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WO2025034192A1 - Complexe afoxolaner soluble dans l'eau, son procédé de production et médicaments antiparasitaires vétérinaires le comprenant - Google Patents

Complexe afoxolaner soluble dans l'eau, son procédé de production et médicaments antiparasitaires vétérinaires le comprenant Download PDF

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Publication number
WO2025034192A1
WO2025034192A1 PCT/UA2024/000009 UA2024000009W WO2025034192A1 WO 2025034192 A1 WO2025034192 A1 WO 2025034192A1 UA 2024000009 W UA2024000009 W UA 2024000009W WO 2025034192 A1 WO2025034192 A1 WO 2025034192A1
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Prior art keywords
afoxolaner
complex
drug
cyclodextrin
dogs
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Yuriy Synytsya
Dmytro POLEVYCHENKO
Artem APRISHKO
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

Definitions

  • the claimed group of inventions relates to a field of veterinary medicine and concerns a water-soluble supramolecular complex with afoxolaner, a method for production thereof, and veterinary drugs comprising said complex as a main active component to prevent or to treat parasite infections in animals caused by ectoparasites and/or endoparasites.
  • Afoxolaner belongs to a class of isoxazolines, it is used to treat and to prevent flea infestation, as well as to treat and to control various ixodic. infestations.
  • Isoxazoline compounds are known in this field of art, and their production and use as antiparasitic agents are described, e.g., in international applications W02005085216 dated 17.01.2008, W02009002809 dated 31.12.2008,
  • a particularly active compound is isoxazoline compound, 4-[5-[3-chloro-5- (trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N- [2-oxo- 2-[(2,2,2-trifluoroethyl)amino]ethyl]-l-naphthalene carboxamide, which is known under a non-patented name afoxolaner and described in the application W02007079162A1 dated 12.07.2007.
  • isoxazoline compounds in particular, afoxolaner
  • a pure form is limited by its bioavailability, since it is not water-soluble and its pure form cannot be delivered to body tissues by means of a water-based blood, but it rather forms regular solutions only in organic solvents, thereby making it necessary to include additional excipients to pharmaceutical compositions based thereon, and the excipients are usually belong to highly toxic compounds.
  • An alternative approach may be to use dispersions of afoxolaner with various solubilizers and surfactants to transport the active substance to the body tissues.
  • compositions facilitate formation of dispersions having a particle size of more than 10 microns, thereby affecting the bioavailability of the active component.
  • the application WO2013119442A1 dated 15.08.2013 teaches parasitocidal oral veterinary compositions comprising systemically-acting active agents being at least one isoxazoline active agent, in particular, afoxolaner, in combination with a pharmaceutically acceptable carrier.
  • systemically-acting active agents being at least one isoxazoline active agent, in particular, afoxolaner
  • a pharmaceutically acceptable carrier in order to provide effective delivery of the active agent by oral administration, it is introduced into a solid or a liquid matrix, where, in order to achieve matrix characteristics, ingredients are used, such as, e.g., hydroxypropyl starch or hydroxypropyl cellulose, while surfactants, in particular, polysorbates, are used as a matrix complex stabilizer.
  • This invention proposes enhanced methods for eliminating, controlling and preventing parasite infections and infestations in animals, the methods comprise oral administration of the inventive composition to the animal in a need thereof.
  • the compositions being used facilitate formation of dispersions having a particle size of afoxolaner of more than 10 microns, thereby affecting the bioavailability of the active component.
  • use of these compositions for parenteral administration is problematic.
  • Natural phosphatides e.g., lecithin, or products of condensation of alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or products of condensation of ethylene oxide with long-chain aliphatic alcohols, e.g., heptadecaethyleneoxycetanol etc., are selected as dispersing agents or lubricants.
  • a surfactant is used, and the surfactant is selected from sorbitol fatty acids ethers (Spans), polyoxyethylene sorbitol fatty acids esters (polysorbates/Tweens), castor oil polyoxyethylene derivatives (Cremaphors), polyoxyethylene stearates or lecithines.
  • the obtained composition is a stable complex of isoxazoline compound, in particular, afoxolaner, having a particle size from about 25 microns to about 250 microns, that is used to create injection compositions having an antiparasitic effect.
  • the effective dose of afoxolaner in the drug is from 5 to 10 mg/kg.
  • the claimed invention attempts to provide a novel supramolecular afoxolaner complex having an increased water solubility and enhanced stability, as well as to develop veterinary drugs comprising this complex which have a high chemical and physical stability and a reduced toxic effect, and which are suitable both for oral and parenteral administration.
  • components of the proposed complex the following is known.
  • Cyclodextrines are cyclic oligosaccharides comprising 6 (a-cyclodextrin), 7 ( -cyclodextrin) or 8 (y-cyclodextrin) glucopyranose units. Structural organization of a molecule of cyclodextrines is such that it comprises an individual external hydrophilic portion that increases water solubility and an individual internal portion that forms a cavity. Hydrophobic areas of most of molecules are able to penetrate into the hydrophobic cavity, thereby forming so-called “inclusion complexes”.
  • cyclodextrines and derivatives thereof in most cases provide a significant increase of solubility of drugs. Besides, it is believed that the most important result that is achieved by the presence of cyclodextrines in pharmacological formulations is increase of the bioavailability of active components which allows to use them in concentrations lower than usual ones, which is essential both in terms of additional reduction of the drug toxicity and in terms of a possible reduction of its price.
  • 2-hydroxypropyl- -cyclodextrin is selected, since it is well studied, non-toxic for mammals and commercially available, and its pharmacological use is disclosed, particularly, in publications (Loftsson, T. and Brewster M E, “Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization.” Sd J Pharm, 1996, 85 (10). P. 1017-25. ; Abdel-Rahman, S M, et al., “Single-dose pharmacokinetics of intravenous itraconazole and hydroxypropyl-beta-cyclodextrin in infants, children, and adolescents. Antimicrob A”).
  • Polysorbate surfactants are used to stabilize the complex and to minimize its segregation and sedimentation of the active agent. It is known that the polysorbate surfactants demonstrate advantageous characteristics for isoxazoline compositions and upon contact with water, they are able to create micelles around the solubilized compound, thus, to maintain the solubilized compound in the aqueous medium.
  • polysorbate 80 is used that is known as Tween 80 and that is commercially available or may be obtained by methods which are known in this field of the art.
  • the claimed invention is based on a task to develop an inclusion complex with afoxolaner that is based on use of 2-hydroxypropyl-P-cyclodextrin as a molecular packer of hydrophobic afoxolaner molecules, while polysorbate 80 is used as the stabilizer of the complex.
  • a supramolecular complex in a form of a finely dispersed powder is obtained, the powder having a particle size of less than 1 micron and characterized by the following composition of components (wt.%): afoxolaner - 1 - 10%,
  • the claimed complex may be obtained only under strict adherence to the Applicant’s method for production thereof which constitutes a subject matter of the claimed invention as well.
  • a method for producing the inventive complex comprises the following steps of: mixing afoxolaner solutions and 2-hydroxypropyl-P- cyclodextrin , while fulfilling a mass ratio in the solutions 2-hydroxypropyl- P-cyclodextrin/afoxolaner of 1 40 storing the mixture of solutions at a room temperature during at least 24 hours adding a polysorbate 80 solution to the stored mixture of the solutions at a mass ratio polysorbate 80 / mixture of solutions of afoxolaner and 2-hydroxypropyl-p-cyclodextrin of 1- 0; drying the obtained mixture until a solvent is completely evaporated and a dry residue is obtained.
  • a veterinary antiparasitic drug comprises said supramolecular complex of afoxolaner and suitable fillers and/or binder and/or preservatives in ratios which are suitable for forming solid forms, in particular, as dragees, tablets, powder, capsules etc.
  • the veterinary drug may further comprise excipients, such as antioxidants and/or food additives having meat flavor and taste.
  • excipients such as antioxidants and/or food additives having meat flavor and taste.
  • the complex content in a single solid form is selected such that it comprises 2-4 mg of afoxolaner per 1 kg of the animal’s body weight.
  • a below-mentioned table provides an exemplary solid dosage form comprising the supramolecular complex of afoxolaner for preventing or treating parasite infections and infestations in animals caused by ectoparasites.
  • the weight of the complex is almost one half of the tablet weight, and the afoxolaner content in the complex is about 2.5 mg which is optimal and sufficient dose per 1 kg of animal weight for achievement of the antiparasitic effect.
  • a veterinary antiparasitic drug comprises said supramolecular complex of afoxolaner and is a colloidal solution in an isotonic medium comprising a weight fraction of afoxolaner in a range of 0.05 0.5 %.
  • the isotonic medium may be 9% sodium chloride solution or 5% glucose solution.
  • Said solvent may be used both for injections and for parenteral use, in particular, for drip skin application.
  • a veterinary drug being a solid dosage form that further comprises one or more active anthelminthic agents.
  • said veterinary antiparasitic drug comprises a composition of the supramolecular complex of afoxolaner with an anthelminthic drug at a mass ratio of anthelminthic drug / afoxolaner complex of 1- 0, while providing the afoxolaner content therein of 2-4 mg based on 1 kg of animal body weight.
  • Preservatives and/or antioxidants and/or food additives may be used as the excipients in ratios which are suitable to form solid forms, in particular, as dragees, tablets, powder, capsules. Milbemycin oxime or pyrantel or praziquantel or febantel or combinations thereof is/are used as the anthelminthic drug.
  • Table 3 provides an exemplary solid dosage form comprising afoxolaner and anthelminthic drugs for preventing or treating parasite infections and infestations in animals caused both by ectoparasites and endoparasites.
  • Formulation of the oral tablet with the supramolecular complex of afoxolaner and anthelminthic active substances, based on 100 mg of the formulation A qualitative formulation of the tablet is provided below taking a 0.4 mg tablet as example:
  • the supramolecular complex is produced in the following way
  • an estimated amount of the solution 3 is poured into the vessel, while maintaining the ratio, and blending a mixture of alcohol solutions for at least 15 minutes.
  • Ixodidae are the most widespread ones, and they occur in Europe, particularly, in Ukraine as well: Ixodes ricinis, Rhipicephalus sanguineus, Dermacentor reticulatis.
  • Sarcoptidae Otodectes cynotis, Notoedres cati, Sarcoptes canis
  • Trombidiformes (Demodex spp., Cheyletiella spp..) pose a threat.
  • reagents for microscopic tests (10% NaOH solution, 70% alcohol, alcohol-ether, chloroform, rosin, castor oil), aspirators for collection of arthropods, flasks for collection of arthropods, sealed polyethylene small bags, tweezers and lancet for collection of mites, skin samples from the study animals, cover glass slides, overlapping glass slides, McMaster chamber, reagents for scatoscopy tests (ammonium nitrate solution having a density of 1.32 g/ml; saturated sodium chloride solution having a density of 1.2 g/ml).
  • Test 1 Determination of acaricidal activity of the drug in in vivo studies on dogs.
  • Dogs of various breed served as study objects, aged from 5 months to 6 years, body weight of from 5 to 45 kg; the animals are held in a housed manner, in crates.
  • Diagnosis of infestation with dermestids mites of Otodectes cynotis species was established based on clinical features and acarological study methods by means of microscopy of scrapes taken from dog ear areas affected by parasites. Therewith, a parasitological damage index was determined - intensity of invasion before and after the treatment, and the drug efficiency was determined according to regulations of the European Medicines Agency and the World Association for the Advancement of Veterinary Parasitology.
  • the dogs were divided into two groups. In the study group of dogs, before use of the drug in a form of tablets, the average intensity of invasion with the mites of Otodectes cynotis species was 34.2 ⁇ 6.2 units per animal, while in the control group of dogs, the average intensity of invasion with the mites of Otodectes cynotis species was 30.6 ⁇ 6.8 units per animal.
  • the study drug in tablets was used in the study group of dogs at the otoacariasis invasion according to the Table 1 with consideration of the animal body weight and, thus, the tablet weight, while the drug was not used in the second control group.
  • the efficiency of the drug for dogs in the animal study group was 95.03% at the average intensity of invasion with the mites of Otodectes cynotis species of 1.6 ⁇ 0.2 units per animal.
  • results of the conducted tests indicate that the drug in the form of the tablet having the claimed afoxolaner content in the supramolecular complex has outstanding acaricidal activity relative to the dermestids mites of Otodectes cynotis species. Therefore, the drug for the dogs is effective against Sarcoptidae invasions in dogs.
  • Test 2 Evaluation of acaricidal activity of the drug at Ixodidae invasion.
  • Diagnosis of infestation with parasitiformes being ectoparasites of the Ixodidae family was established based on clinical features, acarological test methods being observation of skin and body hair coat for presence of Ixodidae. Therewith, a parasitological damage index was determined before the treatment and after the treatment (after 1, 2, 3, 7, 14, 21 and 28 days) and the efficiency of the drugs was determined according to regulations of the European Medicines Agency and the World Association for the Advancement of Veterinary Parasitology.
  • Ixodidae Upon observation of the animal body with a naked eye and by means of the magnifying glass, Ixodidae were found in 14 dogs: Ixodes spp., Dermacentor spp., Rhipicephalus spp. (images and nymphs) which were adhered. In the study group of dogs, before use of the drug in the form of the tablet, the average intensity of the Ixodidae invasion was 22.5 ⁇ 3.7 units per animal (Table 5).
  • the efficiency of the drug in the form of the tablet for dogs in the animal study group was 93.76 % at the average intensity of the Ixodidae invasion of 1.5 ⁇ 0.3 units per animal.
  • the efficiency of the drug in the form of the tablet for dogs in the animal study group was 93.76 % at the average intensity of the Ixodidae invasion of 1.5 ⁇ 0.3 units per animal.
  • the third day of the test upon pelage and skin inspection of the dogs and acarological test, no mites of the species: Ixodes spp., Dermacentor spp., Rhipicephalus spp. (images and nymphs) were found in the animals of the study group.
  • the obtained results indicate that the drug in the form of the tablets for dogs possesses outstanding acaricidal activity against parasitiformes. Duration of the protective action of the drug against Ixodidae of the species: Ixodes spp., Dermacentor spp., Rhipicephalus spp. (imagos and nymphs) in dogs was not less than 28 days.
  • Test 3 Evaluation of therapeutic efficiency of the drug in the form of a solution for external use in adult dogs and puppies.
  • otoacariasis When otoacariasis is suspected, scabs from internal surface of the ear auricles were taken for the test. In order to establish the otoacariasis diagnosis, a vital method by Pryselkova D.R. and a method by Alfymova A.V. were used. The obtained material was tested microscopically for the presence of mites: a mite body was flat, oval shaped, gray-yellow colored; ovicells were oval shaped under 2 mm, coated with a thin shell.
  • Acarological and entomological tests were conducted two times before prescription of the drug, on day 7, 15 after treatment with the drug.
  • blood samples were taken from 5 test animals from the group before, on day 7 and on day 15 after start of the insectoacaricide treatment.
  • the blood samples for hematological and biochemical tests were taken under fasted conditions from a subcutaneous forearm vein. In case of demodecosis, the blood samples were collected before, after 28, 45, 56 and 78 days from the start of the treatment.
  • Results of the tests were processed statistically using a software package Microsoft Excel 2003 (for Windows XP), and a probability of the obtained results were evaluated according to the Student’s test.
  • study group - 5 animals suffering from demodecosis were treated with the drug in the form of the solution for external use by spotting externally, once, by dripping onto a dry unaffected animal skin by means of a dropper pipette (having a volume of 1.5 ml).
  • the drug was applied to the affected areas of the animals suffering from demodecosis and it was spread by finger tips in a glove, while covering up to 1 cm 2 of healthy skin.
  • the treatment was performed 4-fold with 10 days interval until achievement of clinical recovery of the animal which was confirmed by two negative results of acarological tests.
  • a complex therapy was applied to the dogs suffering from demodecosis as follows: antimicrobial drug Enrofloxacin in a dose of 50 mg per 10 kg of body weight during 10 days; Activyl-3 (probiotics for dogs) in a oral dose of 3 g per animal with food during 14 days, hepatoprotective agent Divopride in a dose of 2 tables thrice a day during 14 days and vitamin Decavit in a dose of 1 ml with drinking water 1 time per 5 days during 14 days.
  • Results of clinical and biochemical studies of blood of the study dogs before and after conduction of the acaricidal treatment are provided in Table 7.
  • the total concentration of hemoglobin, red blood cell count in blood and glucose concentration in blood serum of the dogs were lower than reference, while white blood cell count in blood and concentration of total proteins, ALT and AST activity in blood serum were higher than reference, which indicated that there is an inflammation, a hepatotoxic activity, hemorrhage and derangement of metabolism in the organism of suffering dogs.
  • the total hemoglobin concentration was 34.0% increased (p ⁇ 0.05) relative to the parameter before treatment in average, red blood cell count was 22.8% increased, glucose concentration was 38.0% increased, while white blood cell count was 26.4% decreased (p ⁇ 0.05), the total protein count was 7.0% decreased, ALT activity was 60.1% decreased and AST activity was 56.6 % decreased.
  • the external auditory passage was cleaned from crusts and scabs, and then 3 drops of the drug were instilled into each ear.
  • the ear auricle was folded in half in longitudinal direction and its base was massaged.
  • the treatment against otoacariasis was repeated 2 times with interval of 5 days.
  • the obtained complex is effective at reduced dosage, which indicates its high bioavailability and confirms that it may be used for effective oral and parenteral administration.

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Abstract

Les différentes inventions concernent un domaine de la médecine vétérinaire et concerne un complexe supramoléculaire hydrosoluble avec de l'afoxolaner, son procédé de production, et des médicaments vétérinaires comprenant ledit complexe en tant que constituant actif principal pour prévenir ou traiter des infections parasitaires chez les animaux. Le complexe selon l'invention est une poudre fine ayant une taille de particule inférieure à 1 micron qui est une inclusion de molécules d'afoxolaner dans la structure de la 2-hydroxypropyl-β-cyclodextrine, stabilisée par du polysorbate 80 et peut être utilisée dans des médicaments vétérinaires ayant un effet antiparasite pour administration orale et parentérale efficace.
PCT/UA2024/000009 2023-08-07 2024-02-06 Complexe afoxolaner soluble dans l'eau, son procédé de production et médicaments antiparasitaires vétérinaires le comprenant Pending WO2025034192A1 (fr)

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UAA202303779 2023-08-07
UAA202303779A UA130006C2 (uk) 2023-08-07 2023-08-07 Водорозчинний комплекс афоксоланера, спосіб його отримання та ветеринарні протипаразитарні препарати, що його містять

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WO2007079162A1 (fr) 2005-12-30 2007-07-12 E. I. Du Pont De Nemours And Company Isoxazolines servant à lutter contre des animaux nuisibles invertébrés
WO2009003075A1 (fr) 2007-06-27 2008-12-31 E.I. Du Pont De Nemours And Company Procédé de lutte contre les parasites des animaux
WO2009002809A2 (fr) 2007-06-26 2008-12-31 E. I. Du Pont De Nemours And Company Agents de lutte contre les parasites invertebres
WO2009024541A2 (fr) 2007-08-17 2009-02-26 Intervet International B.V. Compostions d'isoxazoline et leur utilisation en tant qu'antiparasitaires
WO2010070068A2 (fr) 2008-12-19 2010-06-24 Novartis Ag Composés organiques
WO2010079077A1 (fr) 2008-12-18 2010-07-15 Novartis Ag Dérivés isoxazolines et leur utilisation en tant que pesticide
WO2013119442A1 (fr) 2012-02-06 2013-08-15 Merial Limited Compositions vétérinaires orales parasiticides comprenant des agents actifs à action systémique, procédés et utilisation associés
WO2019091936A1 (fr) 2017-11-07 2019-05-16 Intervet International B.V. Compositions pharmaceutiques à base d'isoxazoline injectables et leur utilisation contre l'infestation par des parasites

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