WO2012107585A1

WO2012107585A1 - Novel concentrated and stable topical antiparasitic compositions

Info

Publication number: WO2012107585A1
Application number: PCT/EP2012/052364
Authority: WO
Inventors: Florence Guimberteau; Patrick Forget
Original assignee: Ceva Sante Animale Sa
Priority date: 2011-02-11
Filing date: 2012-02-10
Publication date: 2012-08-16

Abstract

The present invention relates to a particular solvent system including at least 35% dimethylsulfoxide (DMSO) for preparing a veterinary composition for topical application for controlling parasites in domestic animals. The topical composition according to the present invention includes, as the active ingredient, a high concentration of neonicotinoids of the tetrahydrofuran family and has excellent stability and persistence.

Description

NEW PEST CONTROL COMPOSITIONS

CONCENTRATED AND STABLE TOPICS Technical field of the invention

The present invention relates to a particular solvent system for the preparation of a topical veterinary pharmaceutical composition for the treatment of parasitic infestations in domestic animals and / or pets. The topical composition according to the present invention comprises, as active ingredient, a compound of the neonicotinoid family formulated in high concentration which exhibits excellent stability and persistence.

Pets are often infested with several parasites that feed on blood, such as dog fleas, cat fleas, ticks, and galls.

Fleas of the genus Ctenocephalides are also intermediate hosts of Dipylidium caninum, which is a parasitic worm of the small intestine of dogs and cats. The carnivore is infested by swallowing the parasitic fleas. This infestation can cause anal pruritus, engorgement of anal sacs, and perineal dermatitis. Therefore, it is sometimes advisable to worm regularly the animals in addition to the fight against fleas.

In the same way, ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp., ...) can also cause stress to the animal and harm its health. They can also harm the man. But the most serious problem of ticks is that they are a vector of pathogens that can affect the animal as much as the man. Major diseases to be avoided include Borellioses (Lyme disease Borellia burgdorferi), Babesioses (Babesia sp. Piroplasmosis), and Rickettsioses. Ticks can also release toxins with paralyzing, inflammatory, and sometimes life-threatening properties. Finally, the gall (Demodex sp., Sarcoptes sp., Otodectes sp., ...) is particularly difficult to fight because there are very few effective active ingredients. It requires frequent treatments. Infestations by these parasites, especially fleas, therefore represent a major health problem for animals that are infested and require the availability of appropriate treatments. There are many insecticidal substances more or less active and more or less expensive. Resistance phenomena appear related to their use, especially in the case of carbamates, organophosphorus compounds and pyrethroids.

Thus, to overcome these phenomena, the N-phenylpyrazole derivatives, and in particular 5-amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-

(Trifluoromethylsulfinyl) -IH-pyrazole-3-carbonitrile (fipronil), described in patents EP 0 295 1 17 and EP 0 352 944, sold in France by Merial under the name Frontline®, is often presented as a product choice for the prevention and treatment of flea infestations.

Neonicotinoids also represent a new class of neurotoxic insecticides capable of binding to nicotinic acetylcholine receptors (nAChRs) within synapses of nerve cells. These are less toxic to mammals than to insects. They include, among others, imidacloprid, thiamethoxam, chothianidin, dinotefuran, nitenpyram, acetamiprid, and thiacloprid. They are composed of three parts, a pharmacophore, an intermediate chain and a heterocycle group. They are often classified into sub-families according to the nature of their pharmacophore. Thus, imidacloprid, thiamethoxam, clothianidin, and dinotefuran all have an N-nitroguanidine-like pharmacophore, while nitenpyram has a nitrophenon-like pharmacophore, and acetamiprid and thiacloprid have an N-type pharmacophore. cyano-amidine. Alternatively, they are classified according to the nature of their heterocyclic group. The sub-family of chloronicotinyls all carry a heterocyclic group of chloropyridine type except dinotefuran which carries a heterocycle group of tetrahydrofuran type. Certain members of these neonicotinoids have previously been described, such as thiamethoxam in European Patent No. EP 2258194, clothianidin in European Patent Application No. EP376279, thiacloprid in European Patent Application No. EP235725, dinotefuran in US Pat. European Patent Application No. EP649845, Acetamiprid in International Publication No. WO 91/04965, Nitenpyram in European Patent Application No. EP302389, or Imidacloprid in European Patent Application No. EP192060.

These active compounds are commercially available for the treatment of pets. For example, imidacloprid is marketed by Bayer Health Care under the designations Advantage ^® , Advantix ^® , or Advocate ^® ; nitenpyram is marketed by Novartis under the name SAS ^® Capstar; and dinotefuran which is marketed by Summit VetPharm under the designation Vectra ^® or Vectra 3D ^® .

Dinotefuran is difficult to formulate in ready-to-use liquid topical antiparasitic compositions. In particular, they do not always have sufficient solubility in the excipients conventionally used for the preparation of so-called "ready-to-use" compositions in Pour-On, Drop-On and / or Spot-On which are always highly concentrated in an agent. active.

In addition, crystallization phenomena occur regularly in topical antiparasitic preparations when they are applied in high concentration of Pour-On, Drop-On and / or Spot-On directly on the skin of the animal. of crystallization had been encountered for the formulation of N-phenylpyrazole derivatives, such as fipronil, and it had then been proposed to overcome this problem by formulating them in a solvent in the presence of a crystallization inhibitor and an alcohol. in dC ₄ . In this regard, European Patent No. EP0881881 describes the solubilization of N-phenylpyrazole derivatives in the presence of a benzyl alcohol and an organic solvent. International Publication No. WO2010 / 070210 describes the use of dipropylene glycol monomethyl ether for the solubilization of N-phenylpyrazole derivatives. Finally, International Publication No. WO2009 / 027506 describes the solubilization of N-phenylpyrazole derivatives in propylene carbonate. This crystallization phenomenon of fipronil is also observed for topical forms containing neonicotinoids of the tetrahydrofuran family and in particular dinotefuran. Thus, to overcome this problem, it has been proposed to formulate dinotefuran in the presence of a mixture of water and alcohol in European patent applications Nos. EP1575356 and EP1536681, or in the presence of a mixture of water and ethyl lactate in European Patent Application No. EP1883299.

The various topical formulations described above, however, have many disadvantages. Most compositions require the application to the animal of a large volume, which can cause undesirable effects, such as the appearance of an unpleasant odor or lead to the appearance of crystals or powder in peel surface of the treated animal. The crystals which result from the recrystallization of the active ingredient are generally removed from the coat by the animal itself which shakes or is cleaned by licking, which reduces the effectiveness of the treatment. In addition, when the treated animal is a pet, the presence of these crystals is undesirable in human contact, and it is also preferable that the formulation does not leave stains or marks on furniture, carpets or any other object of the habitat.

It is therefore in order to remedy the problems encountered with the pest control products currently available on the market, and to propose concentrated compositions of neonicotinoids of the tetrahydrofuran family and in particular dinotefuran so as to reduce the volume of application thereof, while keeping good stability during storage, and especially the absence of formation of crystals after application to the coat of domestic animals, such as the cat than in the dog, which the Applicant has developed what is the subject of the 'Invention. In particular, it aimed to provide a product aimed at the prevention and / or treatment of flea infestations in domestic animals that is easy to formulate, easy to administer, while having a quick action and more that products currently available on the market.

In this regard, the Applicant has discovered that the solubilization of insecticides such as neonicotinoids of the tetrahydrofuran family, and more particularly dinotéfuran, using a sufficient proportion of dimethylsulfoxide solvent (DMSO) could effectively solve the problems encountered in the formulations of the prior art. Indeed, it has surprisingly been found that the formulation of the neonicotinoids of the family of tetrahydrofurans, and especially dinotefuran, with a solvent fraction comprising at least 35% of DMSO allowed systematically to have lower product freezing points. at 0 ° C thus making these formulations suitable for veterinary use in topical application. It has also been discovered that the addition of this solvent fraction also makes it possible to solubilize higher concentrations of active ingredients without the risk of recrystallization. These new veterinary formulations therefore do not require the addition of additional adjuvants such as crystallization inhibitors or other excipients, and therefore offer improved levels of toxicity. Finally, they do not require special conditions for storage, such as reserves at moderate temperatures above freezing.

Another object of the invention is to provide such compositions that are easy to use whatever the animal species, the size of the animal or the nature of its coat. Yet another object of the invention is to provide effective compositions that do not require to wet the entire animal. These objectives are achieved by the antiparasitic compositions according to the present invention.

Summary of the invention

The present invention relates to novel topical insecticidal compositions comprising a high concentration of neonicotinoids of the tetrahydrofuran family, in particular dinotefuran, and a solvent fraction comprising at least 35% of DMSO. These new compositions are specifically formulations known as Pour-On, Spot-On, Drop-On. They are easy to apply and are particularly active in controlling pests such as insects, fleas, ticks, mites or gall on pets, especially dogs and cats.

The present invention also relates to a process for preparing a stable, persistent and effective topical insecticidal composition comprising a strong concentration of neonicotinoids of the tetrahydrofuran family in stable form and in particular without formation of crystals in situ after local application on the animal's coat or skin. The present invention further relates to a method for controlling, eliminating, and / or preventing the infestation of domestic animals by parasites feeding on blood, such as in particular fleas, ticks and / or galls. .

detailed description

The present invention relates to a novel topical antiparasitic composition comprising a high concentration of neonicotinoid insecticide of the tetrahydrofuran family dissolved in a solvent fraction comprising at least 35% DMSO. Preferably, the present invention relates to a novel topical antiparasitic composition comprising a high concentration of dinotefuran dissolved in a solvent fraction comprising at least 35% of DMSO.

The solvent fraction preferably comprises at least 40%, or 45%, or 50% or 55% or 60%, or 65% DMSO.

The proportion of dinotefuran is between 10 and 70%, 15 and 70%, 20 and 70%, 25 and 60%, 30 and 60%, between 40 and 60%, between 35 and 50%, or preferably about 40%, 45%, 50%, or 55% by weight relative to the percentage by weight of the composition.

The additional solvent fraction may consist of any other solvent such as polar, apolar, protic, aprotic solvent, etc. The latter may be chosen for example and without limitation from acetone, 2-butanone, 3-methyl -2-butanone, cyclohexanone, acetonitrile, xylenes, chlorobenzene, methylene chloride, chloroform trichloroethane, benzaldehyde ethylene chloride, sulfolane, methyl-tert-butyl ether, dibutyl ether, ethyl acetate, propyl acetate, amyl acetate, dimethylformamide (DMF), dimethylacetamide (DMAC), N-methyl-2-pyrrolidone (NMP), propylene diethyl carbonate, ethylene carbonate, and mixtures thereof. When the additional solvent fraction consists of an aprotic polar solvent, the latter may be chosen from alcohols, ketones such as acetone and butanone, from disubstituted N, N amines, such as dimethylformamide (DMF), N- methyl-2-pyrrolidone (NMP) among nitriles such as acetonitrile, among esters such as ethyl acetate, propyl acetate, or amyl acetate, among tertiary amines such as triethylamine , or from nitrogen heterocycles, such as pyridine.

When the additional solvent fraction may consist of a protic polar solvent, the latter may be chosen from alcohols, such as methanol, ethanol, isopropanol, hexafluoroisopropanol, and carboxylic acids, such as formic acid and acetic acid, and primary and secondary amines.

The topical antiparasitic compositions according to the present invention preferably do not comprise aprotic or protic polar solvent, or apolar solvent, and therefore comprise the only solvent fraction DMSO as described above.

Furthermore, the additional solvent fraction does not comprise water or apolar solvent such as propylene alkyl ether, ethylene alkyl ether, polyglycol alkyl ether, or diethyl ether. polyglycol alism, or apolar solvents comprising units of polypropylene glycol or polyethylene glycol.

In addition, the topical antiparasitic compositions according to the present invention are preferably free of crystallization inhibitors and otherwise any other excipients capable of modifying the solubility and stability of neonicotinoids of the tetrahydrofuran family.

The term "crystallization inhibitor" is understood to mean an agent or a substance which inhibits the formation of crystals of the neonicotinoid active agent in the solvent, even if the solvents used in the invention fundamentally prevent the crystallization of the active substance. These inhibitors include, for example, polyvinylpyrrolidone, alcohols polyvinyl, copolymers of vinyl acetate and vinylpyrrolidone, mannitol, glycerol, sorbitol, lecithin, sodium carboxymethylcellulose, acrylic derivatives such as methacrylates and the like, anionic surfactants such as alkaline stearates, especially sodium, potassium or ammonium stearate, calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, etc.

The topical compositions of neonicotinoids of the tetrahydrofuran family according to the present invention exhibit superior stability properties especially at temperatures ranging from 0 ° C to 40 ° C, and this for a long time, ranging from one (1) month to least three (3) months. These compositions, however, retain excellent activity against pests such as insects, fleas, ticks, mites and / or galls that infest domestic animals, especially dogs and cats.

In the past, the use of high concentrations of insecticides proved difficult because of the difficulties encountered during the application of the active ingredient, such as unsatisfactory viscosity, insufficient diffusion, evaporation of the active product, problems of recrystallization of the active ingredient, but also problems of insolubility, instability and degradation of the active ingredient, and finally undesirable characteristics of irritation of the skin.

The topical veterinary compositions called Pour-On, Spot-On or Drop-On according to the present invention are applied to the base of the neck of the animal or more generally between the shoulder blades, that is to say at a small place accessible by the animal. A relatively small volume but strongly concentrated in neonicotinoids, must be applied on the animal to avoid the elimination of the product of the coat by the animal itself which is shaken or cleaned by licking, but also any transfer of the product to other objects in the immediate environment of the animal and / or its owner. However, the low solubility of the antiparasitic formulations, especially those containing dinotefuran, limits the ability to obtain high concentrations of pest control active in these formulations. The Applicant has discovered that the insecticide formulation of neonicotinoids of the tetrahydrofuran family and in particular dinotefuran in a solvent fraction comprising at least 35% of DMSO (in weight relative to the percentage by weight of the composition) made it possible to to obtain an excellent solubility of these neonicotinoids with high concentration. Also, the compositions thus obtained had superior stability properties especially at temperatures ranging from 0 ° C to 40 ° C. This is particularly surprising since DMSO is generally not chosen as a solvent for liquid formulations because of its high freezing point near 18 ° C.

Any other solvent equivalent to DMSO can be used as a replacement or addition, such as for example and without limitation methylsulfonylmethane (MSM). The new compositions developed by the applicant are therefore stable under ordinary storage conditions generally available in stores, warehouses, veterinary practices, etc., and therefore do not require special storage precautions or places of storage at temperate temperatures. . In addition, these compositions exhibit a reduction in the crystallization phenomenon of neonicotinoids of the tetrahydrofuran family during storage, crystallization and precipitation on the skin and / or the coat of the animals when it is applied, causing otherwise no sticky or tacky appearance of the coat after application. On the contrary, when the formulations are applied to the animals, there is a rapid disappearance of the applied product without undesirable effect of crystallization of dinotefuran in the form of powder or crystals.

By way of example of neonicotinoids of the family of tetrahydrofurans used according to the invention, mention may be made of dinotefuran or (RS) -1-methyl-2-nitro-3- (tetrahydro-3-furyl methyl) guanidine which has the following chemical structure:

Dinotefuran is present in the compositions according to the present invention in high concentrations, between 10 and 70%, 15 and 70%, 20 and 70%, 25 and 60%, 30 and 60%, between 40 and 60%, and between 40 and 60%. and 50%, or preferably about 40%, 45%, 50%, or 55% by weight of the final composition. Preferably, dinotefuran is formulated at 40%, or 45%, or 50% or 55% by weight of the final composition. All percentages are based on the weight versus percent (%) by weight of the final composition.

The compositions obtained are stable in use in situ on the animal and during storage, and also have a long duration of action, without irritation or toxicity problem. Finally, the compositions according to the invention exhibit sufficient viscosity, thus allowing the retention of the composition when it is administered topically on the skin or the hairs of animals, thus ensuring the release and the action of the insecticide over a long period of time. period guaranteeing the persistence of the effectiveness of the product.

Neonicotinoids of the tetrahydrofuran family are generally available as solids and / or crystals. It thus becomes necessary to dissolve them into a liquid form to allow their use as topical formulations on animals. According to the present invention, it has been discovered that the use of a solvent fraction comprising at least 35% of a particular solvent or solvents, such as DMSO, or any equivalent such as MSM, allows a better solubilization of this active agent, without risk of recrystallization at low temperatures close to 0 ° C. The compositions of the present invention therefore have improved physico-chemical properties in terms of stability, protection against the degradation of the active ingredients, and finally better properties of storage stability and persistence when used in topical application. The new topical compositions are particularly effective in controlling pests such as insects, fleas, ticks and / or galls. They are therefore useful for treating pets, mammals and / or birds, and especially pets such as dogs and cats.

The novel neonicotinoid compositions of the tetrahydrofuran family according to the present invention may further comprise at least one second parasiticidal agent, such as, for example, compounds known as growth regulators or also called "IGR" or "Insect Growth Regulator". , such as the juvenile hormone analogs, namely methoprene or S-methoprene and pyriproxyfen, chitin inhibitors such as lufenuron, chlorfluazurone, hexaflumurone, cyromazine and 1 - (2,6 - difluorobenzoyl) -3- [2-fluoro-4- (1,1,3,3,3,3-hexafluoropropoxy) urea phenyl]; macrocyclic lactones such as avermectins, namely ivermectin, abamectin, doramectin, eprinomectin, selamectin and milbemycins, namely milbemycin oxime, moxidectin and abamectin; organochlorine or organophosphorus derivatives such as diazinon, coumaphos, dichlorvos, fenitrothion, fenthion, bendiocarb, tetrachlorvinphos, and chlorpyrifos; carbamate derivatives such as propoxur, carbaryl, metoxadiazone and fenobucarb; phenyl-pyrazole compounds, such as fipronil or pyriprole; pyrethroids, such as permethrin, deltamethrin, cypermethrin, phenothrin, allethrin, pyrethrin, cyphenothrin, cyfluthrin, and fenvalerate, fenpropathrin and transfluthrin; semicarbazone compounds such as metaflumizone, formamidine compounds such as amitraz; anthelminitics, such as pyrantel, praziquantel, benzimidazoles and imidazothiazoles; synergists such as piperonyl butoxide (DPB), octachlorodipropyl ether (S-421), and N- (2-ethylhexyl) bicyclo [2.2.1] hept-5-ene-2,3-dicarboximide, isobornyl thiocyanatoacetate (LPT1) and N- (2-ethylhexyl) -1-isopropyl-4-methylbicyclo [2.2.2] oct-5-ene-2,3-dicarboximide.

The formulation of the invention offers a very good persistence to dinotefuran and consequently a longer duration of parasite control. The veterinary compositions according to the present invention are in the form of Pour-On, Drop-On or Spot-On for topical local application and / or topical skin application. When formulated in Pour-On, Spot-On and / or Drop-On compositions, they are preferably packaged in single dose pipettes.

The topical compositions according to the present invention may contain other acceptable veterinary excipients, excipients and / or carriers so long as these do not substantially change the solubility and stability properties of the compositions. The topical compositions may then additionally comprise anionic, cationic or nonionic surfactants, diluents, preservatives, gelling agents, emollients, antioxidants, film-forming agents, perfumes, etc.

As examples of surfactants that may be used, mention may be made of the alcohol alkoxylate.

As examples of antioxidants, mention may be made without limitation of butylhydroxyanisol (BHA), butylhydroxytoluene (BHT), ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, and mixtures of those -this.

The other solvents which may optionally be used according to the present invention may be selected from a group consisting of petroleum oil, animal oil, vegetable oil, peanut oil, soybean oil, soybean oil and the like. mineral oil, sesame oil, N, N-diethyl-m-toluamide, eucalyptol, dimethyl isosorbide, diisopropyl adipate, and 1-methoxy-2-propyl acetate.

Furthermore, compounds capable of absorbing UV rays, light stabilizers, viscosity modifiers, antimicrobial agents, colorants, thickeners, vitamins, adhesives, fragrances, carriers, diluents, excipients and / or or physiologically or dermatologically acceptable adjuvants may be included in the compositions and formulations of the present invention. According to a second aspect, the subject of the present invention is also a process for the preparation of a topical composition of neonicotinoids of the tetrahydrofuran family in high concentration in a stable form, resulting in particular in the absence of formation of crystals in situ after local application. on the coat or on the skin of animals.

In this aspect, the method comprises formulating a high concentration of a neonicotinoid of the tetrahydrofuran family, such as dinotefuran, in solution in a solvent fraction comprising at least 35% DMSO. The solvent fraction preferably comprises at least 40%, or 45%, or 50% or 55% or 60%, or 65% DMSO. The concentration of the neonicotinoids of the tetrahydrofuran family is between 10 and 70%, 15 and 70%, 20 and 70%, 25 and 60%, 30 and 60%, 40 and 60%, or between 35 and 50% by weight. or preferably about 40%, 45%, 50%, or 55% by weight of the final composition. Preferably, dinotefuran is formulated at 40%, or 45%, or 50% or 55% by weight relative to the percentage (%) by weight of the total composition is solubilized in a solvent fraction comprising at least 35% of DMSO as described above. The additional solvent fraction may consist of any other solvent such as polar, apolar, protic, aprotic solvent, etc. The latter may be chosen for example and without limitation from acetone, 2-butanone, 3-methyl -2-butanone, cyclohexanone, acetonitrile, xylenes, chlorobenzene, methylene chloride, chloroform trichloroethane, benzaldehyde ethylene chloride, sulfolane, methyl-tert-butyl ether, dibutyl ether, ethyl acetate, propyl acetate, amyl acetate, dimethylformamide (DMF), dimethylacetamide (DMAC), N-methyl-2-pyrrolidone (NMP), propylene diethyl carbonate, ethylene carbonate, and mixtures thereof. When the additional solvent fraction consists of an aprotic polar solvent, the latter may be chosen from alcohols, ketones such as acetone and butanone, from disubstituted N, N amines, such as dimethylformamide (DMF), N- methyl-2-pyrrolidone (NMP) among nitriles such as acetonitrile, among esters such as ethyl acetate, propyl acetate, or amyl acetate, among tertiary amines such as triethylamine, or from nitrogenous heterocycles, such as pyridine.

When the complementary solvent fraction consists of a protic polar solvent, the latter may be chosen from alcohols, such as methanol, ethanol, isopropanol, hexafluoroisopropanol and carboxylic acids, such as formic acid and acetic acid, and primary and secondary amines.

The process according to the preparation of the topical antiparasitic compositions preferably excludes the addition of polar aprotic or protic solvent, or apolar solvent, and therefore comprise the only fraction of solvent DMSO.

Also, the process excludes the addition of water, and the addition of an apolar solvent such as propylene alkyl ether, ethylene alkyl ether, polyglycol alkyl ether, or the like. polyglycol alkyl ether, or apolar solvents comprising units of polypropylene glycol or polyethylene glycol.

Preferably, the process for preparing the topical antiparasitic compositions according to the present invention does not include a step of adding a crystallization inhibitor and, moreover, any other excipients capable of modifying the solubility and the stability of the neonicotinoids of the family of tetrahydrofurans.

The term "crystallization inhibitor" is understood to mean an agent or a substance which inhibits the formation of crystals of the neonicotinoid active agent in the solvent, even if the solvents used in the invention fundamentally prevent the crystallization of the active substance. Such inhibitors include, for example, polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, mannitol, glycerol, sorbitol, lecithin, sodium carboxymethylcellulose, acrylic derivatives such as methacrylates and others. the same, anionic surfactants such as alkaline stearates, especially sodium, potassium or ammonium stearate, calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, etc. The method according to the invention avoids recrystallization and / or precipitation of neonicotinoids of the tetrahydrofuran family during storage and / or during application to the animal. Preventing the crystallization of the neonicotinoids of the tetrahydrofuran family present in high concentrations in the veterinary compositions makes it possible to obtain and maintain better properties of stability and remanence. The neonicotinoid assets of the tetrahydrofuran family used according to this aspect are as described above, and preferably comprise at least dinotefuran, either alone or in combination with other neonicotinoid insecticides of other subfamilies or other such for example an N-phenylpyrazole derivative (such as fipronil).

Topical topical application topical compositions may be prepared by simply mixing the desired proportion of neonicotinoids of the tetrahydrofuran family in a solvent fraction comprising at least 35% DMSO by homogenization if necessary. The methods of preparing the formulations of the invention are well known in the art. For example, a neonicotinoid of the tetrahydrofuran family such as dinotefuran can be mixed in the solvent and other acceptable veterinary excipients are then added.

According to a third aspect, the present invention relates to a method of treating, controlling, eliminating, and / or preventing the infestation of parasites, including fleas, ticks and / or galls or any other parasite animals such as mammals, and / or birds.

The control method is used on pets and / or pets and includes the topical administration of an effective amount of a veterinary composition of neonicotinoids of the tetrahydrofuran family as previously described. The method consists in applying to a very localized region of the skin and / or the coat of the animal, preferably at the level of the base of the neck between the shoulder blades, an effective amount of the new topical formulation of the invention comprising a high concentration of neonicotinoids of the tetrahydrofuran family and a solvent fraction comprising at least 35% of DMSO as previously described, and optionally other acceptable veterinary carriers which do not substantially modify the stability properties of neonicotinoids of the tetrahydrofuran family in the solvent fraction used. Parasitic diseases that can be cured by the formulations of the present invention can be caused by fleas, ticks, galls, sandflies, mites, flies and / or mosquitoes.

Fleas of the genus Ctenocephalides are intermediate hosts of Dipylidium caninum, which is a parasitic worm of the small intestine of dogs and cats. The carnivore becomes infested by swallowing parasitic fleas. This infestation can cause anal pruritus, engorgement of anal sacs, and perineal dermatitis. Therefore, it is sometimes advisable to worm regularly the animals in addition to the fight against fleas.

Ticks {Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp., ...) can also cause stress to the animal and harm its health. They can also harm the man. But the most serious problem of ticks is that they are a vector of pathogens that can affect the animal as much as the man. Major diseases to be avoided include Borellioses (Lyme disease Borellia burgdorferi), Babesioses (Babesia sp. Piroplasmosis), and Rickettsioses. Ticks can also release toxins with crippling, inflammatory, and sometimes life-threatening properties. The gall (Demodex sp., Sarcoptes sp., Otodectes sp., ...) is particularly difficult to fight because there are very few effective active ingredients. It therefore requires frequent treatments.

Preferred formulations are sufficiently persistent to be able to reduce the duration and costs associated with administering formulations to domestic animals, particularly in dogs and cats. The formulations may also be sufficiently persistent to resist washing the domestic animal with an aqueous solution, such as water and soap. The administration of the compositions according to the invention may be intermittent over time and may be administered daily, weekly, biweekly, monthly, bimonthly, quarterly, or even for longer periods.

The time between treatments depends on factors such as the pest (s) to be treated, the degree of infestation, the type of animal, and the environment of the animal. The veterinarian can easily determine a specific administration period for a particular situation. In general, the treatment is performed every month on domestic animals, such as dogs and cats.

The methods according to the invention can also make it possible to fight against parasites permanently in an environment in which the animal is subjected to a high parasite pressure where the administration is at a frequency well below a daily administration in that case.

The treated animals are domestic animals such as pigs, sheep, horses, cows, goats, dogs, cats, poultry and other birds or other mammals.

Examples

Example 1: Formulation A

50 g of dinotefuran are solubilized in 50 g of dimethylsulfoxide (DMSO). The solution thus obtained is stable from a physico-chemical point of view for at least 3 months at temperatures between 4 and 40 ° C.

No crystallization is observed when this solution is applied to a cat or a dog.

Example 2: Formulation B

30 g of dinotefuran are solubilized in 35 g of dimethylsulfoxide (DMSO) and 35 g of N-methyl pyrrolidone (NMP). The solution thus obtained is stable from a physicochemical point of view for at least 3 months at temperatures between 4 and 40 ° C.

No crystallization is observed when this solution is applied to a cat or a dog.

Example 3: Formulation C

40 g of dinotefuran and 4 g of pyriproxifen are solubilized in 56 g of dimethylsulfoxide (DMSO). To accelerate the solubilization of dinotefuran and pyriproxifen, the DMSO is preheated to approximately 45 ° C.

The solution thus obtained is stable from a physico-chemical point of view for at least 3 months at temperatures of between 4 and 40 ° C.

Pipettes are filled with 0.6 mL of Formulation C for a flea efficacy study.

Example 4: Formulation D

10 g of dinotefuran and 10 g of fipronil are solubilized in 60 g of dimethylsulfoxide (DMSO) and 20 g of N-methyl pyrrolidone (NMP).

No crystallization is observed when this solution is applied to a cat or a dog. Example 5: Formulation E

10 g of dinotefuran, 0.2 g of ivermectin and 10 g of fipronil are solubilized in 54.8 g of dimethylsulfoxide (DMSO) and 25 g of N-methyl pyrrolidone (NMP).

No crystallization is observed when this solution is applied to a dog.

Example 6: Formulation F

10 g of dinotefuran, 1 g of pyriproxifen and 54 g of permethrin are solubilized in 35 g of dimethylsulfoxide (DMSO). To accelerate the solubilization of dinotefuran, pyriproxifen and permethrin, DMSO is preheated to about 45 ° C.

Pipettes are filled with 0.8 mL of F formulation for an efficacy study against fleas and ticks.

Example 7: Formulation G

9 g of dinotefuran, 1 g of pyriproxifen and 10 g of fipronil are solubilized in 60 g of dimethylsulfoxide (DMSO) and 20 g of N-methyl pyrrolidone (NMP).

No crystallization is observed when this solution is applied to a dog or a cat.

Example 8: Remanence Formulation C

A flea efficacy study was conducted in stations on cats with the 0.6 mL pipettes obtained in Example 3 according to the recommendations of ΙΈΜΑ reference EMEA / CVMP / EWP / 005/2000-Rev.2.

An efficacy against fleas greater than 95% is obtained after 4 weeks.

The residual effect of the composition for topical application is thus clearly demonstrated. Example 9: Persistence Formulation F

An efficacy study against fleas and ticks is conducted in stations on dogs with the 0.8 mL pipettes obtained in Example 6 according to the recommendations of ΙΈΜΑ reference EMEA / CVMP / EWP / 005/2000-Rev.2.

After 4 weeks, the effectiveness of the composition is greater than 95% for fleas and greater than 90% for ticks.

The residual effect of the composition for topical application is thus clearly demonstrated.

Claims

1. A topical antiparasitic composition comprising an effective amount of neonicotinoids of the tetrahydrofuran family and a solvent fraction comprising at least 35% dimethylsulfoxide (DMSO).

2. Composition according to claim 1, characterized in that the solvent fraction comprises at least 40%, or 45%, or 50% or 55% or 60% dimethylsulfoxide (DMSO).

3. Composition according to any one of the preceding claims, characterized in that it is in the form of formulation Pour-On, Spot-On, or Drop-On.

4. Composition according to claim 3, characterized in that the formulation of Pour-On, Spot-On, and / or Drop-On is in the form of a single-dose pipette packaging. 5. Composition according to any one of the preceding claims, characterized in that neonicotinoids of the family of tetrahydrofurans is dinotefuran.

5. Composition according to any one of the preceding claims, characterized in that the proportion of dinotefuran is between 10 and 70%,

15 and 70%, 20 and 70%, 25 and 60%, 30 and 60%, between 40 and 60%, between 35 and 50% by weight relative to the percentage by weight of the composition.

6. Composition according to any one of the preceding claims, characterized in that the proportion of dinotefuran is about 40%, 45%, 50%, or 55% by weight relative to the percentage by weight of the composition.

7. Composition according to any one of the preceding claims, characterized in that it does not comprise a crystallization inhibitor.

8. Composition according to any one of the preceding claims, characterized in that it is stable for at least 3 months at temperatures in the region of 0 ° C.

9. Composition according to any one of the preceding claims, characterized in that it does not comprise water.

10. Composition according to any one of the preceding claims, characterized in that it further comprises one or more additional parasiticidal agents.

1 1. Composition according to Claim 10, characterized in that the additional parasiticidal agent or agents are chosen from acaricides, inhibitors of the development of fleas, ticks, galls, and / or endoparasites, the active principles against the phlebotomes, or the ectoparasites of domestic animals.

12. Composition according to claim 10 or 1 1, characterized in that the additional parasiticidal agent (s) are chosen from phenylpyrazole derivatives, pyrethroids, insect growth regulators and / or a mixture thereof.

13. Composition according to claim 12, characterized in that the phenylpyrazoles derivative is fipronil.

A composition according to any one of the preceding claims for use in the control, prevention and / or treatment of infestations by fleas, ticks, galls, flies, mosquitoes and / or sandflies in pets.

15. Composition according to any one of the preceding claims, characterized in that it administered by direct application to the skin or the skin. peeling of the animal, shoulder blades or a dorsal line from the base of the tail up to the neck.

16. Composition according to any one of the preceding claims, characterized in that said domestic animals are dogs and / or cats.