Parenteral modoflaner for the control of ectoparasites

Abstract

The present invention encompasses Modoflaner and pharmaceutical compositions comprising Modoflaner for use in preventing and treating ectoparasite infestations by parenteral administration.

Description

Parenteral Modoflaner for the control of ectoparasitesIntroduction

[0001] A number of pests and parasites are known to infest warm-blooded animals. These pests and parasites can be great nuisances to both the animals and their owners. For example, virtually all companion and livestock animals can be affected by ectoparasites, such as ticks, mites, lice, and fleas. Ectoparasites tend to irritate the animals, and also can cause clinical disease and adverse sub-clinical conditions, either by themselves or by carrying vector-transmitted pathogens.

[0002] To date, various treatments have been developed to control ectoparasites on warm-blooded animals. Nevertheless, a need continues to exist for treatments with active agents that are potently efficacious, have a long duration of activity, and / or are safe to the animal recipients and / or their human owners.

[0003] The Inventors have now found that Modoflaner and pharmaceutical compositions comprising Modoflaner exhibit excellent long-acting activity against animal ectoparasites and thus can be used for prolonged control of ectoparasites on animals when administered parenterally, in particular for at least 3 months.Brief description of the invention

[0004] The invention relates to Modoflaner, a crystalline form of Modoflaner and pharmaceutical compositions comprising Modoflaner. The invention also relates to Modoflaner for its use in controlling ectoparasitic infestations of animals for at least 3 months, wherein Modoflaner is administered by parenteral route.

[0005] From PCT application WO2019 / 059412, it is known that Modoflaner (compound 82 and 116) possesses contact ectoparasiticide efficacy against fleas and ticksin vitro. No data on thein vivoefficacy of Modoflaner on these ectoparasites is provided, let alone an efficacy of a parenteral route. Although the carboxamide derivatives of WO2019 / 059412 show good immediate efficacy against ectoparasites such as American Dog Tick and cat fleas at doses of up to 25 mg / kg bodyweight in rats, a decrease of activity is already observed on the 30thday after treatment.

[0006] During evaluation of the efficacy of Modoflaner in dogs, it was found by the Inventors that in about 20% of the dogs (called “non-responder dogs”), a dose of 45 mg / kg of Modoflaner administered orally did not provide efficacy against ticks or fleas (e.g.no flea or tick was killed in experimental infestations) for more than 7 days.

[0007] This result was unforeseeable and unexplained so further investigations were undertaken. Additional experiments led to the discovery that in the non-responder dogs, no Modoflaner was detectable in their bloodstream after oral administration.

[0008] In contrast, plasma concentrations of Modoflaner similar to the ones in the respondent dogs were found in the bloodstream of the non-responder dogs when Modoflaner was administered intravenously.

[0009] These additional experiments revealed that the absence of sufficient amounts of Modoflaner in the bloodstream in about 20% of dog to provide control of an ectoparasitic infestation for more than 7 days was the result of the lack of absorption of Modoflaner and not the result of the almost complete elimination (for example through hepatic bypass or excretion) of Modoflaner from the body.

[0010] In addition to the unexpected lack of efficacy of Modoflaner in all dogs, it was found that the intravenous administration of a dose of 6 mg / kg of Modoflaner resulted in plasma concentrations of Modoflaner providing effective protection against tick and flea infestations for more than 2 months.

[0011] After parenteral administration, Modoflaner is readily absorbed, has a low clearance, a low volume of distribution and a long half-life eliminationin vivo, resulting in plasma concentrations of Modoflaner above the minimum concentration for efficacy against ectoparasites, in particular blood-feeding parasites such as fleas and ticks, for periods of several months,e.g.at least 3 months, at least 4 months, at least 5 months and even at least 6 months without the need to use a sustained release (or long acting) dosage form.

[0012] Therefore, parenteral administration of Modoflaner provides not only a rapid adulticidal efficacy (speed of kill or immediate ectoparasites killing activity) but also a long duration of activity of several months against ectoparasites (persistent ectoparasites killing activity).

[0013] Finally, Modoflaner displays a particularly favorable safety profile and is well tolerated by the animals, even at high doses of up to 400 mg / kg of bodyweight after oral administration.

[0014] These results could not be expected from WO2019 / 059412 since on the one hand, Modoflaner had not been evaluated orally and on the other hands, all the other compounds tested already showed a marked decrease of activity 30 days after administration in rats.Definitions

[0015] As used herein, Modoflaner refers to ((6-fluoro-N-(3-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenylcarbamoyl)-2-fluoro-phenyl)-nicotinamide), having the following formula:

[0016] Modoflaner can be prepared following the procedure described in WO2019 / 059412.

[0017] When the term “about” is used together with a numerical value, for example “about 10”, the whole recitation encompasses a range of + / -5% of said numerical value, that is to say for the specific example of “about 10”, a range from 9.5 to 10.5.

[0018] As used herein, “plasma concentration” or “plasmatic concentration” refers to the concentration of Modoflaner in the plasma derived from full blood. Plasma concentration may be determined by methods well known in the art. Measurements of the plasma concentration at different time points allows drawing a curve of the plasma concentration vs. time.

[0019] As used herein, “Cmax” refers to the peak plasma concentration of Modoflaner,i.e.the highest concentration of Modoflaner in the plasma after a dose of Modoflaner has been administered parenterally to the target animal.

[0020] As used herein, “Tmax” refers to the time point when peak plasma concentration (Cmax) of Modoflaner is reached.

[0021] An "infestation" refers to the presence of parasites on the skin or fur of an animal in numbers that pose a risk of nuisance or harm to humans or animals.

[0022] As used herein, “controlling or control of ectoparasite infestations” encompasses preventing or treating or both preventing and treating ectoparasite infestations. The effect of the treatment can manifest itself directly by killing the ectoparasites, either immediately or after some time has elapsed (e.g., when molting occurs), or indirectly, for example by partially or completely inhibiting the development of ectoparasites or reducing the number of eggs laid and / or the hatch rate.

[0023] As used herein, “preventing or prevention of an ectoparasite infestation” means avoiding the presence of parasites on the skin or fur of an animal in numbers that pose a risk of nuisance or harm to humans or animals. The ectoparasite infestation may be prevented by administering an effective dose of Modoflaner to a non-infested animal,e.g.before said animal enters in contact with an ectoparasite or by administering to an animal that is or has been infested by an ectoparasite an effective dose of Modoflaner to prevent a new ectoparasite infestation or a re-infestation by the offspring of the infesting ectoparasite.

[0024] As used herein, "treating or treatment of an ectoparasite infestation" means reducing the number of ectoparasites already present on the skin or fur of an animal. The ectoparasite infestation can be treated by administering to an infected animal an effective dose of Modoflaner.

[0025] As used herein, the “control of an ectoparasite infestation” refers to a reduction of the number (or count) of the existing or potential ectoparasites on the skin or fur of the animal by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%; 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In the present invention, reference to “at least about x% control” or “control of at least x%” should be understood as meaning that the number (or count) of the existing or potential ectoparasites on the skin or fur of the animal is reduced by at least x%.

[0026] Preferably, the “control of an ectoparasite infestation” refers to the reduction of the number (or count) of the existing or potential ectoparasites on the skin or fur of the animal by at least about 50%, more preferably by at least about 90%. In a specific embodiment, the ectoparasite is a flea, in particular a dog flea (Ctenocephalidescanis) or a cat flea (Ctenocephalidesfelis) and the administration of Modoflaner provides at least 95% of control of the flea infestation for at least 3 months, at least 4 months, at least 5 months and even at least 6 months. In another specific embodiment, the ectoparasite is a tick, in particularIxodesricinus,Ixodes scapularis, Rhipicephalussanguineus,Rhipicephalus (Boophilus)microplus,Dermacentor variabilis,Dermacentor reticulatusandAmblyommaamericanumand the administration of Modoflaner provides at least about 50%, more preferably at least about 90% of control of the tick infestation for at least 3 months, at least 4 months, at least 5 months and even at least 6 months.

[0027] As used herein, the term "about" refers in particular to a range of values ± 10% of a specific value. By way of example, the expression "about 20" includes the values 20 ± 10%, i.e. the values 18 to 22.Detailed description

[0028] The present invention thus relates to Modoflaner for use in controlling an ectoparasite infestation on a mammal for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months, wherein a single dose of Modoflaner ranging from 1 mg / kg to 400 mg / kg, notably from 1 mg / kg to 250 mg / kg bodyweight of said mammal is administered parenterally to said mammal.

[0029] The present invention also relates to a method for controlling an ectoparasite infestation on a mammal for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months, wherein a single dose of Modoflaner ranging from 1 mg / kg to 400 mg / kg, notably from 1 mg / kg to 250 mg / kg, bodyweight of said mammal is administered parenterally to said mammal.

[0030] The present invention further relates to the use of Modoflaner for the manufacture of a medicament intended for controlling an ectoparasite infestation on a mammal for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months, said medicament being suitable for parenteral administration at a dose ranging from 1 mg / kg to 400 mg / kg, notably from 1 mg / kg to 250 mg / kg, bodyweight of said mammal.

[0031] The present invention is also further directed to Modoflaner for use in preventing vector borne diseases, in particular tick borne diseases such as Lyme disease, Ehrlichiosis, Anaplasmosis, Rocky Mountain Spotted Fever or Babesiosis or flea borne diseases such as Bartonellosis, in a mammal, preferably a dog or a cat, wherein a single dose of Modoflaner ranging from 1 mg / kg to 400 mg / kg, notably from 1 mg / kg to 250 mg / kg, bodyweight of said mammal, effective to control ectoparasites transmitting said vector borne disease; in particular ticks or fleas, at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months is administered parenterally to said mammal.

[0032] The present invention is also further directed to Modoflaner for use in preventing and / or controlling flea allergic dermatitis (FAD) in a mammal, wherein a single dose of Modoflaner ranging from 1 mg / kg to 400 mg / kg, notably from 1 mg / kg to 250 mg / kg, bodyweight of said mammal effective to control fleas at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months is administered parenterally to said mammal.

[0033] Preferably, Modoflaner is not administered in a sustained release (or long acting) dosage form.

[0034] In the present invention, themammalmay be domestic livestock mammal or a companion mammal.

[0035] Domestic livestock mammals include cattle (cows, beef, heifers and bulls), horses, donkeys, pigs, sheeps and goats, in particular cattle.

[0036] Companion mammals include, without limitation thereto, dogs, cats, horses, pigs, mice, rats, rabbits and ferrets. Particularly contemplated companion mammals are carnivorous companion mammals, in particular selected from the group consisting in dogs, cats and ferrets. Most preferably, the companion mammal is a dog or a cat.

[0037] In a particular embodiment, the mammal is chosen from cattle (cows, beef, heifers and bulls), dogs and cats.

[0038] In a more particular embodiment, the mammal is chosen from cattle (cows, beef, heifers and bulls).

[0039] In another more particular embodiment, the mammal is chosen from dogs ans cats.

[0040] In the present invention, “ectoparasites” designate insects and acarid pests, in particular arthropods that are injurious to, or spread or act as vectors of diseases in, warm-blooded animals.

[0041] Preferably, the ectoparasite is a tick or a flea.

[0042] Ticks include soft-bodied ticks, such as Argasidae sppe.g., Argas spp. and Ornithodoros spp.); and hard-bodied ticks, such as Ixodidae sppe.g.Ixodes ricinus, Ixodes scapularis, Rhipicephalus spp e.g.Rhipicephalus sanguineus, Rhipicephalus australis or Rhipicephalus (Boophilus) microplus, Haemaphysalis sppe.g.Haemaphysalis longicornis, Dermacentor sppe.g.Dermacentor reticulatus, Dermacentor variabilis and Amblyomma sppe.g.Amblyomma americanum.

[0043] Fleas include Ctenocephalides spp., such as dog fleas (Ctenocephalides canis) and cat fleas (Ctenocephalides felis); Xenopsylla spp., such as oriental rat fleas (Xenopsylla cheopis); Pulex spp., such as human fleas {Pulex irritans); hedgehog fleas (Archaeopsylla erinacei).

[0044] Preferably, the ectoparasite is selected from dog flea (Ctenocephalidescanis), cat flea (Ctenocephalidesfelis),Ixodesricinus,Ixodes scapularis,Rhipicephalussanguineus,Rhipicephalus (Boophilus)microplus,Rhipicephalus (Boophilus) australis,Dermacentor variabilis,Dermacentor reticulatusandAmblyommaamericanum.

[0045] In the present invention, a single dose is administered. By “single dose”, it is meant that Modoflaner is given parenterally once to the animal and Modofaner provides control of the ectoparasite infestation for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months. In some embodiments, Modoflaner provides control of the ectoparasite infestation for at least 9 months.

[0046] In one embodiment, the single dose is administered at one unique time point. In this case, a unique parenteral dose is administered.

[0047] In another embodiment, the single dose is administered multiple times. By “administered multiple times”, it is meant that the amount of Modoflaner that controls the ectoparasite infestation for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months is divided in a plurality of individual parenteral doses, and the plurality of individual parenteral doses is given to the mammal to provide after the administration of the latest dose, a plasma concentration of Modoflaner effective to control ectoparasites for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months. This may be useful, for example, when the animal weighs too much to receive the dose in a single injection. For example, 50% of the amount of Modoflaner that effectively controls the ectoparasite infestation for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months may be administered then the remaining 50% may be administered some hours or some days later.

[0048] The amount of Modoflaner to administer depends on several factors, such as the route of administration (subcutaneous or intravenous for example), the dosage form (solution or suspension for example), the mammal, the ectoparasite, the degree of control sought and the duration of control sought. The single dose of Modoflaner to administer can be determined by those skilled in the art.

[0049] The amount of Modoflaner that is administered should provide a quantity of Modoflaner that is above the minimum plasma concentration providing the sought level of protection for the sought duration. Without limitation thereto, the following minimum plasma concentrations have been identified by the Inventors in dogs:for fleas, such as a dog flea or a cat flea, at least about 95% control of the flea infestation can be achieved when the plasma concentration of Modoflaner is above 50 µg / L,forIxodesricinus, at least about 90% control of theIxodesricinusinfestation can be achieved when the plasma concentration of Modoflaner is above 70 µg / L,forIxodes scapularis, at least about 90% control of theIxodes scapularisinfestation can be achieved when the plasma concentration of Modoflaner is above 70 µg / L,forDermacentor reticulatus, at least about 90% control of theDermacentor reticulatusinfestation can be achieved when the plasma concentration is above 100 µg / L,forDermacentor variabilis. at least about 90% control of theDermacentor variabilisinfestation can be achieved when the plasma concentration of Modoflaner is above 100 µg / L,forRhipicephalussanguineus, at least about 90% control of theRhipicephalussanguineusinfestation can be achieved when the plasma concentration of Modoflaner is above 90 µg / L, andforAmblyommaamericanum, at least about 90% control of theAmblyommaamericanuminfestation can be achieved when the plasma concentration of Modoflaner is above 200 µg / L.

[0050] Typically, the amount of Modoflaner that controls the ectoparasite infestation for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months is ranging from 1 mg / kg to 400 mg / kg bodyweight of said mammal. Modoflaner is safe at administered doses of up to 400 mg / kg but it is preferably administered at doses of up to about to about 200 mg / kg, even more preferably of up to about 100 mg / kg.

[0051] In one particular embodiment, Modoflaner is administered via a single dose of Modoflaner ranging from 1 mg / kg to 200 mg / kg bodyweight of said mammal.

[0052] In particular, said single dose is greater than or equal to 2, 3, 4, or 5 mg / kg bodyweight of said mammal.

[0053] In particular, said single dose is greater than or equal to 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg bodyweight of said mammal.

[0054] In particular, said single dose is greater than or equal to 5, 10, 15, 20, 25 or 30 mg / kg bodyweight of said mammal.

[0055] In particular, said single dose is less than or equal to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said mammal.

[0056] In particular, said single dose is less than or equal to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said mammal.

[0057] In particular, said single dose is less than or equal to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said mammal.

[0058] In particular, said single dose is greater than or equal to 2, 3, 4, or 5 mg / kg bodyweight of said mammal, and less than or equal to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said mammal, said single dose being more particularly from 2.5 to 20, or from 5 to 15 mg / kg bodyweight of said mammal.

[0059] In particular, said single dose is greater than or equal to 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg bodyweight of said mammal, and less than or equal to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said mammal, said single dose being more particularly from 5 or 10 to 30, or from 15 to 20 mg / kg bodyweight of said mammal.

[0060] In particular, said single dose is greater than or equal to 5, 10, 15, 20, 25 or 30 mg / kg bodyweight of said mammal, and less than or equal to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said mammal, said single dose being more particularly from 20 to 50, or from 30 to 40 mg / kg bodyweight of said mammal.

[0061] In particular, said single dose is greater than or equal to 2, 3, 4, or 5 mg / kg bodyweight of said mammal, the mammal being a cattle.

[0062] In particular, said single dose is greater than or equal to 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg bodyweight of said mammal, the mammal being a dog.

[0063] In particular, said single dose is greater than or equal to 5, 10, 15, 20, 25 or 30 mg / kg bodyweight of said mammal, the mammal being a cat.

[0064] In particular, said single dose is less than or equal to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said mammal, the mammal being a cattle.

[0065] In particular, said single dose is less than or equal to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said mammal, the mammal being a dog.

[0066] In particular, said single dose is less than or equal to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said mammal, the mammal being a cat.

[0067] In particular, said single dose is greater than or equal to 2, 3, 4, or 5 mg / kg bodyweight of said mammal, and less than or equal to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said mammal, said single dose being more particularly from 2.5 to 20, or from 5 to 15 mg / kg bodyweight of said mammal, the mammal being a cattle.

[0068] In particular, said single dose is greater than or equal to 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg bodyweight of said mammal, and less than or equal to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said mammal, said single dose being more particularly from 5 or 10 to 30, or from 15 to 20 mg / kg bodyweight of said mammal, the mammal being a dog.

[0069] In particular, said single dose is greater than or equal to 5, 10, 15, 20, 25 or 30 mg / kg bodyweight of said mammal, and less than or equal to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said mammal, said single dose being more particularly from 20 to 50, or from 30 to 40 mg / kg bodyweight of said mammal, the mammal being a cat.

[0070] In particular, said single dose is greater than or equal to 2, 3, 4, or 5 mg / kg bodyweight of said mammal, the mammal being a cattle.

[0071] In particular, said single dose is greater than or equal to 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg bodyweight of said mammal, the mammal being a dog.

[0072] In particular, said single dose is greater than or equal to 5, 10, 15, 20, 25 or 30 mg / kg bodyweight of said mammal, the mammal being a cat.

[0073] In particular, said single dose is less than or equal to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said mammal, the mammal being a cattle.

[0074] In particular, said single dose is less than or equal to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said mammal, the mammal being a dog.

[0075] In particular, said single dose is less than or equal to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said mammal, the mammal being a cat.

[0076] In particular, said single dose is greater than or equal to 2, 3, 4, or 5 mg / kg bodyweight of said mammal, and less than or equal to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said mammal, said single dose being more particularly from 2.5 to 20, or from 5 to 15 mg / kg bodyweight of said mammal, the mammal being a cattle.

[0077] In particular, said single dose is greater than or equal to 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg bodyweight of said mammal, and less than or equal to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said mammal, said single dose being more particularly from 5 or 10 to 30, or from 15 to 20 mg / kg bodyweight of said mammal, the mammal being a dog.

[0078] In particular, said single dose is greater than or equal to 5, 10, 15, 20, 25 or 30 mg / kg bodyweight of said mammal, and less than or equal to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said mammal, said single dose being more particularly from 20 to 50, or from 30 to 40 mg / kg bodyweight of said mammal, the mammal being a cat.

[0079] Generally, when administered parenterally, the amount of Modoflaner providing the minimum plasma concentration effective to control ectoparasites for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months ranges from about 1 mg / kg, preferably at least 3 mg / kg, even more preferably at least 5 mg / kg. Of course, the longer the duration sought, the higher the dose to administer.

[0080] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a cattle for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose of Modoflaner ranging from 2, 3, 4, or 5 mg / kg to 400 mg / kg bodyweight of said cattle is administered parenterally to said cattle.

[0081] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a dog for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose of Modoflaner ranging from 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg to 400 mg / kg bodyweight of said dog is administered parenterally to said dog.

[0082] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a cat for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose of Modoflaner ranging from 5, 10, 15, 20, 25 or 30 mg / kg to 400 mg / kg bodyweight of said cat is administered parenterally to said cat.

[0083] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a cattle for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose of Modoflaner ranging from 1 mg / kg to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said cattle is administered parenterally to said cattle.

[0084] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a dog for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose of Modoflaner ranging from 1 mg / kg to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said dog is administered parenterally to said dog.

[0085] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a cat for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose of Modoflaner ranging from 1 mg / kg to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said cat is administered parenterally to said cat.

[0086] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a cattle for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose is greater than or equal to 2, 3, 4, or 5 mg / kg bodyweight of said mammal, and less than or equal to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said cattle, said single dose being more particularly from 2.5 to 20, or from 5 to 15 mg / kg bodyweight of said cattle.

[0087] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a dog for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose is greater than or equal to 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg bodyweight of said dog, and less than or equal to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said dog, said single dose being more particularly from 5 or 10 to 30, or from 15 to 20 mg / kg bodyweight of said dog.

[0088] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a cat for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose is greater than or equal to 5, 10, 15, 20, 25 or 30 mg / kg bodyweight of said cat, and less than or equal to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said cat, said single dose being more particularly from 20 to 50, or from 30 to 40 mg / kg bodyweight of said cat.

[0089] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a cattle for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose is greater than or equal to 2, 3, 4, or 5 mg / kg bodyweight of said mammal, and less than or equal to 50, 45, 40, 35, 30, 25, 20 or 15 mg / kg bodyweight of said cattle, said single dose being more particularly from 2.5 to 20, or from 5 to 15 mg / kg bodyweight of said cattle, said ectoparasite being a tick or a flea, preferably a tick.

[0090] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a dog for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose is greater than or equal to 2, 4, 6, 8, 10, 12, 14 or 16 mg / kg bodyweight of said dog, and less than or equal to 70, 60, 50, 40, 30, 25 or 20 mg / kg bodyweight of said dog, said single dose being more particularly from 5 or 10 to 30, or from 15 to 20 mg / kg bodyweight of said dog, said ectoparasite being a tick or a flea, preferably a tick.

[0091] In a particular embodiment, the invention concerns Modoflaner for use in controlling an ectoparasite infestation on a cat for at least 3, 4, 5 or 6 months, in particular 6 months, wherein a single dose is greater than or equal to 5, 10, 15, 20, 25 or 30 mg / kg bodyweight of said cat, and less than or equal to 100, 90, 80, 70, 60, 50 or 40 mg / kg bodyweight of said cat, said single dose being more particularly from 20 to 50, or from 30 to 40 mg / kg bodyweight of said cat, said ectoparasite being a tick or a flea, preferably a tick.

[0092] Modoflaner may be administered by anyparenteralroute known to those skilled in the art, including subcutaneously, intraperitoneally, intramuscularly and intravenously. Preferably, Modoflaner is administered subcutaneously or intravenously, more preferably subcutaneously.

[0093] In one particular embodiment, Modoflaner is administered intravenously. The single dose is preferably at least about 5 mg / kg.

[0094] In an exemplary embodiment, a single dose of 6 mg / kg is administered intravenously. This results in the control of ectoparasite infestations, in particular fleas such as dog fleas (Ctenocephalidescanis) and cat fleas (Ctenocephalidesfelis) and ticks such asIxodesricinus,Ixodes scapularis, Rhipicephalussanguineus,Dermacentor variabilis,Dermacentor reticulatusandAmblyommaamericanumfor at least 2 months, in particular in dogs. Such a single dose provides in particular more than 95% in the control of fleas and in particular more than 90% in the control of ticks.

[0095] In another particular embodiment, Modoflaner is administered subcutaneously. The single dose is preferably at least about 2.5 mg / kg, 5 mg / kg, 12 mg / kg, 15 mg / kg or 25 mg / kg, depending on the duration sought, the target animal and the ectoparasite.

[0096] In an exemplary embodiment, a single dose of 15 mg / kg is administered subcutaneously to dogs. This results in the control of fleas, in particular dog fleas (Ctenocephalidescanis) and cat fleas (Ctenocephalidesfelis) and ticks, in particularIxodesricinus,Ixodes scapularis, Rhipicephalussanguineus,Dermacentor variabilis,Dermacentor reticulatusandAmblyommaamericanuminfestation for more than 6 months, in particular 9 months. Such a single dose provides in particular more than 95% in the control of fleas and in particular more than 90% in the control of ticks.

[0097] In another exemplary embodiment, a single dose of 2.5 mg / kg, 5 mg / kg or 15 mg / kg is administered subcutaneously to bovines (Bos taurus and Bos indicus). All the doses resulted in the control of ticks, in particularRhipicephalus (Boophilus)microplusinfestation, for more than 4 months, the 2.5 mg / kg dose providing more than 90% control for more than 3 months and the 5 mg / kg and 15 mg / kg for more than 6 months, preferably more than 9 months with the upper dose of 15 mg / kg.

[0098] In a further exemplary embodiment, a single dose of 30 mg / kg is administered subcutaneously to cats. This results in the control of fleas, in particular dog fleas (Ctenocephalidescanis) and cat fleas (Ctenocephalidesfelis) and ticks, in particularIxodesricinus,Ixodes scapularis, Rhipicephalussanguineus,Dermacentor variabilis,Dermacentor reticulatusandAmblyommaamericanuminfestation for more than 6 months, in particular 9 months. Such a single dose provides in particular more than 95% in the control of fleas and in particular more than 90% in the control of ticks.

[0099] Modoflaner may be administered parenterally in any pharmaceutical dosage form known to those skilled in the art. In one alternative, Modoflaner is administered as an injectable solution (i.e.Modoflaner is dissolved in a vehicle). In another alternative, Modoflaner is administered as an injectable suspension (i.e.Modoflaner is undissolved in a vehicle).

[0100] Exemplary parenteral dosage forms include an injectable solution and an injectable suspension.

[0101] The parenteral dosage form may be an injectable solution. Parenteral dosage forms in the form of a solution typically comprise a solvent in which Modoflaner is dissolved. Examples of solvents include C1-C6alcohols; glycol ethers (e.g.diethyleneglycol monoethyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether); glycerol; propylene glycol; liquid polyethylene glycols (e.g.polyethylene glycol 400), cyclic carbonates (e.g.propylene carbonate); pyrrolidones (e.g.2-pyrrolidone, N-methylpyrrolidone); dimethyl isosorbide (DMI); dimethylacetamide; dimethylsulfoxid; glycerol formal, glycofurol, solketal, benzyl benzoate and mixtures thereof. The parenteral dosage form may optionally comprise an antioxidant. Examples of antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbyl palmitate, α-tocopherol and mixtures thereof.

[0102] Of note is a parenteral formulation in the form of a solution comprising Modoflaner, glycofurol and polyethylene glycol 400 as a vehicle and optionally an antioxidant. Of further note is a formulation wherein the vehicle comprises glycofurol and polyethylene 400 in a volume ratio of 1 / 99 to 99 / 1, preferably 50 / 50 to 99 / 1 and more preferably of 70 / 30 to 90 / 10, in particular 80 / 20, and optionally an antioxidant.

[0103] The injectable suspensions according to the invention may beoilysuspensions,e.g.the vehicle comprises or consists of an oil. Examples of vehicles include oils, such as soybean oil, cotton seed oil, corn oil, sunflower oil, peanut oil, sesame oil, paraffin oil, modified vegetable oils such as triglycerides of capric / caprylic acids, in particular triglycerides of fractionated plant fatty acids with chain lengths of C8 to C10 (sold as MIGLYOL® 810 and MIGLYOL® 812), a triglyceride of fractionated plant fatty acids with chain lengths of C8 and C10 combined with linoleic acid (sold as MIGLYOL® 818), a glycerin ester of fractionated plant fatty acids with chain lengths of C8 and C10 combined with succinic acid (sold as MIGLYOL® 829), a propylene glycol diester of saturated plant fatty acids with chain lengths of C8 and C10 (sold as MIGLYOL® 840), and mixtures thereof.

[0104] Oily suspensions may further comprise one or more co-solvents. Examples of co-solvents are propylene glycol, polyethylene glycols, 2-pyrrolidone, N-methyl-2-pyrrolidone, glycofurol, solketal, glycerol formal, benzyl benzoate, ethyl acetate, triacetin, propylene glycol derivatives (e.g.propylene glycol monolaurate), caprylocaproyl polyoxyl-8 glycerides, isopropyl myristate, or mixtures thereof. The co-solvent should not be present in such amounts that cause the dissolution of of Modoflaner.

[0105] Oily suspensions may further comprise an antioxidant. Examples of antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbyl palmitate, α-tocopherol, ascorbic acid and mixtures thereof.

[0106] Oily suspensions may also contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.

[0107] Of note is an injectable oily suspension, comprising Modoflaner, a modified vegetable oil such as triglycerides of fractionated plant fatty acids with chain lengths of C8 to C10 (sold as MIGLYOL® 810 and MIGLYOL® 812), a triglyceride of fractionated plant fatty acids with chain lengths of C8 and C10 combined with linoleic acid (sold as MIGLYOL® 818), a glycerin ester of fractionated plant fatty acids with chain lengths of C8 and C10 combined with succinic acid (sold as MIGLYOL® 829), a propylene glycol diester of saturated plant fatty acids with chain lengths of C8 and C10 (sold as MIGLYOL® 840), and mixtures thereof and optionally an antioxidant.

[0108] Of further note is an injectable oily suspension, comprising Modoflaner, a propylene glycol diester of saturated plant fatty acids with chain lengths of C8 and C10 (sold as MIGLYOL® 840), and optionally an antioxidant, in particular comprising 15 wt% of Modoflaner and 85 wt% of the a propylene glycol diester of saturated plant fatty acids with chain lengths of C8 and C10 (sold as MIGLYOL® 840) and optionally an antioxidant.

[0109] The injectable suspensions, according to the invention may beaqueoussuspensions,e.g.the vehicle comprise or consists of water.

[0110] Aqueous injectable suspensions according to the invention may include other excipients suitable for the manufacture of aqueous suspensions.

[0111] Aqueous injectable suspensions according to the invention may consist of water as the vehicle or comprise water and a co-solvent or a blend of co-solvents as the vehicle. Examples of co-solvents include water-miscible polar solvents such as ethanol; isopropanol; benzyl alcohol; glycol ethers such as diethyleneglycol monoethyl ether (DGME), Transcutol®, butyl diglycol, dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether; liquid polyethylene glycols (PEGs) such as PEG 400; propylene glycol; carbonates such as propylene carbonate; 2-pyrrolidone; N-methylpyrrolidone; dimethyl isosorbide (DMI); dimethylacetamide; dimethylsulfoxide; glycerol formal or mixtures thereof.

[0112] Aqueous injectable suspensions according to the invention may comprise suspending agents. Examples of suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia.

[0113] Aqueous suspensions, preferably injectable suspensions, according to the invention may comprise dispersing or wetting agents. Examples of dispersing and wetting agents include naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate, poloxamers, sorbitan fatty acid esters (Spans), polyoxyethylene sorbitan fatty acid esters, (polysorbates / Tweens), polyoxyethylene castor oil derivatives (Cremaphors), polyoxyethylene stearates, lecithin and TPGS (d-a-Tocopheryl polyethylene glycol 1000 succinate). The dispersing or wetting agent may be present in the composition in an amount of about 0.01 % w / v to about 0.5% w / v or about 0.05 % w / v to about 0.1 % w / v.

[0114] Aqueous injectable suspensions according to the invention may contain a surfactant. Examples of surfactants include glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters including sorbitan monooleate (Span® 20), polyvinyl alcohol, polysorbates including polysorbate 20 and polysorbate 80, d-a-tocopherol polyethylene glycol 1000 succinate (TPGS), sodium lauryl sulfate, co-polymers of ethylene oxide and propylene oxide (e.g. poloxamers such as LUTROL® F87 and the like), polyethylene glycol castor oil derivatives including polyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor® RH60); propylene glycol monolaurate (LAUROGLYCOL®); glyceride esters including glycerol caprylate / caprate (CAPMUL® MCM), polyglycolized glycerides)(GELUCIRE®, PEG 300 caprylic / capric glycerides (Softigen® 767), PEG 400 caprylic / capric glycerides (Labrasol®), PEG 300 oleicglycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil® M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxy stearates including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate, and the like). Polyethylene glycol stearates (synonyms include macrogol stearates, polyoxylstearates, polyoxyethylene stearates, ethoxylated stearates; CAS No. 9004-99-3, 9005-08-7) are mixtures of mono- and distearate esters of mixed polyoxyethylene polymers. Polyethylene glycol hydroxystearate is a mixture of mono- and diesters of hydroxystearic acid with polyethylene glycols. One polyethylene glycol hydroxystearate that may be used in the compositions is polyethylene glycol 12- hydroxystearate. In another embodiment, the inventive compositions may include the surfactant polyethylene glycol 12-hydroxystearate (Kolliphor® HS 15 from BASF), a mixture of mono- and diesters of 12-hydroxystearic acid with 15 moles of ethylene oxide. Again, these compounds, as well as their amounts are well known in the art. In another embodiment of the invention, the inventive compositions may include polyoxyl castor oil (Kolliphor® EL) as a surfactant. In other embodiments, the inventive compositions may include polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40) or polyoxyl 60 hydrogenated castor oil as surfactants.

[0115] Aqueous injectable suspensions according to the invention may also contain preservatives, for example p-hydroxybenzoate, m-cresol, benzalkonium chloride, methylparaben, propylparaben or benzyl alcohol.

[0116] Modoflaner may be present in the injectable suspension or solution in an amount ranging from about 1% w / v to about 70% w / v of Modoflaner. Preferably, Modoflaner is present in an amount ranging from about 5% w / v to about 20% w / v of Modoflaner, most preferably about 15% w / v.

[0117] The present invention further concerns in a specific embodiment Modoflaner for use in the control of a tick or flea infestation on a dog for at least 6 months, wherein a single dose of Modoflaner of at least 15 mg / kg bodyweight is administered subcutaneously to the dog. The single dose provides in particular 95% in the control of fleas and more than 90% in the control of ticks for at least 6 months.

[0118] The present invention further concerns in a specific embodiment Modoflaner for use in the control of a tick or flea infestation on a cat for at least 6 months, wherein a single dose of Modoflaner of at least 25 mg / kg, preferably about 30 mg / kg, bodyweight is administered subcutaneously to the cat. The single dose provides in particular 95% in the control of fleas and more than 90% in the control of ticks for at least 6 months.

[0119] The present invention further concerns in a specific embodiment Modoflaner for use in the control of a tick infestation on a bovine for at least 3 months, wherein a single dose of Modoflaner of at least 2.5 mg / kg, bodyweight is administered subcutaneously to the bovine animal. The single dose provides in particular more than 90% in the control of ticks for at least 3 months.

[0120] The present invention further concerns in a specific embodiment Modoflaner for use in the control of a tick infestation on a bovine for at least 6 months, wherein a single dose of Modoflaner of at least 15 mg / kg, bodyweight is administered subcutaneously to the bovine animal. The single dose provides in particular 95% in the control of fleas and more than 90% in the control of ticks for at least 6 months, preferably at least 9 months.

[0121] Thanks to its immediate and persistent effects for controlling ectoparasites infestations, Modoflaner also prevents diseases induced by ectoparasites. By killing ticks rapidly during long periods of time, Modoflaner prevents vector borne diseases, in particular tick borne diseases such as Lyme disease, Ehrlichiosis, Anaplasmosis, Rocky Mountain Spotted Fever or Babesiosis and flea borne diseases such as Bartonellosis. For example, Modoflaner prevents babesiosis by blocking pathogen transmission (Babesiacanis) to dogs through the bite by vector ticks (Dermacentor reticulatus).

[0122] Modoflaner is also useful for the control of flea allergy dermatitis (FAD). FAD, also designated as flea bite hypersensitivity, is an immunologic disorder and the most common dermatological disease in domestic animals, specifically dogs and cats. FAD exhibits as a very itchy skin reaction or allergy and predisposes to the development of secondary skin infections and diseases.Treatment schedule

[0123] The surprisingly long durations over which Modoflaner is effective against various ectoparasites can, in many instances, be obtained using low single doses that are non-toxic to the animal without requiring the use of a sustained release formulation.

[0124] Thus, it is possible to reduce the frequency of administration of Modoflaner to at least a quarterly administration, once every five month or half yearly (once every six months), thereby reducing the risks of noncompliance with the treatment schedule.

[0125] In some embodiments, the frequency of administration is reduced to once every three months, preferably once every fourth months, more preferably once every five months or even more preferably once every six months.

[0126] In one embodiment, the present invention relates to Modoflaner for use in controlling an ectoparasite infestation on an mammal, wherein a single dose of Modoflaner is administered once every three months, preferably once every fourth months, more preferably once every five months or even more preferably once every six months.

[0127] In another embodiment, the present invention relates to Modoflaner for use in controlling an ectoparasite infestation on an animal, wherein a single dose of Modoflaner is administered once every three months, preferably once every fourth months, more preferably once every five months or even more preferably once every six months, said dose providing at least 50%, preferably at least 90%, control of the ectoparasite infestation until the next administration.Combinations

[0128] The present invention further relates to Modoflaner for use in controlling an ectoparasite infestation on a mammal for at least 3 months, preferably at least 4 months, more preferably at least 5 months and even more preferably at least 6 months, wherein a single dose of Modoflaner ranging from 1 mg / kg to 400 mg / kg bodyweight of said mammal is administered parenterally to said mammal, as decribed hereinbefore, and wherein Modoflaner is administered in combination with one or more second active principle, in particular an endoparasiticide.

[0129] Endoparasiticides are well-known to thos skilled in the art and include, without limitation thereto, macrocyclic lactones (e.g.the avermectins such as ivermectin, moxidectin, and milbemycin), benzimidazoles (e.g., fenbendazole, albendazole, and triclabendazole), salicylanilides (e.g., closantel and oxyclozanide), substituted phenols (e.g., nitroxynil), pyrimidines (e.g., pyrantel), imidazothiazoles (e.g., levamisole), cyclooctadepsipeptide (e.g., Emodepside), and tetrahydropyrimidines (e.g., praziquantel).

[0130] In one embodiment, Modoflaner is administered in a different composition.

[0131] In one preferred embodiment, Modoflaner and the endoparasiticide are administered in the same composition.

[0132] The dose of the endoparasiticides are generally known in the art and the amount of the endoparasiticide required in the composition may be determined by those skilled in the art.

[0133] Preferably, the composition comprises Modoflaner, and one or more endoparasiticides selected from the group consisting in macrocyclic lactones, in particular ivermectin, moxidectin, milbemycin oxime, selamectin, emamectin, eprinomectin and doramectin and imidazothiazoles, in particular levamisole.

[0134] In one embodiment, the compositions comprise Modoflaner and a macrocyclic lactone. In another embodiment, the compositions comprise Modoflaner, a macrocyclic lactone and an imidazothiazole.

[0135] Exemplary compositions comprise Modoflaner and ivermectin; Modoflaner and moxidectin; Modoflaner and milbemycin oxime; Modoflaner and selamectin; Modoflaner and emamectin; Modoflaner and eprinomectin; Modoflaner and doramectin; Modoflaner, ivermectin and levamisole; Modoflaner, moxidectin and levamisole; Modoflaner, milbemycin oxime and levamisole; Modoflaner, selamectin and levamisole; Modoflaner, emamectin and levamisole; Modoflaner, eprinomectin and levamisole; Modoflaner, doramectin and levamisole.

[0136] Endoparasiticide may be solubilized in the composition, suspended in the composition or present in the composition in the form of microspheres. Examples of microspheres are wax- or fat-based microspheres, for example those described in patent applications WO2017 / 045966 and US6340671; biopolymer-based microspheres, for example those described in patent applications WO2021 / 233967, WO2020 / 225143, WO2019 / 050259 and WO2023 / 200035.Description of the figures

[0137] represents the individual plasma concentration (Y axis, ng / mL) in dogs vs. time (X axis, days) after oral administration of 30 mg / kg bodyweight of crystalline modification IV of Modoflaner.

[0138] represents the plasma concentration (semi log scale, Y axis, ng / mL) in dogs vs. time (X axis, hours) after subcutaneous administration of 12 mg / kg bodyweight of Modoflaner (round dotted line) and intravenous administration of 6 mg / kg bodyweight of Modoflaner (squared dotted line).

[0139] represents an example of a curve obtained from a study as described in example 2. The measured efficacy against an ectoparasite is reported on the Y-axis (%) and the plasma concentration measured at different study days on the X-axis (ng / mL). Each dot represents the efficacy measured for each dog of the treatment group. The regression curve obtained from the data (dashed line) cuts the 90% efficacy line (horizontal line) at the minimum plasma concentration effective to achieve 90% control of the ectoparasite infestation.

[0140] represents an example of a curve obtained from a study as described in example 2. The measured efficacy against after an artificial ectoparasite infestation is reported on the Y-axis (%) and the study day (infestation day) on the X-axis. In this example, the ectoparasites areAmblyommaamericanum(left histogram on each study day) andDermacentor reticulatus(right histogram on each study day) and the dogs are treated orally with the tablet of example 3 at a dose of 45 mg / kg bodyweight. As can be seen from the graph, administration of the tablet of example 3 at a dose of 45 mg / kg bodyweight results in about 100% of control ofAmblyommaamericanumandDermacentor reticulatusfor more than 20 weeks (more than 4 months).

[0141] represents the percentage of efficacy in the control of Rhipicephalus (Boophilus) Microplus on bovines (Y-axis) as a function of the study time (X-axis) from D+1 to D+52.

[0142] represents the percentage of efficacy in the control of Rhipicephalus (Boophilus) Microplus on bovines (Y-axis) as a function of the study time (X-axis) from D+53 to D+101.

[0143] represents the percentage of efficacy in the control of Rhipicephalus (Boophilus) Microplus on bovines (Y-axis) as a function of the study time (X-axis) from D+102 to D+150.

[0144] represents the percentage of efficacy in the control of Rhipicephalus (Boophilus) Microplus on bovines (Y-axis) as a function of the study time (X-axis) from D+151 to D+178.Examples

[0145] Example 1.0: Oral administration, reference out of the present invention

[0146] The objective of the study was to determine the pharmacokinetic parameters of Modoflaner after oral administration of Modoflaner in dogs. Crystalline modification IV of Modoflaner, as described in WO2022 / 101502, was administered orally (as described inof WO2022 / 101502) in a tablet to eight dogs at a dose of 30 mg / kg bodyweight.

[0147] Blood sampling was performed after 12h, 24h, 36h, 48h, 168h (D7), 672h (D28), 1344 (D56), 1680h (D70) and 2016h (D84, last study day).

[0148] From the blood samples, the blood plasma vs. time curve shown inwas obtained.

[0149] Results:there is a high inter-individual variability of Modoflaner plasma concentrations. In two dogs out of the eight, the plasma concentration remains below 400 ng / mL.

[0150] The study was performed again and provided similar results with dogs responding well to Modoflaner and other dogs not responding well (with a low plasma concentration). Among the dogs from these two studies, some dogs were therefore identified as “low oral responders” whereas other dogs were identified as ‘high oral responders”, i.e. dogs that responded very well to the Modoflaner.

[0151] Based on the results of these studies on the oral administration, a further study was performed by intraveinous administration. The objective of the study was to determine the pharmacokinetic profile of Modoflaner, after a single intravenous administration in two populations of dogs based on the results of previous oral efficacy studies with so called “high oral responders” and “low oral responders” (8 dogs per group 1 and 2 respectively).

[0152] Blood specimens were collected from the treated animals from both groups to determine the pharmacokinetic (PK) profile of Modoflaner. Dogs were then observed hourly for 4 hours (h) [± 15 minutes (min)] after modoflaner administration to each animal for signs of abnormal observations. Blood specimens were collected prior to the administration of Modoflaner and at regular intervals after the administration of the Modoflaner to the treated animals (both groups 1 and 2) to determine the pharmacokinetic (PK) profile of Modoflaner.

[0153] The concentrations observed at the first sampling time-point (5 min after the administration, corresponding to the maximal plasma concentration observed after the intravenous a dministration) was 10 700 ± 3240 ng / mL for the “low oral” responder dogs and 13 100 ± 3810 n g / mL for the “high oral” responder dogs, and were considered to be similar between the two populations of dogs. The exposure to Modoflaner is considered to be similar between the “low oral” and the “high oral” responder dogs after a single intravenous administration. The value of half-life elimination demonstrated similar elimination phase between the “low oral” and the “high oral” responder dogs.

[0154] In conclusion, similar pharmacokinetic profiles were observed for “low oral responder” and “high oral responder” dogs with a high distribution and slow elimination of Modoflaner after a single intravenous administration of Modoflaner. Both groups also had similar exposure to Modoflaner and elimination phase. This further study by intraveinous administration demonstrates that the inter-variability observed in the study with oral administration of Modoflaner is not an inter-variability among individuals from the dog species, but a variability due to the mode of administration of the Modoflaner by oral route in dogs.

[0155] Example 1: pharmacokinetic and pharmacodynamics properties ofModoflaner.Example 1.1: Intravenous administration

[0156] The objective of the study was to determine the pharmacokinetic parameters of Modoflaner after intravenous administration of Modoflaner in dogs. Modoflaner was administered intravenously to four dogs at a dose of 6 mg / kg. Formulation consisted of 6 mg / mL of Modoflaner in a 80 / 20 mixture of glycofurol and polyethylene glycol 400.

[0157] Blood sampling was performed after 5 min, 15 min, 30 min, 1, 2, 4, 8, 24, 48, 72, 96, 168h (D7), 336h (D14), 504h (D21), 672h (D28), 840h (D35), 1008h (D42), 1176h (D49), 1344(D56) and 1512h (D63, last study day).

[0158] From the blood samples, the following pharmacokinetics parameters were derived: C0, Cmax, AUClast, AUCinf, V, Cl (clearance) and t1 / 2. The mean results are compiled inTable 1:C0CmaxAUClastAUCINFVClt1 / 2(ng / mL)(ng / mL)(ng.h / mL)(ng.h / mL)(L / kg)(L / h / kg)(Days)N4444444Mean2580020700195000022600002.140.0027422.5SD116018004550004500000.6730.0005545.38CV%4.488.7223.319.931.420.223.9

[0159] Results:in contrast to oral administration, there is only moderate inter-individual variability on Modoflaner plasma concentrations. Modoflaner is quantifiable (> 300 ng / mL) in all plasma samples up to Day 63 (last sampling day), demonstrating the long persistence of Modoflaner in dog’s plasma. The plasma concentration vs. time curves for intravenous and subcutaneous administrations are represented in.Example 1.2: Subcutaneous administration

[0160] The objective of the study was to determine the pharmacokinetic parameters of Modoflaner after subcutaneous administration of Modoflaner in dogs. Modoflaner was administered subcutaneously to six dogs at a dose of 12 mg / kg. Formulation consisted of 12 mg / mL of Modoflaner in an 80 / 20 mixture of glycofurol and polyethylene glycol 400.

[0161] Blood sampling was performed after 15 min, 30 min, 1, 2, 4, 8, 24, 48, 72, 96, 168h (D7), 336h (D14), 504h (D21), 672h (D28), 840h (D35), 1008h (D42), 1176h (D49), 1344(D56), 1512h (D63),1848h (D77), 2184h (D91), 2520h (D105) and 2856h (D119, last study day).

[0162] From the blood samples, the following pharmacokinetics parameters were derived: Tmax, Cmax, Tlast, AUClast, AUCinfand t1 / 2. The mean results are compiled inTable 2:TmaxCmaxTlastAUClastAUCINFt1 / 2(h)(ng / mL)(h))(ng.h / mL)(ng.h / mL)(Days)N666666Mean784189028603070000353000032.7SD17426902490003320008.83CV%22.114.208.139.4227

[0163] Results:there is only moderate inter-individual variability on modoflaner plasma concentrations. Modoflaner is quantifiable (> 300 ng / mL) in all plasma samples up to Day 119 (last sampling day), demonstrating the long persistence of Modoflaner in dog’s plasma.

[0164] When administered subcutaneously, Modoflaner is absorbed slowly but it has a long half-life elimination. The bioavailability of Modoflaner by subcutaneous administration is around 78%.

[0165] A further study was performed according to the same design as disclosed here above to determine the pharmacokinetic parameters of Modoflaner after subcutaneous administration. Modoflaner was administered subcutaneously to dogs in 4 different groups, each being administered with a different formulation comprising Modoflaner at a dose of 15 mg / kg :Aqueous suspension comprising Blanose carboxymethylcellulose, Kolliphor P188, benzyl alcohol and water for injection;Oily suspension of Modoflaner in ethyl oleate;Oily suspension of Modoflaner in Miglyol 840, aluminium monostearate and stearic acid;Oily suspension of Modoflaner in Miglyol 840

[0166] The results of this further study showed that the PK profiles of Modoflaner for each formulation were similar for all the 4 groups.

[0167] Example 2: Determination of the minimum plasma concentration effective to control ectoparasites

[0168] The principle of the study is to establish a relationship between the observed control on ectoparasites (ticks:Ixodesricinus,Ixodes scapularis,Rhipicephalussanguineus,Dermacentor variabilis,DermacentorRecitulatusandAmblyommaamericanum; and fleas:Ctenocephalidesfelis) and the plasma concentration of Modoflaner.

[0169] An example of such a study is presented hereafter.

[0170] 12 dogs (males and females) are acclimatized to the study environment from SD -7 (study day -7, day of enrollment) to SD -3 (± 1 SD, day of inclusion). 6 dogs are randomly allocated to a treatment group (receiving a given dose of Modoflaner) and the 6 other dogs to a control group (not receiving Modoflaner).

[0171] Dogs are infested withC.felisfleas on SD -7 followed by removal counts on SD -6 (24 ± 2 hours after flea infestation) for randomization purposes.

[0172] On SD 0, all dogs assigned to the treatment group are treated with a given dose of Modoflaner. Dogs assigned to the control group are not treated (“sham-dosed”) and serve as negative controls. Clinical assessments, including specific health observations are conducted pre-Modoflaner administration and at 1, 2, 3, and 4 hours after Modoflaner administration on SD 0, on SD 1 at 24 hours and on SD 2 at 48 hours.

[0173] For pharmacokinetic analysis, blood is collected from all dogs in the treatment group prior to Modoflaner administration on SD -1, on SD 0 (2, 6 and 24 hours after Modoflaner administration), on SD 2 (48 hours after Modoflaner administration), SD 3 (72 hours after Modoflaner administration); SD 4 (96 hours after Modoflaner administration) and SDs 7,14, 21, 28, 42, 56, 70, 84, 90, 104, 120 and 130.

[0174] Dogs are artificially infested with 25 pairs of viable, adult, unfed ticks or 100 viable, adult, unfedC.felisfleas. Infestation is considered successful if at least 25 to 50% of the ticks and at least 50% of the fleas can be recovered from the control animals on the days of removal and counting.

[0175] 48 hours after artificial infestation, ticks are removed and counted and final tick count is conducted 72 hours after infestation. Ticks will be found by direct observation, following parting of the hair coat and palpation. Male and female ticks will be counted. Following the tick counts and removal, each dog will be combed to ensure that all ticks were counted and removed. Ticks removed are recorded as live or dead. Acaricidal effect is considered positive if the tick is dead (attached or not to the dog).

[0176] Fleas will be removed and counted 24 hours after Modoflaner administration, and 24 hours after each further infestations. During combing a fine-toothed flea comb will be used to recover fleas present in the animal’s fur. The method of combing will be by several strokes of the comb in each body area of the animal, each time moving in the same direction, following the pattern of the hair coat. After completion of the combing procedure for all body areas, the whole procedure will be repeated once more so that all areas will be combed a minimum of 2 times. If fleas are still present, the combing procedure will be continued until no live fleas are found.

[0177] The efficacy against ticks and fleas is calculated for the Modoflaner group at each assessment day according to the formulas given below (with consideration of available guidelines, EMEA / CVMP / 005 / 2000-Rev.3).

[0178] Efficacy against ticks is calculated as follows:

[0179] Efficacy (%) against ticks = 100 x (Mc – Mt) / Mc, where:

[0180] Mc = Mean number of live ticks (attached or not) on dogs in the control group at a specific time point.

[0181] Mt = Mean number of live ticks (attached or not) on dogs in the IVP groups (treatment group) at a specific time point.

[0182] Efficacy against fleas will be calculated according to the following formula:

[0183] Efficacy (%) against fleas = 100 x (Mc – Mt) / Mc, where:

[0184] Mc = Mean number of live fleas on dogs in the negative control group (group 5) at a specific time point.

[0185] Mt = Mean number of live fleas on dogs in the IVP groups (groups 1, 2, 3 or 4) at a specific time point.

[0186] Next, the relationship between the efficacy recorded against an ectoparasite and the Modoflaner plasma concentration is established from the obtained data. A “cut-off” value can be set at the desired degree of control (Efficacy, for example 90%) and the corresponding plasma concentration of Modoflaner can be derived (using a regression curve, or tendency slope). An example is shown inforAmblyommaamericanum.

[0187] From this study, it is also possible to determine the duration of efficacy for a given dosage form. An example is given inforAmblyommaamericanum, in the case of a treatment group of dogs treated with 45 mg / kg of crystalline form IV of Modoflaner in a hard tablet.

[0188] Example 3: Evaluation of pharmacokinetics and tick-killing efficacy ofModoflaneragainst Rhipicephalus (Boophilus)microplustick in experimentally-infected bovines.

[0189] The purpose of this study was to assess the tick-killing efficacy of Modoflaner againstRhipicephalus(Boophilus)microplustick in bovines experimentally infested through a traditional and modified stable test. Moreover, the pharmacokinetic parameters of the test formulation, an oily suspension containing Modoflaner, were assessed.

[0190] 35 healthyBos taurusandBos indicusmales and females (breed Dutch) aged over 6 months and weighing between 80 and 250 kg were acclimatized, of which 28 bovines were randomly assigned to 4 different groups:Experimental groupTotal of animalsTest formulation (mg / kg of active ingredient)Negative Control Group (NCG)7Placebo, no active ingredientTreated Group 1 (TG1)7Modoflaner 2.5 mg / kg, subcutaneousTreated Group 2 (TG2)7Modoflaner 5 mg / kg, subcutaneousTreated Group 3 (TG3)7Modoflaner 15 mg / kg, subcutaneous

[0191] The test formulation was a Modoflaner solution in N-methyl pyrrolidone (about 16%w / w).

[0192] Female tick counts were performed at D-3, D-2, and D-1 (pre-treatment) then daily from D+1 to the ast day of the study (post-treatment).

[0193] For efficacy assessment, the animals in the different groups were infested before treatment at D0 with 2500 to 5000 R. microplus larvae aged 14 days old, from a strain resistant to pyrethroids, avermectins, and organophosphates and after treatment at D0 with 5000 larvae, divided into 2 installments of 2500 larvae for each day according to the following schedule:Experimental groupPre-treatment infestations*Post-treatment infestationsTreated Group 1 (TG1)D-25, D-23, D-21, D-19, D-17, D-15, D-13, D-11, D-9, D-7, D-5, D-3, and D-1D+6, D+7, D+13, D+14, D+20, D+21, D+27, D+28, D+34, D+35, D+41, D+42, D+48, D+49, D+55, D+56, D+62, D+63, D+69, D+70, D+76, D+77, D+83, D+84, D+90, D+91, D+97, D+98, D+104, D+105, D+111, D+112 D+118, D+119, D+125, D+126, D+132, D+133, D+139, D+140, D+146, D+147, D+153, D+154, D+160, D+161, D+167, D+168, D+174, D+175, D+181, D+182, D+188, D+189, D+195, D+196, D+202, D+203, D+209, D+210, D+216, D+217, D+223, and D+224Treated Group 2 (TG2)Treated Group 3 (TG3)Negative Control Group (NCG)Tick-killing efficacy was assessed as follows:

[0194] To estimate the treatment efficacy, the means of recovered female ticks from animals fromTreated Groups 1, 2, and 3 (GT1, GT2, and GT3)was compared to means from animals in theNegative Control Group (NCG).

[0195] The following formula was used:

[0196]

[0197] Where:

[0198] Ta = mean number of female ticks from animals in Treated Groups 1, 2, and 3 (GT1, GT2, and GT3), at the treatment day (D+1 to D+224);

[0199] Tb = mean number of female ticks from animals in Treated Groups 1, 2, and 3 (GT1, GT2, and GT3) within 3 days prior to treatment (D-3, D-2, and D-1);

[0200] Ca = mean number of female ticks recovered from animals from Negative Control Group (NCG) at the treatment day (D+1 to D+224)

[0201] Cb = mean number of female ticks recovered from animals in Negative Control Group (NCG) within 3 days prior to treatment (D-3, D-2, and D-1).

[0202] Residual efficacy levels were estimated by using the mean of detached female ticks after each post-treatment infestation, both from theNegative Control Group (NCG)and fromTreated Groups 1, 2, and 3 (GT1, GT2, and GT3), between the period of 18 and 24 days after each re-infestation, a window that corresponds to the width of the female tick fall period after a single infestation (21 days ± 3).

[0203] The indication of the residual protection period against re-infestation were expressed in weekly intervals. The following formula was used:

[0204]

[0205] Where:

[0206] MedGC = mean female ticks detached in the Negative Control Group (NCG) in the period between 18 and 24 days after each re-infestation.

[0207] MedGT = mean of female ticks detached in Treated Groups 1, 2, and 3 (GT1, GT2, and GT3) between 18 and 24 days after each re-infestation.

[0208] A statistical analysis was then performed as follows:

[0209] Statistical analysis was performed by comparing mean female tick counts among theNegative Control Group (NCG)andTreated Groups 1, 2, and 3 (GT1, GT2, and GT3). Initially, the data normality assessment will be performed through the Shapiro-Wilk test. If the data is parametric, a one-criterion ANOVA test will be used. If that data is non-parametric, data will become parametric by Log(10+1) transformation and a one-criterion ANOVA test will then be applied. All analyses will be performed using the statistical computing software BioStat 5.0. The confidence level taken into consideration will be 95% (p≤0.05).

[0210] The results are presented into.

[0211] Briefly, it can be seen that at the 2.5 mg / kg dose, Modoflaner provides control of a Rhipicephalus (Boophilus) microplus infestation up to day 147 (more than 4 months). A control above 90 % is observed until day 91 (3 months).

[0212] When the dose is 5 mg / kg and 15 mg / kg, Modoflaner provides more than 90% control of a Rhipicephalus (Boophilus) microplus infestation up to day 168 (about 5 months and a half) and up to 259 days for 15 mg / kg.

[0213] Example4: Evaluation of tick-killing efficacy ofModoflaneragainstAmblyommaamericanumin experimentally-infected cats.

[0214] The efficacy evaluation on cats has been conducted in a similar way to example 2, with a 30 mg / kg dose.

[0215] The results of the efficacy study are provided in the following table:TimeD0D7D28D56D70D84D98Efficacy (%)090.910099.798.899.7100

[0216] As shown in this table, Modoflaner provides effective protection against Amblyomma americanum, the tick species least susceptible to Modoflaner, for more than 3 months at a 30 mg / kg dose.

[0217] The study was prolongated up to 168 days in order to determine if the Modoflaner provides an effective protection against Amblyomma americanum for more than 3 months at a dose of 30 mg / kg in cats.

[0218] The results are shown in the following table, representing the ticks count at 72h after treatment and infestation with Amblyomma americanum:TimeD112D126D140D154D168Efficacy (%)96.896.097.494.692.3

[0219] As shown in this table, Modoflaner provides effective protection against Amblyomma americanum (the tick species the least susceptible to Modoflaner) at least until D168, i.e. at least for 24 weeks (i.e. 6 months), at a 30 mg / kg dose.

[0220] Example5: Evaluation of tick-killing efficacy ofModoflaneragainstDermacentor variabilis and Ixodesricinusin experimentally-infected cats.

[0221] The study from Example 4 also included the determination of the effective protection provided by Modoflaner against two other ticks species (Dermacentor variabilis and Ixodes ricinus) in cats after at least 6 months of administration by subcutaneous injection at a dose of 30 mg / kg.

[0222] Cats were infested with Ixodes ricinus ticks at D35 and D189. Cats were also infested with Dermacentor variabilis ticks at D181.

[0223] Ticks were counted at 48 hour after infestation for Dermacentor variabilis and Ixodes ricinus at D35, and at 24 hour post infestation at D188 with Ixodes Ricinus.

[0224] The results obtained represent the percentage of efficacy of Modoflaner against each species of ticks.

[0225] The percentages of efficacy determined for the Ixodes ricinus infestation at D35 and D189 were both 100%. Therefore, Modoflaner provides effective protection against Dermacentor variabilis ticks at least until D189, i.e. for at least 26 weeks.

[0226] The percentage of efficacy determined for Dermacentor variabilis infestation at D182 was 100%. Therefore, Modoflaner provide effective protection against Dermacentor variabilis ticks at least until D182, i.e. for at least 26 weeks.

[0227] It was therefore shown that Modoflaner provides effective protection against Dermacentor variabilis and Ixodes ricinus tick infestations for at least 6 months (respectively at least until 26 and 27 weeks) when administered to cat by subcutaneous injection at a 30 mg / kg dose.

[0228] Example6: Evaluation offlea-killing efficacy ofModoflanerin experimentally-infected cats.

[0229] The study according to Example 4 and 5 also included an evaluation of the effective protection provided by Modoflaner against fleas in cats after at least 6 months of administration by subcutaneous injection at a dose of 30 mg / kg.

[0230] At D188, cats were infested with Ctenocephalides felis fleas. The number of fleas was counted 24 hour post infestation.

[0231] At D189, the percentage of efficacy of the Modoflaner against fleas was 100%.

[0232] Therefore, Modoflaner provides effective protection against fleas at least until D189. The effective protection is obtained for at least 27 weeks.

[0233] Example 7 : Evaluation of thekillingofCtenocephalidesfelisfleasand early prevention against Dermacentor variabilis tickbyModoflaneradministered by subcutaneous injectionto cats

[0234] The objective of the study was to confirm the efficacy of two Modoflaner formulations (aqueous and oily formulations) at a dose of 30 mg / kg when administered subcutaneously against Dermacentor variabilis ticks and Ctenocephalides felis fleas on experimentally infested cats.

[0235] This study was an efficacy study using (minimum dose of 0.2 mL / kg or 30 mg modoflaner / kg) of Modoflaner against ticks (D. variabilis) and fleas (C. felis) on 3 groups of eight cats over a period of two weeks.

[0236] Two Modoflaner formulations were tested:Oily suspension comprising Modoflaner (15%), ethyl oleate, Palmstar and stearic acid.Aqueous suspension comprising Modoflaner (15%), blanose carboxymethylcellulose, Kolliphor P188, benzyl alcohol and water for injection.

[0237] The 24 cats included in the study were randomly allocated to three groups : Group 1 : sham administration as Negative control, Group 2 : oily formulation administration, Group 3 : aqueous formulation administration.

[0238] On Day 0, all cats assigned to groups 2 and 3 received the Modoflaner formulation (oily formuation in Group 2 and aqueous formulation in Group 3). The volume of the products administered was calculated according to the cat’s individual body weight.

[0239] Cats were infested with approximately 100 (± 10) viable, adult, unfed C. felis fleas on Days -1, and 2. On Day 1 (D0+24h), an in-situ flea count was performed, and any surviving fleas were re-infested immediately after completing the count. Removal counts of fleas were performed on Days -6, 2, and 3.

[0240] Cats were infested with approximately 50 viable, adult, unfed D. variabilis ticks on Day 10 with an approximate sex ratio of 25 females / 25 males. Ticks were removed and counted at 48 hour after infestation at D12.

[0241] Results on fleas: The oily suspension demonstrated 99.1% efficacy on Day 1 (D1) and 100% efficacy on Days 2 and 3 (D2, D3). Similarly, the aqueous suspension showed 94.9% efficacy on D1 and 100% efficacy on D2 and D3. These results confirm that Modoflaner effectively treats fleas regardless of the formulation used and provides early preventive action from Day 2 onward.

[0242] Results on ticks: The oily suspension (Group 2) achieved 99.0% efficacy at 48 hours on Day 12 (D12) and the aqueous suspension (Group 3) showed 87.0% efficacy at 48 hours on D12. These results indicate that Modoflaner provides early preventive action against Dermacentor variabilis ticks in the days following administration.

[0243] Example8 : Evaluation of theflea-killing efficacy againstCtenocephalidesfelisfleas andtick-killingagainstAmblyommaamericanumandDermacentorreticulusticksofModoflaneradministered by subcutaneous injectionto dogs

[0244] The objective of this study was to assess the onset of efficacy of two formulations containing modoflaner as the active ingredient against induced infestations of adult stage Ctenocephalides felis, as well as an early prevention and efficacy against adult stage Amblyomma americanum and Dermacentor reticulatus following a single subcutaneous administration at a dose rate of 0.1 mL / kg body weight to dogs.

[0245] 18 dogs were randomly allocated to 3 groups (sham administration, and two treatment groups), based on the total counts of live fleas, obtained one day (D-6) after an initial C. felis flea infestation conducted on Day -7.

[0246] On Day 0, all dogs assigned to a treatment received their respective Modoflaner formulation :Group 2 : Oily suspension comprising Modoflaner (15%), ethyl oleate, Palmstar and stearic acid.Group 3 : Aqueous suspension comprising Modoflaner (15%), blanose carboxymethylcellulose, Kolliphor P188, benzyl alcohol and water for injection.

[0247] The volume of the products administered was calculated according to the dog’s individual body weight. Dogs assigned to group 1 were sham treated and served as a Negative Control (NC).

[0248] During the study, dogs were infested with approximately 100 (± 10) viable, adult, unfed C. felis fleas on Days -7, -1, 2 and 7. Fleas were removed and counted 24 hour after flea infestation or treatment administration on Days -6, 1, 2, 3, and 8. Fleas removed and counted on Day 1 were re-infested on the same animal after quantification.

[0249] Dogs were also co-infested with approximately 50 (± 4) viable, adult, unfed A. americanum and D. reticulatus ticks (~ 25 male: 25 female) on Day 10. In situ tick counts for both species were performed on Day 12 (approximately 48 h post- infestation). Thereafter, both species of ticks were removed and counted on Day 13 (72h post-infestation).

[0250] Results on fleas : Both formulations demonstrated high efficacy (>96%) at all assessed time points (Days 1, 2, 3, and 8) based on LS mean flea counts. Specifically, the oily formulation (Group 2) achieved 99.1% efficacy on Day 1 (D1), 100% on D2, 99.8% on D3, and 100% on D8. Similarly, the aqueous formulation (Group 3) showed 96.2% efficacy on D1, 100% on D2, 100% on D3, and 100% on D8. Efficacy against fleas was therefore observed on the first day and persisted until the final assessment time point (Day 8) for both formulations.These results demonstrate that the administration of Modoflaner by subcutaneous injection provides efficacy in the treatment as well as control of fleas infestations from the first day of administration through Day 8.

[0251] Results on ticks :

[0252] Results on Amblyomma americanum ticks: On Day 12 (D12), efficacy was 98.9% for the oily formulation (Group 2) and 100% for the aqueous formulation (Group 3). On day 13 (D13), efficacy was 99.1% for the oily formulation (Group 2) and remained 100% for the aqueous formulation (Group 3). These results confirm that subcutaneous administration of Modoflaner effectively controls A. americanum tick infestations in the early days following treatment.

[0253] Results on Dermacentor reticulatus ticks: Both formulations demonstrated high efficacy (>97%) at all assessed time points. On Day 12 (D12), both oily formulation (Group 2) and aqueous formulation (Group 3) achieved 100% efficacy. The same results were observed on Day 13 (D13). These findings confirm that subcutaneous administration of Modoflaner provides effective early control of D. reticulatus tick infestations.

[0254] In conclusion, both formulations of the modoflaner 15% solution (oily and aqueous suspensions at a dose rate of 0.1 mL / kg) demonstrated an early prevention against A. americanum and D. reticulatus ticks (≥ 90%) and treatment (≥ 95%) as well as early prevention against C. felis fleas after a single subcutaneous administration.

Claims

Modoflaner for use in controlling an ectoparasite infestation on a mammal for at least 3 months, wherein a single dose of Modoflaner ranging from 1 mg / kg to 400 mg / kg, notably from 1 mg / kg to 250 mg / kg, bodyweight of said mammal is administered parenterally to said mammal.Modoflaner for use according to claim 1, wherein the single dose of Modoflaner ranges from 2 mg / kg to 200 mg / kg of bodyweight of the mammal.Modoflaner for use according to one of the preceding claims, wherein the single dose of Modoflaner provides control of an ectoparasite infestation on the mammal for at least 4 months, preferably at least 5 months, more preferably at least 6 months.Modoflaner for use according to any of the preceding claims, wherein the single dose of Modoflaner provides more than 50%, preferably more than 90% control of the ectoparasite infestation.Modoflaner for use according to any of the preceding claims, wherein the ectoparasite is a tick, preferably selected from the group consisting in Ixodes ricinus, Ixodes scapularis, Rhipicephalus sanguineus, Dermacentor variabilis, Dermacentor Recitulatus, Rhipicephalus (Boophilus) microplus and Amblyomma americanum or a flea, preferably selected from the group consisting in Ctenocephalides felis and Ctenocephalides canis.Modoflaner for use according to any of the preceding claims, wherein the mammal is a companion animal, preferably selected from the group consisting in a dog, a cat, a ferret, a rabbit, a guinea pig and a horse, preferably a dog.Modoflaner for use according to any of the preceding claims, wherein the mammal is a dog, said dog having a plasma concentration of Modoflaner that is below 400 ng / ml after 48 hours when administered a dose of 45 mg / kg orally.Modoflaner for use according to any of claims 1 to 5, wherein the mammal is a domestic livestock animal, preferably selected from the group consisting in cattle such as cows, beef, heifers and bulls; horses; donkeys; pigs; sheeps; and goats, preferably cattle.Modoflaner for use according to anyone of the preceding claims, wherein Modoflaner is administered intramuscularly, subcutaneously or intraveneously.Modoflaner for use according to the preceding claim, wherein Modoflaner is administered subcutaneously.Modoflaner for use according to claim 1, wherein:the mammal is a dog, the dose of Modoflaner is at least 10 mg / kg, preferably at least 15 mg / kg, and the dose provides more than 90% control of the ectoparasite infestation for at least 6 months, orthe mammal is a cat, the dose of Modoflaner is at least 20 mg / kg, preferably at least 30 mg / kg, and the dose provides more than 90% control of the ectoparasite infestation for at least 6 months, orthe mammal is cattle, the dose of Modoflaner is at least 5 mg / kg and the dose provides more than 90% control of the ectoparasite infestation for at least 6 months.Modoflaner for use according to anyone of the preceding claims, wherein Modoflaner is administered in combination with an endoparasiticide, preferably in the same composition.Modoflaner for use according to the preceding claim, wherein the endoparasiticide is selected from the group consisting in macrocyclic lactones, benzimidazoles, salicylanilides, substituted phenols, pyrimidines, imidazothiazoles, cyclooctadepsipeptides and tetrahydropyrimidines.Modoflaner for use according to the preceding claim, wherein the endoparasiticide is selected from the group consisting in macrocyclic lactones, benzimidazoles, salicylanilides, substituted phenols, pyrimidines, imidazothiazoles, cyclooctadepsipeptides and tetrahydropyrimidines.Modoflaner for use according to the preceding claim, wherein the endoparasiticide is a macrocyclic lactone selected from the group consisting in ivermectin, moxidectin, milbemycin oxime, selamectin, emamectin, eprinomectin and doramectin