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WO2021122521A1 - Composition pour lutter contre les poux chez la volaille - Google Patents

Composition pour lutter contre les poux chez la volaille Download PDF

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Publication number
WO2021122521A1
WO2021122521A1 PCT/EP2020/086111 EP2020086111W WO2021122521A1 WO 2021122521 A1 WO2021122521 A1 WO 2021122521A1 EP 2020086111 W EP2020086111 W EP 2020086111W WO 2021122521 A1 WO2021122521 A1 WO 2021122521A1
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WO
WIPO (PCT)
Prior art keywords
isoxazoline compound
isoxazoline
cfs
lice
compound
Prior art date
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Ceased
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PCT/EP2020/086111
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English (en)
Inventor
Nilce Maria SOARES
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Intervet International BV
Intervet Inc
Original Assignee
Intervet International BV
Intervet Inc
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Priority to BR112022011046A priority Critical patent/BR112022011046A2/pt
Priority to MX2022007309A priority patent/MX2022007309A/es
Publication of WO2021122521A1 publication Critical patent/WO2021122521A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • the present invention relates to the treatment or prevention of parasitic arthropod infestations of animals.
  • Infestations caused by lice in the egg industry have generated economic losses. The consequences include drops in egg production, skin irritation, weight loss and decreased feed intake.
  • Chickens are less commonly infested with Menopon gallinae (on feather shafts), Lipeurus caponis (mainly on the wing feathers), Cuclotogaster heterographus (mainly on the head and neck), Goniocotes gallinae (very small, in the fluff), Goniodes gigas (the large chicken louse), Goniodes dissimilis (the brown chicken louse), Menacanthus cornutus (the body louse), Uchida pallidula (the small body louse), or Oxylipeurus dentatus. Turkeys may also be infested with Chelopistes meleagridis (the large turkey louse), and Oxylipeurus polytrapezius (the slender turkey louse).
  • Conventional methods include chemicals that are applied as sprays, coarse or solid stream, mist, fog, dusts and/or as wash solutions to empty or populated animal premises and their environment.
  • Other control measures include dusting or spraying the infested poultry animals with powdered or liquid synthetic organic chemicals formulations or adding the powdered synthetic organic chemicals to the litter or dust bath.
  • synthetic organic chemical groups that have been used in such chemical treatment include pyrethroids, organophosphates, carbamates, spinosad, and the like.
  • Lice are best controlled on caged chickens or turkeys by spraying with pyrethroids, carbaryl, coumaphos, malathion, or stirofos. Birds on the floor are more easily treated by scattering carbaryl, coumaphos, malathion, or stirofos dust on the litter. Using such methods eggs are not killed, so insecticide treatment should be repeated after 10 days.
  • the invention provides a new method and composition to control chewing/ biting lice of poultry.
  • the present invention relates to use of an isoxazoline compound of Formula (I)
  • R 1 is halogen, CF 3 , OCF 3 , CN, n is an integer from 0 up to and including 3, preferably 1 , 2 or 3,
  • R 2 is Ci-C 3 -haloalkyl, preferably CF 3 or CF2CI,
  • T is a 5 to 12 membered mono or bicyclic ring system, which is optionally substituted by one or more radicals Y,
  • Q is X-NR 3 R 4 , NR 5 -NR 6 -X-R 3 , X-R3 ora 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;
  • X is CH 2 , CH(CH 3 ), CH(CN), CO, CS,
  • R 3 is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonyl- methyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylamino- carbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, halo- ethylaminocarbonylcyclopropyl, al
  • R 4 is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxy- methyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethyl- aminocarbonylethyl;
  • R 5 is hydrogen, alkyl or haloalkyl
  • R 6 is hydrogen, alkyl or haloalkyl; or R 3 and R 4 together form a substituent selected from the group consisting of: an or a salt or solvate thereof for the manufacture of a medicament for the treatment or protection of poultry from lice infestation after oral administration of a composition comprising an effective amount of at least one isoxazoline compound of Formula (I).
  • the invention provides a composition comprising an effective amount of such compound of Formula (I) or a salt or solvate thereof, when used for the elimination of lice infestations of laying hens and/ or for the protection of laying hens from infestation by lice, wherein the composition is administered orally.
  • isoxazoline compound of formula (I) is fluralaner.
  • composition is administered 2 times 7 or 14 days apart.
  • Another embodiment is a method of treating a flock of poultry that are diagnosed or suspected to be infested by lice, comprising administering orally an effective amount of at least one isoxazoline compound of Formula (I) or a salt or solvate thereof to the animals via the drinking water.
  • Another embodiment is a method of protecting a flock of poultry from lice infestation comprising orally administering an effective amount of at least one isoxazoline compound of Formula (I) or a salt or solvate thereof via the drinking water.
  • the inventors of the current invention discovered that lice infestations of poultry animals, especially laying hens can be treated or prevented by administering an effective amount of an isoxazoline compound of formula (I) orally, especially via the drinking water.
  • Such method is effective in both treating existing lice infestations and preventing new lice infestation of animals; b) the resistance breaking properties of such isoxazoline compounds are very favorable; c) such method is more convenient than prior art application of other compounds in premises, because such method can be used while the poultry animals occupy the premises e.g. in case of laying hens during the laying period, and such method does not require specific safety equipment for the administration (as e.g. required for premise application of synthetic organic chemicals in poultry houses); d) such method is more convenient than prior art application on animals (e.g. spray application or dust) because it avoids labor intensive techniques and avoids stress in the poultry animals during such prior art methods.
  • prior art application on animals e.g. spray application or dust
  • a further advantage of the administration of an isoxazoline compound via drinking water to laying hens is that this allows adjusting the dosage and the administration scheme, so that while still being effective, no discarding of eggs would be necessary because of the very low concentration of the isoxazoline compound, especially fluralaner in the eggs.
  • This uncritical low concentration of fluralaner in eggs allows using eggs for human consumption from laying hens that have been treated with isoxazoline compounds (especially fluralaner).
  • isoxazoline compounds offers a number of benefits compared to the existing methods of controlling lice in poultry.
  • the administration of an effective amount of an isoxazoline compound via the drinking water to lice infested animals increases egg production and improves egg size and egg quality compared to infested, but not treated animals. It can further improve reproduction performance in breeding stocks.
  • the current invention would be a breakthrough in the control of avian lice control, allowing effective control/ potentially elimination of lice from poultry flocks.
  • the inventors of the current invention found that by drinking water administration of one or more of the isoxazoline compounds as defined above to poultry animals, lice, including chewing lice of poultry animals can be effectively controlled and both existing infestation of the poultry animals can be treated and re-infestation of the animals from the environment can be prevented.
  • the drinking water administration of isoxazoline compounds as defined above, especially of fluralaner, in a dosage that is effective to treat or prevent arthropod infestation can be used in laying hens during the egg production period because no discharging of eggs from animals for human consumption would be necessary.
  • Lice are common external parasites of birds. They belong in the order Mallophaga, the chewing lice. More than 40 species have been reported from domesticated fowl. Many species of bird lice exist, but only a few are commonly seen. Chicken lice are e.g. chicken body louse ( Menacanthus stramineus) and shaft louse ( Menopon gallinae). Lice will transfer from one bird species to another if these hosts are in close contact. Lice are not highly pathogenic to mature birds, but louse-infected chicks may die. Clinical evidence indicates that lice may irritate nerve endings, thus, interfering with the rest and sleep. Lousiness frequently accompanies manifestations of poor health such as internal parasitism, infectious disease, and malnutrition, as well as poor sanitation.
  • treating or “treat” or “treatment” is intended the application or administration of an isoxazoline compound or composition to animal that has been diagnosed to have a parasitic lice infestation for the eradication of the parasite infestation or the reduction of the number of parasites, infesting the animal. It is a medical care given to animals infested with ectoparasites
  • the effect can be e.g. ovicidal, larvicidal and/or adulticidal or a combination thereof.
  • the effect can manifest itself directly, i.e. killing the parasites either immediately or after some time has elapsed, for example when molting occurs, or by destroying their eggs, or indirectly, e.g. reducing the number of eggs laid and/or the hatching rate.
  • “Protection” means that a new infestation of the poultry animal a poultry mob or flock with lice parasites is prevented by killing adult parasites and any development/larval stages, that are able to infest the host, before infestation of the host or, by killing or inhibiting the parasites when they infest an animal that has been treated with an isoxazoline compound as described before or preventing generation of offspring of the parasites e.g. reducing the number of eggs laid and/or the hatching rate.
  • Prophylactic period means the time, expressed in days or weeks after the treatment, that a veterinary test product will prevent the ectoparasite re-infestation of the animal hosts. Sometimes referred to as the prophylactic period or the persistent efficacy period (WAAVP guidelines 2006)
  • an “active pharmaceutical ingredient “(or active ingredient, or pharmaceutically active ingredient or pharmaceutically acceptable active ingredient) is a substance used in a pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in humans or animals.
  • an “effective amount,” is the amount or quantity of an isoxazoline compound as described above that is required to treat or prevent parasitic chewing lice infestations of animals, i.e. to alleviate or reduce lice numbers on an animal, and/or to inhibit the development of parasite infestations on an animal.
  • This amount is readily determined by observation or detection of the parasite numbers or eggs on the animal both before and after administering an isoxazoline compound as described above to such animals, e.g. the parasite count is reduced, after a first administration, by 5% to about 100%, preferably more than 50%, more than 70%, more than 90%, more than 95%, more than 99.5 % or 100%.
  • the lice count is reduced by 100%, i.e. the effective amount results in elimination of all lice on a treated animal, i.e. that no chewing lice are found when the poultry animals are investigated as described above.
  • the administration allows to completely inhibit or kill the lice and preferably all viable eggs present on the animal.
  • Factors affecting the effective amount may include, for example, the parasite species to be treated and the development stages of the parasites, the type (e.g. species and breed, age, and condition of the infested animals; the environmental conditions (temperature, humidity), pharmacological considerations, such as the activity, efficacy, potency, selectivity, pharmacokinetic, and toxicologic profiles of the particular isoxazoline compound administered; and whether the isoxazoline compound being administered is part of a combination of active ingredients.
  • the preferred amount of the compound according to this invention can vary.
  • Pests animals are bird animals that are kept for laying eggs or producing meat such as fowl animals, ducks, geese, turkey, pheasants etc.
  • “Fowl animals” are chickens ( Gallus gallus domesticus).
  • the term "Laying hen” or “layer” is a common term for adult female chickens ( Gallus domesticus), that are primarily kept for laying eggs. Such eggs are generally used for consumption as human food.
  • the term “laying hens” in this application includes breeding stocks that are kept for producing eggs from which future laying hens hatch.
  • Replacement chickens also known as grower or pullets, are female chicken animals aged 12- 17 weeks. The term “replacement” means that they will be replacing older laying hens destined to be removed at the end of their laying cycle.
  • “Broilers” are a gallinaceous domesticated fowl, bred and raised specifically for meat production.
  • a lice infestation is diagnosed by inspecting the poultry animals especially the animals suspected to be infested by lice with the naked eye.
  • the isoxazoline compounds for use in the current invention are known in the art and these compounds and their use as antiparasitics are described, for example, in US patent application US 2007/0066617, and International Patent applications WO 2005/085216, WO 2007/079162, WO 2009/002809, WO 2009/024541 , WO 2009/003075, WO 2010/070068 and WO 2010/079077, the disclosures of which, as well as the references cited herein, are incorporated by reference.
  • This class of compounds is known to possess excellent activity against blood sucking ectoparasites, i.e. parasitic insect and acarids, such as ticks and fleas.
  • composition, method or use according to the invention comprises an isoxazoline compound of the Formula (I)
  • R 1 is halogen, CF 3 , OCF 3 , CN, n is an integer from 0 up to and including 3, preferably 1 , 2 or 3,
  • R 2 is CrC 3 -haloalkyl, preferably CF 3 or CF2CI,
  • T is a 5 to 12 membered mono or bicyclic ring system, which is optionally substituted by one or more radicals Y,
  • Q is X-NR 3 R 4 , NR 5 -NR 6 -X-R 3 , X-R3 ora 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;
  • X is CH 2 , CH(CH 3 ), CH(CN), CO, CS,
  • R 3 is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonyl- methyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylamino- carbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, halo- ethylaminocarbonylcyclopropyl, al
  • Z A is hydrogen, halogen, cyano, halomethyl, preferably CF3;
  • R 4 is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxy- methyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethyl- aminocarbonylethyl;
  • R 5 is hydrogen, alkyl or haloalkyl
  • R 6 is hydrogen, alkyl or haloalkyl; or R 3 and R 4 together form a substituent selected from the group consisting of: or a salt or solvate thereof.
  • T is selected from
  • the radical Y is preferably hydrogen, halogen, methyl, halomethyl, ethyl or haloethyl.
  • Q in Formula (I) is selected from Q-9 wherein R 3 , R 4 , X and Z A are as defined above and Z B is Preferred compounds of Formula (I) are listed in Table 1:
  • the isoxazoline compound is represented by Formula (II) Formula (II) wherein
  • R 1a , R 1b , R 1c are independently from each other hydrogen, Cl or CF 3 .
  • R 1a and R 1c are Cl or CF 3 and R 1b is hydrogen,
  • Y is methyl, bromine, Cl, F, CN or C(S)NH2 and Q is as described above.
  • R 3 is H and R 4 is -CH 2 -C(0)-NH-CH 2 -CF 3 , -CH 2 -C(0)-NH-CH 2 -CH 3 , -CH 2 -CH 2 -CF 3 or -CH 2 -CF 3 .
  • the isoxazoline compound is selected from fluralaner, afoxolaner, sarolaner, lotilaner and tigolaner.
  • the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-/ ⁇ /- [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3). This compound is also known as fluralaner.
  • the isoxazoline compound is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2, 2, 2-trifluoroethyl)amino]ethyl]-1 -naphthalene- carboxamide (CAS RN 1093861 -60-9).
  • This compound is also known as a 4-[5-(5-chloro-a,a,a- trifluoro-m-tolyl)-4,5-dihydro-5-(trifluoromethyl)-1 ,2-oxazol-3yl]-/ ⁇ /-[2-oxo-2-[(2,2,2- trifluoroethylamino]ethyl]naphthalene-1-or afoxolaner.
  • Afoxolaner is for example disclosed in WO 2007/079162.
  • the isoxazoline compound is 1-(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 3'H-spiro[azetidine-3, 1 '-isobenzofuran]-1 -yl)-2-(methylsulfonyl)ethan-1 -one, preferably 1 -(5'- ((5S)-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H- spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one (CAS RN: 1398609-39- 6).
  • the isoxazoline compound is 3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]thiophene-2-carboxamide, preferably methyl-N-(2- oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[(5S)-5(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl]thiophene-2-carboxamide (CAS RN: 1369852-71-0). This compound is known as lotilaner.
  • the isoxazoline compound is 2-chloro-/ ⁇ /-(1-cyanocyclopropyl)-5-[1-[2-methyl-5-(1, 1,2,2, 2-pentafluoroethyl)-4- (trifluoromethyl)pyrazol-3-yl]pyrazol-4-yl]benzamide (CAS RN 1621436). This compound is known as tigolaner.
  • the isoxazoline compound is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N- [(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928789-76-8).
  • the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan- 3-yl)benzamide (CAS RN 1164267-94-0) that was disclosed in WO 2009/0080250.
  • the isoxazoline compound is 5-[5-(3,5-dDichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N- [2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]- 2-thiophenecarboxamide (CAS RN 1231754-09-8) that was disclosed in WO 2010/070068.
  • fluralaner corresponding to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl- 4,5-dihydroisoxazol-3-yl]-2-methyl-/ ⁇ /-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide).
  • the isoxazoline compounds may exist in various isomeric forms.
  • a reference to an isoxazoline compound always includes all possible isomeric forms of such a compound.
  • a compound structure that does not indicate a particular conformation is intended to encompass compositions of all the possible conformational isomers of the compound, as well as compositions comprising fewer than all the possible conformational isomers.
  • the compound is a chiral compound. In some embodiments, the compound is a non-chiral compound.
  • the method (or use) of this invention comprises to use racemic mixtures, for example, equal amounts of the enantiomers of such isoxazoline compounds as described above.
  • the method of this invention includes isoxazoline compounds that are enriched compared to the racemic mixture in an enantiomer of Formula (I). Also included are the essentially pure enantiomers of such isoxazoline compounds.
  • enantiomeric excess which is defined as (2x-l)-100 %, where x is the mole fraction of the dominant enantiomer in the mixture (e.g., an ee of 20 % corresponds to a 60:40 ratio of enantiomers).
  • compositions for use in the current invention have at least a 50 % enantiomeric excess; more preferably at least a 75 % enantiomeric excess; still more preferably at least a 90 % enantiomeric excess; and the most preferably at least a 94 % enantiomeric excess of the more active isomer.
  • enantiomerically pure embodiments of the more active isomer Isoxazoline compounds as described above can comprise additional chiral centers. The method of this invention comprises racemic mixtures as well as enriched and essentially pure stereo configurations at these additional chiral centers.
  • the isoxazolines comprise a chiral (or asymmetric) carbon at the 5-position of the isoxazoline ring.
  • the chiral carbon has a left-handed (or "S" or "sinister”) configuration.
  • S left-handed
  • the chiral carbon has a right-handed (or "R” or "rectus”) configuration.
  • R right-handed
  • An example of such a compound is:
  • the active enantiomer (s)-fluralaner is used.
  • the active enantiomer (s)-afoxolaner INN Esafoxolaner
  • an isoxazoline structure that does not indicate a particular conformation is intended to encompass compositions of all the possible conformational isomers of the isoxazoline, as well as compositions comprising fewer than all ⁇ e.g., just one of) the possible conformational isomers.
  • isoxazoline compound in this specification includes enantiomers, salts and solvates thereof that can be produced by conventional methods.
  • salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • solvate is used herein to describe a molecular association comprising one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol.
  • solvent molecules e.g. water or ethanol.
  • hydrate is used when said solvent is water.
  • Isoxazoline compounds of Formula (I) can be prepared according to one or other of the processes described e.g. in patent applications US 2007/0066617, WO 2007/079162,
  • existing lice infestation can be controlled, preferably eliminated within 2 days after administration.
  • no live lice and/ or viable eggs can be found on treated animals 42 days after treatment.
  • the current invention can be also used to control (treat and/ or prevent infestation) resistant lice populations of poultry animals.
  • Resistance can be defined as exposure to a low dose of pesticide that enables some lice to survive, and these have genes that may allow them to survive higher doses that would normally kill all lice. Continued use of the same chemical or chemical group allows the resistant lice to survive, breed and increase in numbers until they make up the majority of the population. Sometimes, when resistance is present, treatment suppresses lice, but does not completely eradicate them. These suppressed infestations are difficult to detect and increase the chance of lice spreading between flocks.
  • the current invention can be used on animals that are infested with lice resistant to any one of organophosphates, synthetic pyrethroids, neonicotinoids, spinosyn or benzoyl phenyl urea compounds and will still provide effective treatment/ protection.
  • effective (dosage) amount of isoxazoline compounds are between 0.1 mg/kg bodyweight of the treated animal and 50 mg/kg bodyweight, or 0.25 mg/kg bodyweight to 10 mg/ kg bw, or 0.5 mg/ kg bw to 7.5 mg/kg bw In one embodiment the effective dosage is 1 mg/kg bodyweight.
  • Such effective amount of an isoxazoline compound, especially fluralaner is in one embodiment split into two dosages that are administered 7 or 14 days apart.
  • the split dose (each of them containing e.g. 50% of a regular dose) is administered 7 days apart, e.g. 2 times a dose of an isoxazoline compound (e.g. fluralaner) of 0.5 mg/ kg bodyweight.
  • a single dose of an effective amount of the isoxazoline compound is administered to an animal, that has been diagnosed to be infested with lice.
  • the administration of an effective amount of an isoxazoline compound via drinking water administration is useful to lice of breeding and egg laying poultry animals and other types of fowl that are kept for a production cycle that exceeds a period of approximately 8 weeks., especially if such animals are kept on a commercial scale, such as, laying hens, rearing pullets or replacement chickens, layer breeders, and broiler rearing pullets and breeders.
  • such method can be also used in other types of poultry animals, such as e.g. turkey, geese, ducks, pigeons, quails or pheasants.
  • a single dose of an effective amount of the isoxazoline compound is administered to a poultry animal, that has been in contact with a animal that has been diagnosed with a chewing lice infestation and is therefore at risk to be infested.
  • the isoxazoline compound is administered via drinking water.
  • an effective amount of the isoxazoline compound as described above is incorporated in the drinking water that is offered to animals that are either infested by parasitic arthropods (that require treatment) or, to animals, that are not infested, but that are at risk of infestation by parasitic arthropods (prevention of parasitic arthropods).
  • the isoxazoline compound as defined above is administered to a population that comprises poultry animals that are infested by parasitic arthropods.
  • “medicated drinking water” By incorporating an effective amount of the isoxazoline compound as described above in the drinking water that is offered to animal, “medicated drinking water” is formed. Such medicated drinking water is administered via the usual drinking water system in the poultry house. Medicated drinking water is formed by adding to (or mixing with) drinking water a (concentrated) pharmaceutical composition as described below, that is either solved in drinking water, miscible with the drinking water or that result in a suspension of the isoxazoline compound in the drinking water.
  • the isoxazoline compound in the medicated water needs to be homogeneously distributed during the treatment period (as defined below) and allow the administration of an effective and accurate amount of the compound to all animals that have access to such medicated water.
  • all animals in a unit e.g. a poultry house are treated at the same time, i.e. the medicated water is made available to all poultry animals in a certain production unit.
  • this invention also is directed to a pharmaceutical composition for use in the prevention or treatment of parasitic arthropod infestations of laying hens that are producing eggs for human consumption, comprising an effective amount of an isoxazoline compound as described above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition is also referred to as “concentrated pharmaceutical composition” or either as “concentrated solution” or “concentrated suspension”.
  • the isoxazoline compound as disclosed above is generally present in such concentrated pharmaceutical compositions in an amount of about 0.1 mg/ml to about 500 mg/ml.
  • a preferred pharmaceutical composition according to the current invention is a concentrated solution.
  • Such concentrated solution comprises between 1.5 mg/ml and 100 mg/ml of the isoxazoline compound, especially fluralaner.
  • An example for a suitable concentrated solution of isoxazoline compounds, especially fluralaner, is a pharmaceutical composition that comprises an isoxazoline compound, and a pharmaceutically acceptable carrier comprising diethylene glycol monoethyl ether and a polysorbate surfactant.
  • An alternative concentrated pharmaceutical composition for use in the current invention comprises an isoxazoline compound as described above in the form of a concentrated suspension, especially a concentrated aqueous suspension.
  • Such concentrated suspension comprises between 100 mg/ml and 500 mg/ml of the isoxazoline compound, especially fluralaner.
  • such concentrated suspension is an aqueous suspension of wet milled isoxazoline compound, especially fluralaner, particles in a composition comprising a polysorbate surfactant.
  • aqueous suspension composition may comprise a preservative such as benzyl alcohol and antifoaming agents such as simethicone.
  • Such pharmaceutical compositions may be manufactured by processes known in the art. These processes include, for example, a variety of known mixing, dissolving, and emulsifying processes.
  • a concentrated pharmaceutical composition comprising the isoxazoline compound as described above and a pharmaceutically acceptable carrier either as a (micellar) solution, or as a suspension, is prepared.
  • a pharmaceutically acceptable carrier either as a (micellar) solution, or as a suspension.
  • Such concentrated pharmaceutical composition is then diluted (in one or more steps) with water to form medicated drinking water.
  • Medicated water is produced by diluting an amount (volume) of the (concentrated) pharmaceutical composition that comprises the isoxazoline compound as described above in a dosage that provides (after dilution) an effective amount for all animals treated with a volume of drinking water that corresponds to the volume that will be consumed during the treatment period to a large extent by such animals.
  • Such medicated drinking water is then offered to the animals for consumption through a drinking water system.
  • Such drinking water systems on commercial farms can be complex systems of tanks, pipes, coils, pen drinkers and cups and/or nipples.
  • An average stable may contain hundreds of meters of pipes with many coils and hundreds of individual cups and/or nipples.
  • treatment period usually less than 24 hours, e.g. 4-5 hours to 8 hours, as sole drinking water source with the aim of ensuring that an effective amount of the isoxazoline compound as described above is consumed by each animal during this time.
  • Medicated drinking water can be made available during the treatment period to a single animal; or at the same time to a group of animals or to all animals in a single stable (house) or farm.
  • the isoxazoline compound as described above can be delivered through a drinking water system of choice by means of mixing and diluting the concentrated pharmaceutical composition as described above with drinking water in the central water tank or separate medication and storage tank to form medicated drinking water that is offered to animals for consumption.
  • the concentrated pharmaceutical composition as described above is injected continuously into a high- or low- pressure ring system for drinking water distribution, using a dosage dispenser or dosing pump system or proportioner medication system.
  • the isoxazoline compound concentration in the medicated drinking water is depending on the effective amount, the total body weight of the animals treated, the animal water consumption and the treatment period.
  • the medicator uses for example 10 ml of the concentrated composition and further dilutes with water in about a 1 :200 ratio to obtain medicated drinking water having an isoxazoline compound e.g. fluralaner concentration of 0.001 to about 1 mg/ml, especially from about 0.05 to about 0.2 mg/ml.
  • the medicated water has a concentration of between 0.002 and 0.02 mg/ml of the isoxazoline compound.
  • the concentration is calculated to provide the effective amount of fluralaner per body weight (BW) of the poultry animals being treated in the range of from about 0.5 mg to about 2 mg of fluralaner per kilogram of body weight per day in the volume of drinking water normally consumed by the poultry animals being treated in a 2 to 24 hour treatment period, preferably 4-5 to 8 hours.
  • a single administration of an effective amount isoxazoline compound as described above can be sufficient to treat a parasitic infestation. However, multiple doses of the isoxazoline compound can be used.
  • One period of making medicated water as described above available to poultry animals (duration generally up to one day) is a single administration visa drinking water.
  • the treatment frequency of the drinking water administration is depending on the parasite treated or prevented (and its biological lifecycle, which might be dependent on the environmental conditions in the poultry house, e.g. the temperature) and the production cycle of the host poultry animal treated.
  • the isoxazoline compound as described above, especially fluralaner is administered via drinking water administration at least once or more than once, i.e. 2 times or 3 times in one production cycle of poultry animals.
  • this is the laying period.
  • a production cycle is the period that a group of poultry animal remains in a poultry house (e.g. the fattening period in case of broilers).
  • Preferred is an administration frequency of two times per laying period. The duration of the laying period varies but is generally between one year and two years.
  • the specific time interval can vary between the various parasitic arthropods and can be depending on the environmental conditions that influence the parasite lifecycle.
  • the parasites can be reached that developed (following the lifecycle of the parasites) from not susceptible, or difficult to reach parasite stages, e.g. that matured from the juvenile stages of the parasites (such as eggs, nymphs or pupae) during this period.
  • the parasite population can be significantly reduced to a level that would only cause minimal damage to the animal and minimal production losses during this production cycle, or even more than one production cycle.
  • One specific benefit of such administration regimen is that a low dosage of the isoxazoline compound can be administered so that residues in eggs can be minimized by such administration regimen while maintaining effective control of parasitic arthropods.
  • compositions are known to be suitable for oral administration to animals, but they vary for the different animal species.
  • Excipients may comprise conventional non active pharmaceutically and veterinarily acceptable components e.g. fillers, binders, flavoring agents, solvents, colorants, glidants, preservatives.
  • the pharmaceutical excipients are excipients with which the person skilled in the art is familiar, such as those which are described in the European Pharmacopoeia.
  • the product according to the current invention conventionally further comprises physiologically acceptable formulation excipients known in the art e.g. as described in “Gennaro, Remington: The Science and Practice of Pharmacy” (20th Edition, 2000) incorporated by reference herein. All such ingredients, carriers and excipients must be substantially pharmaceutically or veterinary pure and non-toxic in the amounts employed and must be compatible with the pharmaceutically active ingredients.
  • physiologically acceptable formulation excipients known in the art e.g. as described in “Gennaro, Remington: The Science and Practice of Pharmacy” (20th Edition, 2000) incorporated by reference herein. All such ingredients, carriers and excipients must be substantially pharmaceutically or veterinary pure and non-toxic in the amounts employed and must be compatible with the pharmaceutically active ingredients.
  • fluralaner showed an efficacy of 100% from Day 7 to Day 42.
  • level of M. cornutus infestation was checked using a scale from 1 to 4 in both groups.
  • the average score on day -5 was 1.8 in both TG and CG.
  • Fluralaner caused no adverse effects in treated birds and was highly effective to eliminate the infestation of M. cornutus from the second day up to the 42nd day after the first treatment administration.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
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  • Agronomy & Crop Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Environmental Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de traitement ou de prévention d'infestations par les poux d'animaux de volaille par administration orale d'un composé d'isoxazoline de formule (I).
PCT/EP2020/086111 2019-12-16 2020-12-15 Composition pour lutter contre les poux chez la volaille Ceased WO2021122521A1 (fr)

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BR112022011046A BR112022011046A2 (pt) 2019-12-16 2020-12-15 Composição para controle de piolhos em avinos
MX2022007309A MX2022007309A (es) 2019-12-16 2020-12-15 Composicion para control de piojos en aves de corral.

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EP19216376.4 2019-12-16
EP19216376 2019-12-16

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
US12304903B2 (en) 2020-07-24 2025-05-20 Elanco Us Inc. Process for making an isoxazoline compound and intermediate thereof
US12497370B2 (en) 2019-12-18 2025-12-16 Elanco Tiergesundheit Ag Isoxazoline derivatives

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WO2011075591A1 (fr) 2009-12-17 2011-06-23 Merial Limited Dihydroazoles antiparasitaires et compositions les incluant
WO2011124998A1 (fr) 2010-04-08 2011-10-13 Pfizer Inc. Dérivés de 3,5-diphényl-isoxazoline substitués comme insecticides et acaricides
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12497370B2 (en) 2019-12-18 2025-12-16 Elanco Tiergesundheit Ag Isoxazoline derivatives
US12304903B2 (en) 2020-07-24 2025-05-20 Elanco Us Inc. Process for making an isoxazoline compound and intermediate thereof

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