FR3039400A1 - NEW VETERINARY COMPOSITIONS FOR THE PREVENTION AND SIMULTANEOUS TREATMENT OF ENDOPARASITES AND ECTOPARASITES - Google Patents

Abstract

The present invention relates to a veterinary pharmaceutical composition comprising, in an acceptable pharmaceutical carrier, a combination of fipronil, selamectin and praziquantel.

Description

The present invention relates to the field of pharmaceutical compositions for veterinary use intended for the prevention and treatment of parasitic infestations in animals. More particularly, the present invention is intended for pets, especially dogs and cats, and is preferably addressed to them.

PRIOR ART

Ectoparasites

The animals are often infested by one or more external parasites (ectoparasites) feeding on blood or epidermal productions such as fleas, ticks, lice, Trombicula, or mites responsible for scabies (Sarcoptes, Notoedres, Cheyletielles. .).

Fleas are wingless insects with laterally compressed bodies and highly developed, jump-adapted legs that live in the fur of animals. The approximately 2,000 listed species belong to the order of the siphonaptera. In Europe, two main species are listed: the cat and dog flea (Ctenocephalides felis) and the dog flea (Ctenocephalides canis). Flea bites cause itching in both animals and humans. The saliva of the flea (secreted with each bite) can also, according to the individuals, cause allergic reactions. These reactions result in various skin and itchy lesions. 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.

Ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp., ...) are mites, occasional parasites of animals, more rarely of humans. Tick bites are painful and can become infected. A massive infestation can cause anemia. But the most serious problem of ticks is that they are vectors 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), Ehrlichiosis (Ehrlichia canis) and Rickettsioses.

Mallophagi or grinding lice are small insects that do not bite animals, but feed on the integument of their host. Among them, the species

Trichodectes canis is particularly harmful because it is vector of worm infestation of the species Dipylidium caninum. Lice of the species Felicola subrostratus are the only parasitic lice of the cat.

Scabies is a disease caused by the presence of tiny parasites in the epidermis, such as Notoedres sp, Sarcoptes sp or Otodectes sp. In particular, the parasite Otodectes cynotis lives in the ear canal and is responsible for the disease called "ear scabies". Scabies is particularly difficult to fight; it requires repeated treatments.

To get rid of these ectoparasites, different treatments have been developed to destroy both adult parasites and eggs.

In particular, fipronil, of the chemical formula 5-amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (trifluoromethylsulfinyl) -1H-pyrazole-3-carbonitrile, is a powerful antiparasitic fight against infestations by fleas and ticks. This molecule belongs to the phenylpyrazole family.

Advantageously, fipronil may be formulated so as to be administered topically, and to have a residual effect, as is presented in application WO 2010/070210.

The commercial product Frontline® combo is an organic solution of fipronil and S-methoprene, allowing applications in "spot-on", that is to say in topical application in a single point on the skin of the animal. This product is used to treat infestations by fleas, ticks and grinding lice (especially those of the species Felicola subrostatus).

Endoparasites

Animals may also be infested with one or more internal parasites (endoparasites) such as heartworms, intestinal worms such as tapeworms (Taenia taeniaeformis), dipylidium (Dipylidium caninum), hookworms (Ancylostoma tubaeforme, Ancylostoma braziliense, Uncinaria stepnocephala), roundworms (Toxocara canis, Toxicaceae, Toxascaris leonina), whipworm (Trichuris sp), echinococci (Echinococcus sp), and pulmonary worms.

Heartworm disease, also known as heartworm disease, is a parasitic disease that primarily affects dogs and cats, caused by Dirofllaria immitis, a nematode (or roundworm) of the genus Dirofilaria. The worms are found mainly in the pulmonary arteries, the right heart and the vena cava.

Tapeworms or Tœnias are long ribboned and segmented flatworms belonging to the class of Cestodes, parasites of the digestive tract of vertebrates. Some species (Taenia pisiformis, for example) affect the dog or cat specifically. Täniases can cause abdominal pain, nausea, intestinal transit disorders or appetite disorders.

Roundworms (nematodes) are also common parasites. Among them, the hookworm is a parasitic worm that lives in the duodenum of its host, which can be a mammal such as a dog or a cat. The A. braziliense and A. tubaeforme species infest cats, while A. caninum infests dogs. Hookworms are much smaller than other roundworms. The main symptom of an infection with hookworm is anemia, which results from the loss of iron and protein in the intestine. Indeed, these worms suck the blood and damage the mucous membrane.

Among roundworms, roundworms (such as Toxocara canis and Toxocara catï) are parasitic nematodes that cause ascariasis. The symptoms caused by these parasites include a growth of pups (such as puppies, kittens) slowed down; leanness, irregular appetite or lack of appetite; a dull, quilted coat hair loss diarrhea; and anal pruritus. The diagnosis is usually made during the examination of stool by a laboratory.

These endoparasites are treated by the administration of dewormers that eradicate gastrointestinal parasites. Commonly used dewormers include commercial products such as Profender® containing a combination of emodepside and praziquantel, and Stronghold® containing selamectin.

Praziquantel is a derivative of pyrazinoisoquinoline and is effective against flatworms (Cestodes) such as Dipylidium caninum, Echinococcus multilocularis, Echinococcus granulosus, Taenia taeniaforms and Taenia spp.

The Profender® commercial product is available as a spot-on topical solution for cats, as well as modified release tablets for dogs.

Selamectin is a semi-synthetic compound of the avermectin class. It works by paralyzing and / or killing a large number of invertebrate parasites. Selamectin has adulticidal, ovicidal and larvicidal action against fleas.

The commercial product Stronghold® is indicated in dogs and cats for the treatment and prevention of flea infestations {Ctenocephalides spp.) By a single administration. It is also indicated in the prevention of heartworm disease (due to Dirofilaria immitis) by monthly administration of the drug, as well as for the treatment of ear scab (due to Octodectes cynotis).

In cats only, Stronghold® is indicated for the treatment of lice infestations (Felicola subroptatus), ascaridosis (Toxocara cati) and intestinal hookworms.

In dogs only, Stronghold® is indicated for the treatment of sarcoptic mange, crushing lice infestations (due to Trichodectes canis), and treatment of intestinal ascaridosis due to Toxocara canis.

Treatments used to fight pest infestations

In order to effectively fight against internal or external parasites of pets, and reduce drug intake, work is currently being conducted to propose to the owners of animals pharmaceutical compositions comprising combinations of different assets. These combinations make it possible in particular to treat concomitantly animals infested with both endoparasites and ectoparasites.

International application WO 2010/109214 discloses combinations comprising four compounds: a phenyl pyrazole insecticide (fipronil), a macrocylic lactone (moxidectin), an insect growth regulator (methoprene), and a 2-acyl isoquinoline derivative 4-oxo-1,2,3,6,7,11b-4H-pyrazino [2α] (praziquantel). These active ingredients are diluted in a solvent such as N-methyl pyrrolidone.

International application WO 2011/123773 describes combinations comprising four compounds: a 1-arylpyrazole agent (fipronil), a macrocylic lactone (eprinomectin), an insect growth regulator (methoprene), and an anthelmintic agent (praziquantel). These active ingredients are diluted in a solvent such as benzyl alcohol or N-methyl pyrrolidone or combinations thereof. This composition can be administered topically in a "spot-on" form.

Although these quaternary compositions all include a macrocylic lactone, the choice of this lactone is irrelevant to achieve these pharmaceutical combinations.

Surprisingly, in their search for a more effective combination for the prevention and treatment of endoparasites and ectoparasites of animals, especially domestic animals, the inventors have demonstrated that a particular macrocylic lactone, selamectin, has a synergistic action in vivo with fipronil increasing its effects on fleas, including prolonging its action over time. The invention thus presents a product for the prevention and treatment of endoparasites and ectoparasites infestations in animals, which has a broad spectrum of action, which is easy to administer, having a rapid action and remanent. The invention also has a stable veterinary composition, the conservation of which does not require any particular precaution, while ensuring a maintenance of the activity of the active principles.

SUMMARY OF THE INVENTION The invention relates to veterinary pharmaceutical compositions for topical administration comprising, in an acceptable pharmaceutical carrier, a combination of fipronil, selamectin and praziquantel. The invention also relates to a veterinary pharmaceutical composition for topical administration, which consists of a combination of fipronil, selamectin and praziquantel in an acceptable pharmaceutical carrier.

According to a preferred aspect of the invention, said veterinary composition comprises, as an acceptable pharmaceutical carrier, a solvent chosen from the following solvents: N-methyl pyrrolidone (NMP), benzyl alcohol, Dowanol PM (2-butoxyethanol), glycofurol, diethylene glycol monoethyl ether (Transcutol), isopropylidene glycerol (Solketal), dimethyl isosorbide (DMI), propylene glycol monocaprylate (Capryol 90) or a mixture thereof. The subject of the invention is also the veterinary composition as described above for its use as a veterinary medicinal product. The subject of the invention is also the veterinary composition as described above, for its use in the prevention and / or the treatment of infestations by endoparasites and ectoparasites.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a veterinary pharmaceutical composition for topical application comprising, in an acceptable pharmaceutical carrier, a combination of fipronil, selamectin and praziquantel. The invention also relates to a veterinary pharmaceutical composition for topical administration, which consists of a combination of fipronil, selamectin and praziquantel in an acceptable pharmaceutical carrier and which optionally comprises one or more additional compounds chosen from antioxidants solubilizing agents, penetration promoters, viscosifying agents, preserving agents, coloring and / or opacifying agents, unappealing or repellent substances and perfumes or odoriferous compounds.

The Applicant has set itself the objective of combining three chemically different active principles, having different modes of action, within a chemically and physicochemically stable composition for several months, which is formulated in such a way as to obtain an optimal activity of the active ingredients, without prejudice to the organoleptic quality of the product when applied (in particular, the absence of unwanted sagging or significant crystallization of the active ingredients on the surface of the skin or hair).

The terms below are defined to assist in a better understanding of the invention.

The molecule "Fipronil" works by inhibiting the GABA complex of arthropod nerve cells, blocking the transfer of chlorine ions across the membrane to the pre- and post-synaptic levels by binding to the chlorine channel. It causes an uncontrolled activity of the central nervous system and the death of insects and mites. It acts mainly by contact with parasites. CAS number 120068-37-3, it exists in the form of two enantiomers, whose chemical formulas are shown below (S, top and R, bottom):

The molecule "Selamectin" paralyzes and kills a wide range of invertebrate parasites, modifying the permeability of cell membranes to chloride ions, which disrupts neurotransmission. Consequently, the electrical activity of the nematode nerve cells and that of the arthropod muscle cells are inhibited, hence the paralysis and / or death of the parasites concerned. It acts mainly systemically, the parasites being affected following their consumption of ranimal blood.

From CAS number 220119-17-5, it has the following chemical formula:

The molecule "Praziquantel" acts on parasites by modifying the permeability of their cell membranes to calcium ions, which blocks the neuromuscular functions of the parasite, leading to paralysis followed by death of the parasite. It acts systemically, the parasites being affected following their consumption of blood from the animal. From CAS number 55268-74-1, it has the following chemical formula:

The term "combination" refers to a combination of several active ingredients, acting in a complementary and / or synergistic manner on endoparasites and / or ectoparasites infesting animals, especially domestic animals.

According to a particular aspect of the invention, the veterinary pharmaceutical composition consists of a combination of fipronil, selamectin and praziquantel. This composition does not include, in addition to the acceptable pharmaceutical vehicle, other active ingredients.

It is understood that the composition according to the invention can be preserved as a combination of the three active ingredients, and that it can also be prepared extemporaneously by mixing the three active ingredients stored separately.

By the expression "synergistically", it is understood within the meaning of the invention that said synergy is observed in tests carried out in vivo on infected animals. Indeed, even if it has been reported a synergy of action between two compounds in vitro on the viability of chips of the species D. immitis treated by incubation with said compounds, this can not be compared to an action during the time when said compounds are deposited by topical application on the skin of the animal. It is indeed well known to those skilled in the art that in vitro results can not be extrapolated in most cases to applications in vivo, that is to say in a complex environment because depending on a large number physical and physicochemical factors, capable of independently altering the activity of each of the active ingredients used in combination.

The term "infestation" refers to the invasion of a living organism by parasites, including endoparasites and / or ectoparasites.

Veterinary compositions

The compositions according to the invention deliver an effective amount of three active compounds acting in concert for the prevention and treatment of parasitic infestations, in particular acting simultaneously for the prevention and treatment of infestations by endoparasites and ectoparasites.

By "effective amount" is meant a sufficient amount of a composition of the invention to eradicate or reduce the number of parasites infesting the host species. In some embodiments, an effective amount of the active agent is at least 80% effective against the target parasite infesting the host species. In other embodiments, an effective amount of the active substance is at least 90% effective against the target parasites. Preferably, an effective amount of the active agent achieves at least 95%, at least 98% or even 100% efficiency against the target pest (s).

In a preferred embodiment of the invention, the composition according to the invention comprising fipronil, selamectin and praziquantel, has efficacy against fleas for at least about 36 days, at least about 43 days, at least about 50 days, or at least about 57 days.

The veterinary composition is intended to be administered topically. The compositions intended for topical administration notably comprise skin solutions such as solutions for "on-on" or "spot-on" application, sprays, ear compositions, shampoos, creams, ointments and patches. and the baths. Preferably, the active agents present in each of these formulations are solubilized.

In veterinary medicine, the administration of a topically active ingredient has many advantages over oral and parenteral administration. Indeed, besides the fact that the application of such a composition is extremely easy, it is, moreover, free of any asepsis constraint and causes animals no pain or stress; finally, it has the advantage over the oral form of guaranteeing the effective taking of the active principle by the animals. Nevertheless, topical administration to the animal requires in certain cases certain precautions: it is especially necessary to immobilize the animal for at least one minute after application so that the product does not spill. For the comfort of the animal and its owner, it is of course preferable not to repeat the operation too often.

According to one particular embodiment of the invention, the composition is suitable for a cutaneous local application in "spot-on".

According to this aspect of the invention, the composition is in the form of a liquid composition or cutaneous solution, to be applied in one go, at one or more points directly on the skin of the animal, generally between the shoulder blades, especially in dogs.

The liquid composition can then be packaged in containers for the determination of the composition, and whose volume is less than or equal to 25 ml, and preferably between 0.1 to 10 ml and more preferably between 0.25 to 10 ml. ml.

According to this preferred embodiment, the veterinary pharmaceutical composition suitable for a "spot-on" application is preferably packaged in single-dose pipettes. The pipettes may consist of one or more films whose constituent material may be chosen from polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene chloride, cycloolefin copolymer (COC), polychlortrifluoroethylene (PCTFE), or derivatives thereof, alone or in admixture.

According to this preferred aspect of the invention, the veterinary composition comprises the following doses of active agents: Fipronil: from 6 to 25% by weight / volume; • Selamectin: from 4 to 8% by weight / volume; Praziquantel: 10 to 14% w / v.

In the present description, unless otherwise indicated, the percentage ranges are expressed by weight relative to the total volume of the composition. It should be noted that the values presented are understood as approximate values; thus "from 6% to 25% by weight / volume" means "from about 6% to about 25%". Furthermore, it is understood that the ranges include the lower and upper terminals as indicated.

In a first aspect, the veterinary composition according to this aspect of the invention comprises from 6 to 25%; or from 6 to 20%; from 6 to 17%; from 6 to 15%; from 6 to 12%; or from 6 to 10% w / v of fipronil.

In a second aspect, the veterinary composition according to this aspect of the invention comprises from 4 to 8%; or from 5 to 7% w / v of selamectin.

According to a third aspect, the veterinary composition according to this aspect of the invention comprises from 10 to 14%; or from 11 to 13% w / v of praziquantel.

The veterinary composition according to this aspect of the invention may advantageously be composed of doses of the following active agents: Fipronil: about 8% by weight / volume; • Selamectin: about 6% w / v; • Praziquantel: about 12% w / v.

Solubilization of compounds

One of the main advantages of the veterinary composition according to the invention is that the three active agents are solubilized in the composition. Each active ingredient is indeed in dissolved form, that is to say in a molecular state promoting transcutaneous passage and allowing the systemic effect, including praziquantel and selamectin.

Fipronil, whose activity resides in contact with the target parasite, is solubilized to limit deposits and facilitate its diffusion on the surface of the skin of the animal, allowing it to have a optimal efficiency.

This solubilized form of the three active principles is obtained thanks to a particular choice of solvents, as described below.

The composition may be in the form of a solution or a mixture of two immiscible phases between them where the assets would be solubilized in one of the phases. In particular, a composition in the form of a shampoo will comprise as main solvent water, and the presence of surfactants will solubilize the active ingredients in this solvent.

According to a preferred aspect of the invention, the veterinary composition is characterized in that fipronil, selamectin and praziquantel are all in soluble form in the composition.

The term "soluble" refers to the fact that the active ingredient is completely in dissolved form in its solvent, to form a homogeneous mixture called solution. According to this name, there is no residue of the active ingredient in solid form.

One of the main advantages of the invention lies in the fact that several active ingredients are combined in the same composition and that, by a single topical administration to an animal, many parasites, both internal and external, can be destroyed. partially or completely at different stages of their development.

The term "acceptable pharmaceutical carrier" denotes a vehicle that makes it possible to guarantee both the solubility of the three active ingredients, a stability over time, including in random storage conditions, and to allow a topical application of these active principles. which must be evenly distributed over the skin and coat of the animal, and / or enter the bloodstream of the animal to allow the treatment of endoparasites.

The compositions according to the invention are indeed intended for cutaneous administration with a systemic passage of two active principles; during this administration, selamectin and praziquantel cross the cutaneous barrier and join the blood system.

It is therefore essential to adequately select the pharmaceutical carrier of the composition according to the invention, which must have the following advantages: - allow a perfect dissolution of the three active ingredients; - guarantee the stability of active ingredients over time; - allow the passage of the cutaneous barrier of praziquantel and selamectin, intended to join the blood system of the treated animal; - allow diffusion and distribution of fipronil on the animal's coat; - do not have a toxic character and in particular do not irritate the skin of the animal.

It is known that the stability of certain active ingredients can be affected when these active ingredients are conditioned in a single solution. This is especially true for avermectins, including selamectin. These molecules are indeed poorly soluble in water and do not support acidic pH. In contrast, many antiparasitics need to be stored in an aqueous medium at acidic pH to provide optimal stability. Thus, the choice of a suitable vehicle to ensure the stability over time of the three active ingredients of the present veterinary composition is a delicate and unpredictable step.

Surprisingly, a particular choice of solvents makes it possible not only to preserve the modes of action of these three active ingredients, but also their solubilization and their stabilization in the formulation.

According to one aspect of the invention, the veterinary composition is characterized in that the acceptable pharmaceutical carrier is a solvent, preferably an organic solvent.

This organic solvent may advantageously be chosen from pharmaceutically acceptable solvents or their mixtures, such as: N-methyl pyrrolidone (NMP), benzyl alcohol, Dowanol PM (2-butoxyethanol), glycofurol, NN dimethylacetamide, diethylene glycol monoethyl ether (Transcutol), isopropylidene glycerol (Solketal), dimethyl isosorbide (DMI), propylene glycol monocaprylate (Capryol 90) or a mixture thereof.

Advantageously, the organic solvent will be a mixture of at least two solvents selected from N-methyl pyrrolidone (NMP), benzyl alcohol, Dowanol PM (2-butoxyethanol), glycofurol, NN dimethylacetamide, diethylene glycol monoethyl ether (Transcutol), isopropylidene glycerol (Solketal), dimethyl isosorbide (DMI), and propylene glycol monocaprylate (Capryol 90).

According to one particular aspect of the invention, the solvent will consist of a mixture of benzyl alcohol and at least one other organic solvent, especially chosen from N-methyl pyrrolidone (NMP) and Dowanol PM (2-butoxyethanol). ), glycofurol, and NN dimethylacetamide.

According to a preferred embodiment, the solvent is chosen from one of the following combinations of organic solvents: benzyl alcohol and N-methyl pyrrolidone; - benzyl alcohol and Dowanol PM; - benzyl alcohol and glycofurol; - benzyl alcohol and transcutol; - DMI and solketal; glycofurol, capryol 90 and solketal; - capryol 90 and solketal.

The proportions of each of the solvents may vary and will especially be between 20% solvent 1/80% solvent 2, or 30% solvent 1/70% solvent 2, or 40% solvent 1/60% of solvent solvent 2, or alternatively 50% of each solvent, it being understood that the percentages are calculated on the total volume of solvent, and not on the volume of the veterinary composition.

According to a preferred embodiment, the solvent consists of a mixture of benzyl alcohol and N-methyl pyrrolidone (NMP).

The respective preferred proportions of these solvents are as follows: 50% benzyl alcohol / 50% NMP; or else - 20% benzyl alcohol / 80% NMP.

A preferred composition according to the invention comprises: • Fipronil: from 6 to 25% w / v; • Selamectin: from 4 to 8% by weight / volume; Praziquantel: 10 to 14% w / v; • Benzyl alcohol: from 10% to 40% by weight / volume; and at least one other organic solvent in an amount of 10% to 60% w / v.

Advantageously, the other organic solvent is selected from N-methyl pyrrolidone (NMP), Dowanol PM (2-butoxyethanol), glycofurol, NN dimethylacetamide, diethylene glycol monoethyl ether (Transcutol), isopropylidene glycerol (Solketal ), dimethyl isosorbide (DMI), and propylene glycol monocaprylate (Capryol 90). The invention therefore has as its main object a veterinary pharmaceutical composition for topical administration, which consists of a combination of fipronil, selamectin and praziquantel in an acceptable pharmaceutical carrier.

However, the compositions according to the invention may advantageously comprise, in order to broaden or complete the action spectra of the active agents already present in the compositions according to the invention, one or more additional active agents, preferably chosen from among others. endoparasiticidal and / or ectoparasiticidal compounds. Those skilled in the art will be able to adapt the effective amounts of the active agents according to the galenic form of the composition.

The veterinary composition according to the invention, adapted for topical application, may also comprise excipients and other compounds well known to those skilled in the art, such as antioxidants and preservatives.

The veterinary composition according to the invention may in particular comprise at least one additional compound chosen from: antioxidants, intended to inhibit the oxidation in the composition; solubilizing agents which allow the solubilization of the active ingredients, the cleaning, or which make it possible to avoid the deposits of fipronil in the form of crystals; skin penetration promoters to promote the passage of the cutaneous barrier and the systemic effect of the product; viscosizing agents used in order to facilitate the spreading of the product and to improve the distribution of the product; - preservatives; used to fight against a possible bacterial proliferation; coloring and / or opacifying agents used to mark the treated animal or to mask a change in the color of the product over time; - an unappealing or repulsive substance that prevents licking by animals during topical application; perfumes or odorous compounds, particularly useful when the composition will be a shampoo or a bath. As a nonlimiting preferred example, the solvent used in the composition according to the invention as an acceptable pharmaceutical carrier is selected from: • pyrrolidones such as 2-pyrrolidone, or N-methylpyrrolidone; Cyclic carbonates such as ethylene carbonate, propylene carbonate, butylene carbonate, or glycerine carbonate; Glycol ethers such as ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, diethylene glycol monoethyl ether (Transcutol®), diethylene glycol monomethyl ether (Dowanol) DPM), propylene glycol monoethyl ether, propylene glycol monomethyl ether (Dowanol PM), dipropylene glycol n-butyl ether, or diethylene glycol monoethyl ether acetate; • alcohols such as benzyl alcohol, ethanol, methanol, propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, or 3-pentanol ; Polyethylene glycols such as PEG 200, PEG 300 or PEG 400; Dimethylsulfoxide; • acetone, acetonitrile; • butyldiglycol; Dimethylacetamide, monomethylacetamide, ethylacetamide; Dimethylformamide; • propylene glycol, ethylene glycol, butylene glycol; • diethylphthalate; • triacetin; • methyl acetate, ethyl acetate, butyl acetate; • diisobutyl adipate, diisopropyl adipate; • glycerol; • isopropylidene glycerol (Solketal); • triethyl acetate glycerol; • glycerol forms; • dimethyl isosorbide (DMI), isosorbide dicaprylate; Benzyl benzoate, ethyl benzoate, C12-C15 alkyl benzoate; • ethyl lactate, ethyl oleate, ethyl heptanoate; • oleic acid; Caprylocaproyl macrogol-8 glycerides, oleoyl macrogol-6 glycerides; • propylene glycol monocaprylate (Capryol 90 or Capryol PGMC), propylene glycol monolaurate; Isopropyl myristate, isopropyl palmitate; • Neopentyl glycol dicaprylate / dicaprate; • PEG-4 diheptanoate; • glycofurol; • the water ; • vegetable oils such as soybean oil, cottonseed oil, capric / caprylic triglycerides (Miglyol 812 or 8ION); • mineral oils such as vaseline oil; • semi-synthetic oils; Waxes such as beeswax, carnauba wax ... or a mixture of at least two of them.

The composition may also include an antioxidant. By way of non-limiting example, mention may be made of the following antioxidant agents: • butylhydroxyanisole; • butylated hydroxytoluene; • ascorbic acid, ascorbyl palmitate; • sodium metabisulphite; • propyl gallate; • sodium thiosulphate; • alpha tocopherol; • monothioglycerol; or a mixture of at least two of them.

As solubilizers that can be used in the invention, mention will be made by way of non-limiting example: film-forming agents such as polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone; Polyethylene glycols; • benzyl alcohol; • mannitol, glycerol, sorbitol; Polyoxyethylenesorbitan esters; • lecithin; • sodium carboxymethylcellulose; Acrylate derivatives such as methacrylate; • cyclodextrins • anionic surfactants: alkali stearates (sodium, potassium, ammonium, calcium, triethanolamine), sodium abietate, alkyl sulphates (sodium lauryl sulphate, sodium diotylsulphosuccinate, sodium dodecylbenzenesulphonate, sodium cetyl sulphate ); • fatty acids derived from coconut oil; Cationic surfactants: quaternary ammonium ions, cetyltrimethylammonium bromide, octadecylamine hydrochloride; Nonionic surfactants: sorbitan esters, in particular polyoxyethylenated sorbitan esters (polysorbate 80, polyoxyethylenated alkyl ethers, polyethylene glycol stearate, polyethylene castor oil derivatives, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, • amphoteric surfactants such as lauryl-substituted betaine compounds, or a mixture of at least two of them.

As skin penetration promoters that may be used in the invention, mention may be made, by way of non-limiting example, of: • polyglycolized glycerides (Labrasol); Limonene, α-pinene or Π-carene, which are odorous compounds; Terpene alcohols such as Γα-terpineol, terpine-4-ol or carveol; Terpene ketones such as carvone, pulegone, piperitone or menthane; Terpene oxides such as limonene oxide, α-pinene oxide, 1,8-cineol and the bound compounds; Cyclohexene oxide or cyclopentene oxide; Ethyl 3- [acetyl (butyl) amino] propanoate (IR3535), N, N-diethyl-3-methylbenzamide (DEET) and their derivatives; • caprylic alcohol, decyl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleic alcohol, linoleic alcohol and alcohol. linolenic alcohol; • dimethylacetamide; • Transcutol® (Diethylene glycol monoethyl ether); Dimethylsulfoxide; Dimethyl isorbide; • chelating agents; or a mixture of at least two of them.

As viscositing agents that can be used in the invention, mention may be made in particular of: polybutene polymers; • povidone; • maltodextrin; • polydextrate, dextrates (EMDEX); • carboxypolymethylene (Carbomer®); Polyethylene glycols such as PEG 200, PEG 300 or PEG 400; • celluloses, such as hydroxypropyl celluloses; or a mixture of at least two of them.

As preservatives that may be used in the invention, mention may be made in particular, by way of nonlimiting example: benzalkonium chloride, benzethonium chloride; • benzoic acid, benzyl alcohol; • bronopol; • butylparaben, ethylparaben, methylparaben, propylparaben; • Cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, imidurea; • phenol, phenoxyethanol, phenylethyl alcohol; • phenylmercury acetate, thimerosal, phenylmercury borate, phenylmercury nitrate; • potassium sorbate, sodium benzoate, sodium propionate, sorbic acid; or a mixture of at least two of them.

As colorants and / or opacifiers that can be used in the invention, mention may be made in particular of: • dyes or dyes; • aluminum lacquer; • caramel; • dyes based on iron oxide; • zinc oxide; • titanium dioxide; or a mixture of at least two of them.

There are many other compounds fulfilling these functions well known to those skilled in the art. Moreover, the person skilled in the art, based on this general knowledge, will be able to select the excipients necessary for the various galenic forms contemplated in the present invention.

Veterinary kits

Preferably, the veterinary composition according to the invention will be provided to the user in the form of a kit comprising said veterinary composition, or the compositions described above, packaged in such a way as to be administered easily. , and also comprising a notice indicating the quantities to be administered according to the weight and the condition of the animal. The invention also relates to veterinary kits comprising, in separate packages, the compounds fipronil, selamectin and praziquantel, which can be combined directly on the skin of the animal, in order to realize extemporaneously the composition according to the invention.

Thus, according to one embodiment of the invention, praziquantel and fipronil are formulated together in the same composition, and applied concomitantly with another formulation comprising selamectin directly on the skin of the animal.

According to another embodiment of the invention, selamectin and fipronil are formulated together in the same composition, and applied concomitantly with another formulation comprising praziquantel directly on the skin of the animal.

According to another embodiment of the invention, selamectin and praziquantel are packaged together in the same composition, and applied concomitantly with another formulation comprising fipronil directly on the skin of the animal.

According to another embodiment of the invention, fipronil is formulated and applied concomitantly with a formulation comprising selamectin and optionally with another formulation comprising praziquantel, directly on the skin of the animal. The invention relates to the combined action of these three active agents, optionally with another active having an activity on ectoparasites or endoparasites.

According to this embodiment of the invention, a formulation comprising the combination of fipronil, praziquantel and selamectin and further another formulation comprising at least one additional active agent having ectoparasite activity, in an acceptable pharmaceutical carrier and which comprises optionally one or more additional compounds chosen from antioxidants, solubilizing agents, penetration promoters, viscosifying agents, preserving agents, coloring and / or opacifying agents, unappealing or repulsive substances and perfumes or odorous compounds, is applied to the skin of the animal.

According to another embodiment of the invention, a formulation consisting of a combination of fipronil, selamectin and praziquantel in an acceptable pharmaceutical vehicle and which optionally comprises one or more additional compounds chosen from antioxidants, solubilizers, promoters penetrating agents, viscosifying agents, preserving agents, coloring and / or opacifying agents, unappealing or repulsive substances and fragrances or odoriferous compounds, on the one hand and furthermore another formulation comprising at least one additional active ingredient having a activity on endoparasites, are applied concomitantly on the skin of the animal.

Uses of the veterinary composition

The veterinary composition described above is intended in particular to be used as a veterinary medicinal product. Thus, the present invention also relates to said veterinary composition for its use as a veterinary medicament.

In particular, this veterinary composition can be used in all kinds of therapeutic applications and on all animal populations, especially mammals, such as in particular domestic mammals, and more particularly cats, dogs, hamsters, rabbits, rabbits india, ferrets, and other mammalian species listed in the Decree of 11 August 2006, issued by the Ministry of Ecology and Sustainable Development (Ref DEVN0650509A - Official Journal of the French Republic No. 233 of 7 October 2006, p. 14920).

The present composition can be used for the treatment and / or prevention of parasite infestation in animals, which includes mammals, birds, and fish. Preferentially, mammals include ruminants, equines, camelids, dogs, cats, and new pets (NAC), which include ferrets or rodents.

It is understood that the amount of drug to be administered may vary depending on the weight of the animal considered and the desired effect, as well as the dosage to be adapted according to the frequency of treatment. These assays are well known to those skilled in the art and will be easily determinable by the latter, based on his general knowledge.

According to a particular aspect of the invention, the veterinary composition described above is used in the prevention and / or treatment of infestations by endoparasites and ectoparasites.

In particular, the term "ectoparasites" refers to the fleas of the cat (Ctenocephalides felis) and the dog (Ctenocephalides canis), the grinding lice, the ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp., .. .) and the parasites responsible for scabies, of the type Demodex sp., Sarcoptes sp. or Otodectes sp.

In particular, the term "endoparasites" refers to roundworms (Toxocara cati, Toxocara canis), heartworms, hookworms and tapeworm.

The veterinary composition for its use as a medicament is especially characterized in that it is intended to be administered to domestic animals, in particular dogs or cats.

The veterinary composition for its use in the prevention and / or treatment of infestations with endoparasites and ectoparasites is particularly characterized in that it is intended to be administered to domestic animals, in particular to dogs or cats. In particular, the veterinary composition or the compounds forming part of the veterinary kit are characterized in that the compounds are administered according to the following doses: • Fipronil: between 0.1 and 100 mg / kg; preferably between 1 and 20 mg / kg; between 2 and 17 mg / kg; between 3 and 15 mg / kg; between 3 and 10 mg / kg and even more preferably at a dose of about 5 mg / kg live weight of animal; • Selamectin: between 0.1 and 100 mg / kg; preferably between 1 and 12 mg / kg; even more preferably at a dose of about 6 mg / kg live weight of animal; • Praziquantel: between 0.1 and 600 mg / kg; preferably between 1 and 200 mg / kg; or between 5 and 100 mg / kg and more preferably at a dose of between 12 and 60 mg / kg body weight of animal.

The live weight of an animal refers to the weight of a live animal, standing, in standardized conditions (in the morning, fasting since the day before).

The present invention also relates to a method for treating and / or preventing parasitic infestations, or domestic animals, of administering a composition according to the invention to infested animals or to healthy animals in order to avoid their infestation. The method according to the invention also makes it possible to reduce the rate of infestation and to keep it low.

EXAMPLES

The present invention will be better understood with the aid of the examples presented below. It is understood, however, that these examples are given solely by way of illustration of the subject of the invention, of which they in no way constitute a limitation.

Example 1. Flea Treatment: In Vivo Synergistic Effect of Fipronil and Selamectin

Synergistic effects of co-administration of fipronil and selamectin are observed in the treatment of flea-infested cats (C.felis). 24 healthy cats were infected with flea administration (100 adult fleas) per day (-2) and then divided into four groups: 1) infested, untreated cats; 2) cats treated with fipronil: use of the commercial product FIPROTEC, generic of FRONTLINE, marketed by CIPLA VET; 3) cats treated with selamectin: use of the commercial product REVOLUTION, marketed by PFIZER; 4) cats treated with the combination of fipronil and selamectin. The administration of the treatment products is done at once on Day 0, by application in 'spot-on' on the skin of the animal. Cats in groups (2) and (3) received a single site dose between the shoulder blades; cats in group (4) are treated by deposition at two sites, between the shoulder blades and under the head.

The spot-on solutions are deposited in the same area on the animal, but not exactly in the same place in order to avoid possible interactions between the different solvents present in each of the two products, which could have happened if the application had taken place at exactly the same point.

The doses administered, as recommended by the manufacturers' instructions for use, are presented in Table 1 below:

Table 1

The cats are then reinfested once a week (Day 7, Day 14, Day 28, Day 35, Day 42, Day 49 and Day 56).

The fleas are then removed by means of a fine comb, by at least two complete passages of the comb on the fur of the animal; and the number of live fleas is counted on Day 1 (24 hours post-treatment) and then 24 hours after each re-infestation, for each group of cats.

The counting results of live fleas, presented in Table 2 below, indicate that: - in untreated group 1, the number of live fleas is between 57.3 and 80.5, regardless of the counting day ; Groups 2, 3 and 4 have statistically significantly fewer live fleas than group 1.

Efficacy results were calculated as percentage of live fleas relative to the control group (1) of untreated cats, and are presented in Table 2 below:

Table 2

Table 3 below summarizes the results of treatment efficacy compared to the untreated group:

Table 3

These results show that: - the efficacy of fipronil (group 2) varies between 31.1% (day 50) and 89.2% (day 8); the efficacy of selamectin (group 3) varies between 20.9% (day 50) and 96.6% (day 8); the efficacy of the combination fipronil and selamectin (group 4) varies between 54.4% (57th day) and 100% (8th and 15th days).

It thus appears that the effectiveness of the combination fipronil and selamectin is greater, regardless of the day of counting chips, the effectiveness observed for the products used separately. In particular, at the 36th and 50th days, the percentage of effectiveness is higher than that observed with fipronil or selamectin used alone. The synergistic effect between these two compounds, in terms of efficacy of treatment against cat fleas, is therefore demonstrated experimentally in vivo by the results of Tables 2 and 3.

Example 2. Choice of a suitable solvent

The solubility of these three chemical molecules: fipronil, selamectin and praziquantel, has been tested in different solvents to determine the ideal solvent to achieve complete solubility of desired doses of active ingredients.

In Table 4 below, the + indicates that the stated dose is soluble, the - it is not, the +/- indicating partial solubility, and NM means unmeasured.

Table 4

It appears from this table that the two solvents that allow effective solubilization of the three active ingredients are: N-methyl pyrrolidone, and N, N-dimethylacetamide. Benzyl alcohol also appears to be a good solvent, to be improved to obtain fipronil in a completely soluble form.

Combinations of different solvents can nevertheless make it possible to obtain solubilization and stability of the active ingredients in the composition.

Table 5 below shows compositions comprising combinations of solvents, all of which make it possible to obtain the three active compounds in soluble form.

For each mixture of solvents, the following aspects were tested: - cutaneous tolerance: the test is carried out with the formulas without active ingredients (placebo) then, if no problem identified, with the formulas with actives and measurement of the reactions observed (3 animals tested for each formula). The term 'optimize' means that one in three animals has mild skin effects. - "Crash test": stability test, performed under 'accelerated conditions' by placing the compositions at 50 ° C for 14 days. - Crystallization at 5 ° C: measurement of the possible precipitation after dissolution in the solvent: the test is performed by placing the composition overnight at 5 ° C, to highlight non-stable solutions. - Carcinogenic risk (CMR status of solvents).

The results are indicated as follows: V / C: validated and / or compliant; NV or NC: not validated or non-compliant; To optimize. Figures show percentages by weight / volume.

Table 5

It can be seen from this table that the combinations of solvents and of active principles, at the doses presented, make it possible to obtain the compositions according to the invention having the advantages mentioned in the present description.

Example 3. Examples of formulations according to the invention The figures in Table 6 below indicate the percentages by weight / volume.

Table 6

PATENT REFERENCES WO 2010/070210 WO 2010/109214 WO 2011/123773

Claims (11)

A veterinary composition for topical application comprising, in an acceptable pharmaceutical carrier, a combination of fipronil, selamectin and praziquantel. 2. Veterinary composition according to claim 1, characterized in that it is suitable for local cutaneous application in "spot-on". Veterinary composition according to claim 2, comprising the following active agent doses: Fipronil: from 6 to 25% w / v; • Selamectin: from 4 to 8% by weight / volume; Praziquantel: 10 to 14% w / v. 4. Veterinary composition according to one of claims 1 to 3, characterized in that fipronil, selamectin and praziquantel are all in soluble form in the composition. 5. Veterinary composition according to one of claims 1 to 4, characterized in that the acceptable pharmaceutical carrier is a solvent is selected from the following solvents: N-methyl pyrrolidone (NMP), benzyl alcohol, Dowanol PM (2-butoxyethanol) , glycofurol, NN dimethylacetamide, diethylene glycol monoethyl ether (Transcutol), isopropylidene glycerol (Solketal), dimethyl isosorbide (DMI), propylene glycol monocaprylamine (Capryol 90) or a mixture thereof. 6. Veterinary composition according to claim 5, characterized in that the solvent consists of a mixture of N-methyl pyrrolidone (NMP) and benzyl alcohol. 7. Veterinary composition according to one of claims 1 to 6, characterized in that it consists of a combination of fipronil, selamectin and praziquantel in the acceptable pharmaceutical vehicle and which optionally comprises one or more additional compounds selected from the agents antioxidants, solubilizing agents, penetration promoters, viscosifying agents, preserving agents, coloring and / or opacifying agents, unappealing or repellent substances and perfumes or odoriferous compounds. Veterinary composition according to one of claims 1 to 7 for use as a veterinary medicament. 9. Veterinary composition according to one of claims 1 to 8 for its use in the prevention and / or treatment of infestations with endoparasites and ectoparasites. 10. A veterinary composition for its use according to claim 9, characterized in that the ectoparasites are selected from fleas, ticks, lice crushers, and parasites responsible for mange, and the endoparasites are selected from roundworms, worms. of the heart, hookworms and tapeworm 11. Veterinary composition for use according to one of claims 8 to 10, characterized in that it is intended to be administered to dogs or cats.