulatory (IGR) compounds which act either by blocking the development of the immature stages (eggs and larvae) to adult stages or by inhibiting the synthesis of chitin.

Furthermore, FR patent specification A-2,713,889, which generally describes the combination of at least one compound of the insect growth regulatory (IGR) type comprising compounds having 30 juvenile hormone activity and chitin synthesis inhibitors with at least one of three N-aryldiazole compounds, especially fipronil, is known to fight many harmful insects belonging to highly varied orders.

The compositions can be used in very different forms without specifying what uses, e.g. veterinary, health or plant protection, these | 2 | B1 different forms are determined or to which parasites to which they are respectively determined.

The only use which is likely to be veterinary is associated with the example of making a pesticide collar which is a slow release formulation.

The invention provides an improvement of the methods for controlling fleas in small mammals and especially in cats and dogs.

In particular, the invention aims to use already known parasiticides to produce a composition which is highly active against the fleas of these animals.

15

Finally, the object of the invention is to provide a novel composition which is thus manufactured and especially intended for the control of fleas.

The term fleas is to be understood in the meaning of the present invention as referring to all the common or random species of parasitic fleas of the order Siphonaptera and in particular the species Ctenocephalides, especially C. felis and C. canis, rat fleas (Xenopsylla cheopis) and human fleas. (Pulex 25 irritance).

The very high efficiency of the composition according to the invention implies not only high immediate efficiency but also very long-lasting efficiency after the animal has been treated.

30

The invention has for its object to be used in a method for controlling fleas in small mammals and especially in cats and dogs for a long period of time, which is characterized in that the animal is treated locally on the skin, preferably located to a small surface area ( spot-on administration), in parasitically effective doses and ratios, to place at least one compound (A) 1- [2,6-Cl 2

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DK 177441 B1 phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole and on the other hand at least one ovicidal compound (B) of the insect growth regulatory (IGR) type selected from azadirachtin, diophenolane, phenoxycarb, hydroprene, quinoprene, methoprene, 5 pyriproxyphene, tetrahydroazadirachtin and 4-chloro-2- (2-chloro-2-methylpropyl) -5- (6-iodo-3-pyridylmethoxy) pyridizin-3 (2H) -one, in a liquid vehicle which is acceptable to the animal and is suitable for local or punctual application to the skin, wherein the liquid vehicle and the concentration of compounds (A) and 10 (B) are adapted for "spot-on" punctual application by application to the skin .

The compounds (B) of the insect growth regulatory (IGR) type that mimic juvenile hormones are azadirachtin (Agridyne) diophenolane (Ciba Geigy) phenoxycarb (Ciba Geigy) hydroprene (Sandoz) quinoprene (Sandoz) 20 methoprene (Sandoz) pyriproxyfene (Sumoz) (Agridyne) 4-chloro-2- (2-chloro-2-methylpropyl) -5- (6-iodo-3-pyridylmethoxy) pyridizin-3 (2H) -one, these compounds being defined by their international, common name (The Pesticice Manual, 10th Edition, 1994, editor Clive Tomlin, UK).

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The preferred compounds (B) are methoprene, pyriproxyphenes and hydroprene.

5

It is preferred that the administration of the two types of compounds be parallel and preferably joint.

It is preferred that the treatment be performed every two or preferably every three months on cats and dogs.

Preferably, the treatment is carried out such that a dose of 0.1 to 40 and in particular of 1 to 20 mg / kg for compound (A) and a dose of 0.1 to 40 and 15 in particular 1 to 30 mg is administered to the animal. / kg with respect to compound (B).

The preferred dosages are from 5 to 15 mg / kg with respect to compound (Δ) and from 0.5 to 15 mg / kg with respect to preferred compounds (B), or from 10 to 20 mg / kg with respect to 20 other compounds (B).

In another embodiment of the method, compounds (A) and (B) can be administered in a temporally separated and divided manner. In this case, it is preferred to allow the administrations to alternate at an interval of e.g. 1 month between two administrations, the first administration being preferably done with compound (A).

It will be apparent that the dose values thus indicated are average values which may vary over a wide range, since in practice a formulation with specified doses of compound (A) of the derivative of 1-N-phenylpyrazole type and of compound (B) will be administered to animals of comparatively different weights. As a result, the actual 35 doses administered are often smaller or larger by a factor which may be up to 2, 3 or 4 relative to the preferred dose without causing any toxic risk to the animal in the event | 5 | B1 of an overdose, while at the same time maintaining a true efficiency of possible lesser duration in the event of a sub-dose.

The purpose of this method is non-therapeutic and relates in particular to the purification of the animal's hair and skin by eliminating the parasites present as well as their remnants and excrement. Thus, the treated animals have hair that is more comfortable to look at and touch.

10

The method described above can also be used to control ectoparasites, especially blood mites.

It is also an object of the invention to provide a composition and, in particular, a composition for use for long-term protection against fleas in small mammals and especially in cats and dogs, which composition is characterized in that it comprises at least one compound ( Δ), 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole and on the other hand at least one ovicidal compound (B) of the insect growth regulatory (IGR) type that mimics juvenile hormones selected from azadirachtin, diophenolane, phenoxycarb, hydroprene, quinoprene, methoprene, pyriproxyphene, tetrahydroazadirachtin and 4-chloro-2- (2-chloro-2-methylpropyl) -5-25 (6- iodine-3-pyridylmethoxy) pyridizine-3 (2H) -one, in a liquid vehicle acceptable to the animal and suitable for local or punctual administration to the skin where the liquid vehicle and the concentration of compounds (A) and (B) are adapted for punctual spot-on application when applied to the skin.

30

The invention has for its object to provide a composition in the form of a spot-on formulation for use in the long-term protection of small mammals against fleas, which composition is characterized in that it comprises at least one compound A), 1-35 [2.6- C2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole and comprises at least one ovicidal compound (B) of the insect growth regulatory (IGR) type that mimics juvenile | 6 | DK 177441 B1 hormones selected from azadirachtin, diophenolane, phenoxycarb, hydroprene, quinoprene, methoprene, pyriproxyphene, tetrahydroazadirachtin and 4-chloro-2- (2-chloro-2-methylpropyl) -5- (6-iodo-3-pyridylmethoxy) pyridizine -3 (2H) -one in a mammalian liquid vehicle suitable for local application to the skin, the vehicle comprising a crystallization inhibitor, an organic solvent having a dielectric constant of between 10 and 35 and an organic co-solvent having boiling point below 100 ° C and having a 10 dielectric constant of between 10 and 40.

The compound 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole can be prepared according to one of the methods described in patent application WO-A-87 / 3781, 15 93/6089, 94/21606 or European Patent Application EP-A-0,295,117, or any other method which falls within the expertise of a person skilled in the chemical synthesis. For the chemical preparation of the compositions of the invention, one skilled in the art is considered to have among other things the complete content of "Chemical Abstracts" and the documents cited therein.

Among the above-mentioned compounds of the IGR type, methoprene, pyriproxyphenes and hydroprene are preferred.

The weight ratios of the compound 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole and compound (B) are preferably between 80/20 and 20 / 80th

The liquid vehicle can be simple or complex and is adapted to the chosen route of administration and method.

Advantages of spot-on administration (spot-on administration) may advantageously comprise: b) a crystallization inhibitor present in particular at a ratio of from 1 to 20% (w / v), preferably from 5 to 15%, | 7 ~ 1 DK 177441 B1 as this inhibitor satisfies the sample according to: 0.3 ml of a solution A comprising 10% (w / v) of the compound 1- [2,6-Cl2-4-CF3-phenyl ] -3-CN-4- [SO-CF3] -5-NH2-pyrazole in the solvent below, together with 10% of this inhibitor, is deposited on a slide at 20 ° C for 24 hours, followed by the bare it is observed whether there are few or no crystals, especially fewer than 10 crystals and 10 preferably 0 crystals, on the preparation glass; c) an organic solvent having a dielectric constant of between 10 and 35, preferably between 20 and 30, the contents thereof being solvent c) in the total composition, preferably 15 is the difference which supplements the composition up to 100%; d) an organic co-solvent with a boiling point of less than 100 ° C, preferably below 80 ° C, and with a dielectric constant of between 10 and 40 , preferably between 20 and 30, this co-solvent being advantageously v to be present in the composition in a d) / c) weight / weight ratio (W / W) of between 1/15 and 1/2. The solvent is volatile, in particular, it serves as a drying promoter and is miscible with water and / or with solvent c).

25

While not preferred, the spot-on administration composition may optionally comprise water, especially to an extent of 0 to 30% (v / v, v / v), in particular from 0 to 5%.

30

The spot-on administration composition may also comprise an antioxidant which is intended to inhibit oxidation with air, this agent being particularly present in a ratio of 0.005 to 1% (w / v) and preferably 0.01 to 0.05%.

35

The compositions of the invention, which are intended for pet animals, especially cats and dogs, are generally administered by becoming | 8 | DK 177441 B1 applied to the skin ("spot-on" or "pour-on" administration); this is generally a local administration within a surface area of less than 10 cm 2, especially between 5 and 10 cm 2, and especially at two points and preferably located between the shoulders of the animal. Once applied, it especially spreads throughout the animal's body and then dries without crystallizing or modifying the appearance of the coat (especially in the absence of any whitish deposit or dusty appearance) or the grip of the coat.

10

The spot-on administration compositions of the present invention are particularly advantageous because of their effect, rate of action, and the pleasing appearance of the animal's fur after administration and drying.

15

As organic solvent c) which can be used according to the invention may be mentioned in particular: acetone, acetonitrile, benzyl alcohol, butyldiglycol, dimethylacetamide, dimethylformamide, dipropylene glycol-n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomer , monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, especially N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate or a mixture of at least two of these solvents.

As crystallization inhibitor b) which can be used according to the invention, in particular, mention may be made of: 30-polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylene sorbedol; lecithin, sodium carboxymethyl cellulose, acrylic derivatives such as methacrylates and the like, anionic surfactants such as alkali metal stearates, especially sodium, | 9 | DK 177441 B1 potassium or ammonium stearate; calcium stearate; triethanolamine; natriumabietat; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids, especially those derived from coconut oil, cationic surfactants such as water-soluble quaternary ammonium salts of the formula N + R'R '' R '' 'R' '' ', Y' 'wherein the groups R are optionally hydroxylated hydrocarbon groups , 10 and Y "is an anion of a strong acid such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used, amine salts of the formula N + R'R''R 'wherein the groups R are Octadecylamine hydrochloride is among the cationic surfactants that can be used, nonionic surfactants such as optionally polyoxyethylenated sorbitan esters, especially polysorbate 80, polyoxyethylene alkylated ethers; polyethylene glycol stearate polyoxyethylene fatty acids, copolymers of ethylene oxide and propylene oxide, 25-amphoteric surfactants such as substituted betaine lauryl compounds, or fort preferably a mixture of at least two of these crystallization inhibitors.

In a particularly preferred way, a crystallization inhibitor pair, namely the combination of a polymer-type film-forming agent and a surfactant, will be used. In particular, these agents will be selected from the compounds mentioned as crystallization inhibitor b).

10 DK 177441 B1

Among the polymeric film-forming agents which are particularly advantageous are: -the various polyvinylpyrrolidone grades, 5 -polyvinyl alcohols, and copolymers of vinyl acetate and vinylpyrrolidone.

In the case of surfactants, non-ionic surfactants and preferably polyoxyethylenated sorbitan esters, and in particular various polysorbate grades, are particularly preferred. polysorbate 80.

The film-forming agent and surfactant can be incorporated in substantially equal or identical amounts within the limit of the total amount of the other-mentioned crystallization inhibitor.

The pair thus produced ensures the purpose of the absence of crystallization on the hairs and the maintenance of the cosmetic appearance of the coat in a remarkable manner, ie. without any tendency to stickiness or to sticky appearance, despite the high concentration of active material.

As co-solvent d), in particular, absolute alcohol, isopropanol and methanol can be mentioned.

Particularly used as antioxidants are conventional agents such as: butyl hydroxyanisole, butyl hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate and sodium thiosulfate or a mixture of not more than two of these agents.

The spot-on administration compositions of the invention are usually prepared by simple mixing of the ingredients as previously indicated; advantageously mixed initially with the active material in the main solvent and the other ingredients or adjuvants then added.

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DK 177441 B1

The volume administered may be from approx. 0.3 to 1 ml and preferably approx. 0.5 ml for cats, and from approx. 0.3 to 3 ml for dogs according to animal weight.

In a particularly preferred manner, the composition of the invention may be in the form of a concentrated emulsion, suspension or solution for spot-on administration on a small area of the animal's skin generally between the two shoulders (spot-on type solution). In a clearly less preferred manner, forms of solution or suspension may be provided for atomization, dissolution, suspension or emulsion for pouring or spreading on the animal (pour-on type solution), oil, cream, ointment or any other liquid. formulation for topical administration.

15

Advantageously, the ready-to-use composition contains a dose of 0.1 to 40 mg / kg of compound (A) and 0.1 to 40 mg / kg of compound (B).

Preferably, a ready-to-use dosage formulation contains, in particular, one for spot-on administration of 1 to 20 mg / kg and especially 2 to 10 mg / kg of compound (A), fibronil, and from 1 to 30 mg / kg and preferably 2 to 10 mg. / kg of a preferred compound (B) or 10 to 20 mg / kg of another compound (B).

25

Advantageously, ready-to-use dosage preparations for animals weighing 1-10, 10-20 and 20-40 kg, respectively, can be provided.

In another embodiment intended for time-division administration, a composition in the form of a kit divided into the same package may be combined combining a composition containing a compound (A), fipronil, and a composition containing compound (B), preferably the pyriproxyphenes, each of the compositions including a vehicle which allows the administration thereof on the skin.

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DK 177441 B1

Preferably, each of the two compositions is intended for local spot-on administration, and preferably a container containing just the required dose is provided for each administration.

Thus, a set in a package, e.g. contain three containers, each containing a single dose of compound (A), and three containers, each containing a single dose of compound (B), the (A) containers being separated from the (B) containers by labels. , shapes or colors as well as a note specifying that (A) containers and (Containers) should be used interchangeably at an interval of, for example, one month, starting with, for example, an (A) container.

The compositions of the invention, and in particular the compositions for spot-on administration, have proven to be extremely effective for the very long-term treatment of fleas on mammals and especially small mammals such as cats and dogs.

The discovery that compound (A) such as fibronil is dissolved in sebum so that the entire animal is covered and concentrated in the sebaceous glands from which it is gradually released over a very long period of time is a probable explanation for this long-lasting effect of these preparations and may could also explain the long-lasting effect of the associated compound (B).

They also have some effect on other parasitic insects and especially on blood mites, and it will be apparent that the administration of the composition of the invention can be extended to a treatment for ectoparasites or even endoparasites against which the composition is found to be effective. have real utility which is practically capable of being achieved in accordance with criteria in veterinary engineering.

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DK 177441 B1 Thus, e.g. a preparation based on fibronil and fluazuron is also used against especially blood mites.

Where appropriate, the composition of the invention may also comprise another insecticide and in particular imidaclopride.

Other advantages and features of the invention will become apparent from the examples set forth in the description below.

The formulation example which follows comprises as compound (A) fibronil.

For example. to prepare a composition for topical administration to the skin in accordance with the invention, the following 15 ingredients may advantageously be mixed together: α1 - compound (B) at a ratio of 1 to 20% (percent by weight per volume w / v) 20 α2 - compound ( A) in a ratio of 1 to 20%, preferably 5 to 15%, (percent by weight per volume w / v).

By way of example, the compositions of the invention comprise the following concentrations (w / v) of compounds (A) and (B) in a liquid medium comprising one representative of each of components b, c and d. The total volume is 1 ml.

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Example 1 fipronil 10% pyriproxyphene 5% 5 Example 2 fipronil 5% pyriproxyphene 5%

Example 3 Fipronil 5% Pyriproxyphene 20%

Example 4 Fipronil 10% 15 Methoprene 30%

Example 5 Fipronil 10% 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4-trifluoromethyl) phenylurea 5%.

Cats are each attacked with 100 fleas and re-attacked every 10 days. At the time of the first manifestation, they receive a topical administration on the skin of 0.1 25 mg / kg of the composition of Example 1. Two months after the treatment and 10 days after the last exposure to infestation, no fleas are detected and the collected eggs are found to be non-viable.

30 Dogs treated in accordance with the same procedure with compositions of Examples 1 and 2 exhibit the same effect of treatment 2 months after administration of the preparation.

Claims (41)

1. In DK 177441 B1 anion of a strong acid - amine salt of the formula N + R, R ,, R ,,,, wherein the groups R are optionally hydroxylated hydrocarbon groups; nonionic surfactants selected from sorbitan esters optionally polyoyethylated, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated castor oil derivatives, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids and copolymers of ethylene oxide and propylene oxide, and 10-amphoteric surfactants, or a mixture of at least two of these crystallization inhibitors. 1. In DK 177441 B1 the formula (I) and compounds of type (B) are between 80/20 and 20/80. A composition for use for long-term protection against fleas in small mammals and especially in cats and dogs, characterized in that it comprises at least one compound (A) 1- [2,6-Cl2-4-CF3 -phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole, and, on the other hand, at least one ovicidal compound (B) of the insect growth regulatory (IGR) type that mimics juvenile hormones selected from azadirachtin , diophenolane, phenoxycarb, hydroprene, quinoprene, methoprene, pyriproxyphene, tetrahydroazadirachtin and 4-chloro-2- (2-chloro-2-methylpropyl) -5- (6-iodo-3-pyridylmethoxy) pyridizin-3 (2H) -one , in a liquid vehicle acceptable to the animal and suitable for local or punctual administration to the skin, wherein the liquid vehicle and the concentration of compounds (A) and (B) are adapted for spot-on "spot-on" application upon application on the skin. 1. In DK 177441 B1 Composition according to claim 1, characterized in that at least one compound (B) of the IGR type is selected from the methoprene, pyriproxyphene and hydroprene. Composition according to claim 2, characterized in that the compound (B) of the IGR type is the pyriproxyphene. 25 Composition according to claim 2, characterized in that the compound (B) of the IGR type is a methoprene. Composition according to claim 1, characterized in that the IGR-type compound (B) is diophenolane. Composition according to claim 1, characterized in that the compound (B) of the IGR type is a phenoxycarb. A composition according to any one of claims 1-6, characterized in that the weight-to-weight ratio of compounds (A) with Composition according to any one of claims 1-7, characterized in that the liquid vehicle and the concentration of compounds (A) and (B) are adapted for local administration in a zone with a surface area of less than 10 cm 2. A composition according to any one of claims 1-8, characterized in that it contains a dose of from 0.1 to 40 mg / kg of compound (A) and from 0.1 to 40 mg / kg of compound (A). B). Composition according to claim 9, characterized in that it contains a dose from 1 to 20 mg / kg of compound (A) and from 1 to 30 mg / kg of compound (B). A composition according to any one of claims 1-8, characterized in that it also comprises a crystallization inhibitor (b) which is preferably present in a ratio of 1 to 20% (w / v). A composition according to claim 11, characterized in that the crystallization inhibitor (b) is selected from: polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, ethylene ethylene, glycerol, sorbitol, polyoxyethylene selected from alkali metal stearates, sodium abietate, alkyl sulfates, sodium dioctylsulfosuccinate or fatty acids, 35. cationic surfactants selected from water-soluble quaternary ammonium salts of the formula N + R'R''R '' 'R'1' ', Y- wherein the groups R are optionally hydroxylated hydrocarbons groups and Y- is one The composition of claim 12, characterized in that 15 anionic surfactants are selected from sodium stearate, potassium stearate, ammonium stearate, calcium stearate, triethanolamine stearate, sodium lauryl sulfate, sodium cetyl sulfate, sodium dodecylbenzenesulfonate or a fatty acid derived from coconut acid. 20 14. The composition of claim 12, characterized in that cationic surfactants are selected from water-soluble quaternary ammonium salts of the formula N + R'R''R '' 'R' '', Y- wherein the groups R are optionally hydroxylated hydrocarbon groups, and Y- is halide, sulfate or sulfonate anion. The composition of claim 12, characterized in that cationic surfactants are cetyltrimethylammonium bromide. The composition of claim 12, characterized in that the amine salt is octadecylamine hydrochloride. The composition according to claim 12, characterized in that nonionic surfactants are polysorbate 80. The composition according to claim 12, characterized in that amphoteric surfactants are substituted lauryl compounds of DK 177441 B1 1. betaine. A composition according to any one of claims 11 or 12, characterized in that it comprises a crystallization inhibitor pair formed by the combination of a polymer-type film-forming agent and a surfactant. A composition according to claim 19, characterized in that the film-forming agent is selected from: 10. polyvinylpyrrolidone, - polyvinyl alcohols, and - copolymers of vinyl acetate and vinylpyrrolidone and in that the surfactant is selected from nonionic surfactants. 21 in DK 177441 B1 characterized in that it comprises at least one compound (A), 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2- pyrazole and comprises at least one ovicidal compound (B) of the insect growth regulatory (IGR) type that mimics juvenile 5 hormones selected from azadirachtin, diophenolane, phenoxycarb, hydroprene, quinoprene, methoprene, pyriproxyphene, tetrahydroazadirachtin and 4-chloro-2 (2-chloro) -2-methylpropyl) -5- (6-iodo-3-pyridylmethoxy) pyridizin-3 (2H) -one in a liquid vehicle which is acceptable to mammals and suitable for topical application to the skin, the vehicle comprising a crystallization inhibitor, a organic solvent having a dielectric constant of between 10 and 35 and eT organic co-solvent having a boiling point below 100 ° C and having a dielectric constant of between 10 and 40. 15 Composition according to claim 20, characterized in that the nonionic surfactant is a polyoxyethyl sorbitan ester. A composition according to any one of claims 1-21, characterized in that it comprises an organic solvent (c) having a dielectric constant of between 10 and 35, the content of which of the total composition preferably represents the difference of 100%. of the composition. Composition according to claim 22, characterized in that the organic solvent (c) is selected from acetone, acetonitrile, benzyl alcohol, butyldiglycol, dimethylacetamide, dimethylformamide, dipropylene glycol-n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethyl ethyl , monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, or a mixture of at least two of these solutions. Composition according to claim 23, characterized in that | The organic solvent (c) is N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, or a mixture of at least two of these solutions. Composition according to claim 24, characterized in that the organic solvent (c) is diethylene glycol monoethyl ether, Composition according to any one of claims 22-25, characterized in that it also comprises an organic co-solvent (d) having a boiling point of less than 100 ° C and having a dielectric constant of between 10 and 40, which co-solvent is miscible with water and / or with the solvent (c), this co-solvent being present in a co-solvent (d) / solvent (c) to weight ratio (w / w) of between 1/15 and 1/2. Composition according to claim 26, characterized in that the organic co-solvent (d) has a boiling point below 80 ° C. Composition according to claim 26, characterized in that the co-solvent has a dielectric constant of between 20 and 30. Composition according to claim 26, characterized in that the co-solvent (d) is selected from absolute ethanol, isopropanol and methanol. 30 A composition according to any one of claims 1-29, characterized in that it comprises 1-20% (w / v) 1- [2,6-Cl 2 -4-CF 3 -phenyl] -3-CN 4- [SO-CF3] -5-NH2-pyrazole and 1-20% (w / v) of compound (B). A composition according to any one of claims 1-29, characterized in 20 | characterized in that it comprises 10% (w / v) 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole and 30% ( weight / volume) methoprene. 5 A composition according to any one of claims 1-29, characterized in that it comprises 5-20% (w / v) 1- [2,6-Cl2-4-CF3-phenyl] -3-CN 4- [SO-CF3] -5-NH2-pyrazole. 10 A composition according to any one of claims 1-29, characterized in that it comprises 5-15% (w / v) 1- [2,6-Cl2-4-CF3-phenyl] -3-CN 4- [SO-CF3] -5-NH2-pyrazole. 15 A composition according to any one of claims 26-33, characterized in that the organic solvent (c) is selected from N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol 20 and diethylphthalate and wherein the co-solvent (d) is selected from absolute ethanol, isopropanol and methanol. The composition of any of claims 11-34, k characterized in that the crystallization inhibitor (b) 25 is polyvinylpyrrolidone. A composition according to any one of claims 1-29, characterized in that it comprises 5-15% (w / v) 1- [2,6-Cl2-4-CF3-30 phenyl] -3-CN -4- [SO-CF3] -5-NH2-pyrazole and 1-20% of at least one compound (B). A composition according to claim 36, characterized in that compound (B) is methoprene. 35 38. Preparation in the form of a spot-on formulation for long-term protection of small mammals against fleas, known A composition according to claim 38, characterized in that the organic solvent (c) is selected from N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethylphthalate or a mixture of at least two of these solutions. Composition according to claim 38, characterized in that the co-solvent (d) is selected from absolute ethanol, isopropanol and methanol. 25 A composition according to claim 39 or 40, characterized in that the organic solvent (c) is diethylene glycol monoethyl ether.