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WO2022226660A1 - Utilisation d'isoxazoline pour protéger des poissons contre des parasites - Google Patents

Utilisation d'isoxazoline pour protéger des poissons contre des parasites Download PDF

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Publication number
WO2022226660A1
WO2022226660A1 PCT/CA2022/050663 CA2022050663W WO2022226660A1 WO 2022226660 A1 WO2022226660 A1 WO 2022226660A1 CA 2022050663 W CA2022050663 W CA 2022050663W WO 2022226660 A1 WO2022226660 A1 WO 2022226660A1
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Prior art keywords
isoxazoline
fish
fluralaner
days
composition
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John O'halloran
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/111—Aromatic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/10—Shaping or working-up of animal feeding-stuffs by agglomeration; by granulation, e.g. making powders
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
    • 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
    • A61K31/33—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
    • 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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/20—Animal feeding-stuffs from material of animal origin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/20—Animal feeding-stuffs from material of animal origin
    • A23K10/22—Animal feeding-stuffs from material of animal origin from fish
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats

Definitions

  • the present disclosure relates to methods of use of compounds for treating or preventing parasite infection, such as sea lice infection, in fish, such as salmon.
  • Parasites such as sea lice are ectoparasites that latch onto the skin of fish during free-swimming larval stages, feeding on fish’s blood, mucus, and skin, larger numbers of sea lice result in loss of growth performance, decrease animal welfare and can cause fish mortality.
  • Ectoparasite infestation in aquaculture is a significant commercial concern, and an infestation in, for example, farmed salmon can affect wild salmon stocks.
  • Economically important species of sea lice include Lepeophtheirus salmonis and various Caligus species including Caligus clemensi , Caligus elongatus and Caligus rogercresseyi, can cause deadly infestations of wild fish as well as farm-grown fish.
  • Affected fish include salmonid such as Atlantic salmon ( Salmo salar), Chinook salmon ( Oncorhynchus tshawytscha ), coho salmon ( Oncorhynchus kisutch ), chum salmon ( Oncorhynchus keta ), pink salmon ( Oncorhynchus gorbuscha ), Sockeye salmon ( Oncorhynchus nerka), and rainbow trout ( Oncorhynchus mykiss ; the anadromous form of which is known as steelhead trout).
  • the control of sea lice in commercial salmon farming can include chemical treatments that are applied in a bath by temporarily placing a tarp around a cage containing the fish and water or pumping fish into a well boat, however, such treatments are restrained by concerns about even mixing of the chemical, releasing the chemical into the environment and the sea lice developing resistance. In particular, where high doses of chemical are employed, resistance development could accelerate.
  • Fluralaner is an isoxazoline that is generally known for treating fleas and ticks in cats and dogs, and for treating mites in poultry, sold under the tradenames BravectoTM and ExzoltTM.
  • medication is given once at 25 to 50 mg/kg of dog weight and it provides protection against flea and tick for 12 weeks.
  • the drug is provided in drinking water for one day at 0.5 mg/kg of chicken weight and the treatment is repeated 7 days later.
  • Current uses of fluralaner are believed to be limited to domesticated or industrial animals and birds, and on crops to treat insect pests.
  • isoxazoline such as fluralaner is an effective treatment for controlling sea lice infestation in fish such as salmon, showing high sea lice removal and low wastage of feed.
  • the present disclosure includes a use of an isoxazoline such as fluralaner, a composition comprising an isoxazoline such as fluralaner and at least one excipient, or a medicated fish feed comprising fish feed granules or pellets coated or mixed with a composition comprising an isoxazoline and at least one excipient, for preventing or treating parasite infection in a plurality of fish, wherein the isoxazoline, composition or medicated fish feed is for use at a daily dose comprising at least about 0.005 mg isoxazoline ( e.g . fluralaner)/kg of fish, up to about 5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 5 to 15 days.
  • an isoxazoline such as fluralaner
  • a composition comprising an isoxazoline such as fluralaner and at least one excipient or a medicated fish feed comprising fish feed granules or pellets coated or mixed with a
  • the isoxazoline comprises fluralaner, afoxolaner, lotilaner, or a veterinary acceptable salt of any of the foregoing. In an embodiment, the isoxazoline is fluralaner.
  • the at least one excipient comprises carrier, pork liver flavour, sucrose, maize starch, sodium lauryl sulfate, disodium embonate monohydrate, magnesium stearate, aspartame, glycerol, soya-bean oil, polyethylene glycol such as Macrogol 3350, vegetable oil, or an approved pharmacopeia excipient.
  • the excipient is an approved pharmacopeia excipient.
  • the carrier comprises fish oil, fish meal, shrimp meal, krill meal, krill oil, poultry meal, protein concentrate, select amino acids, water or combinations thereof.
  • the carrier comprises a fish oil, optionally further comprises a krill meal.
  • the isoxazoline (e.g . fluralaner), composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 1 , 2, 3, 4, or 5 times daily, for 5 to 15 days.
  • the daily dose comprises 0.01 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 1 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the daily dose comprises 0.07 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 0.7 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the daily dose comprises 0.01 , 0.1 , 0.5, 0.75, or 1 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises 0.1 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the isoxazoline (e.g. fluralaner), composition, or medicated fish feed is for use at a total dose of about 0.025 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 75 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the fish is salmonid.
  • the salmonid is a salmon or trout.
  • the salmonid is Salmo salar , Oncorhynchus tshawytscha, Oncorhynchus kisutch, Oncorhynchus keta, Oncorhynchus gorbuscha , Oncorhynchus nerka, or Oncorhynchus mykiss.
  • each salmonid has an average mass of less than or equal to 5 kg, optionally an average mass of from 25 g to 5 kg.
  • the parasite is a sea louse.
  • the sea louse is at any stage of life-cycle.
  • the sea louse is pre adult sea lice, copepodites, chalimus, adult sea lice, or gravid female lice.
  • the sea louse is Lepeophtheirus or Caligus , optionally the Lepeophtheirus is Lepeophtheirus salmonis , optionally the Caligus is Caligus ciemensi, Caligus eiongatus, or Caligus rogercresseyi.
  • the present disclosure also includes a fish feed composition (i.e. a fish feed or a fish feed additive) comprising fluralaner in a dosage described in this disclosure.
  • a fish feed composition i.e. a fish feed or a fish feed additive
  • the present disclosure also includes a use of fluralaner for preventing or treating sea lice in fish, wherein the fluralaner is administered in a composition described in this disclosure.
  • the present disclosure also includes a kit for preparing a medicated fish feed for reducing or treating parasites in a fish population, comprising a supply of fluralaner or a salt thereof in a container, and printed instructions for feeding the fluralaner at a daily dose per kg of fish biomass per day for a total number of days of dosage period as described herein.
  • the treated fish is optionally a salmon, such as an Atlantic salmon or Pacific salmon, or rainbow trout ( Oncorhynchus mykiss). It will be appreciated by a person skilled in the art that any fish in need of prevention or treatment of infection could receive the compositions described herein, including the list of fish in US 5,504,081 columns 5 and 6, and for prevention or treatment of a wide variety of parasites including the genera of parasites listed in column 5 of US 5,504,081 , and the foregoing is incorporated herein by reference.
  • the disclosure relates to compositions and methods of using the isoxazoline class of insecticides in fish feed to control parasites, typically saltwater crustacean parasites.
  • parasites typically saltwater crustacean parasites.
  • certain freshwater parasites may also be treated.
  • This class of products includes, but is not limited to, the compounds fluralaner, afoxolaner, and lotilaner. These insecticides control the pest, such as sea lice, by impairing the nervous system of insects and crustaceans.
  • T erms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ⁇ 5% of the modified term if this deviation would not negate the meaning of the word it modifies.
  • coat or a derivative thereof as used herein as related to fish feed granules or pellets refers the granules or pellets being covered or having spread over their outer surface, for example, an active ingredient or composition of the present disclosure.
  • Such covering or spreading includes spraying or dusting the granules or pellets with the active ingredient or composition (or rolling the granules or pellets in the active ingredient or composition), or for sealing the active ingredient or composition onto the feed with applications of edible fats.
  • An alternative to coating is to mix the active ingredient or composition with feed ingredients that are then extruded into feed granules or pellets.
  • excipient refers to a substance formulated with the active ingredient of the present disclosure.
  • An excipient can be, but is not limited to, anti-adherents, coatings, colours, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, attractant, or carrier.
  • an excipient can be pork liver flavour, sucrose, maize starch, sodium lauryl sulfate, disodium embonate monohydrate, magnesium stearate, aspartame, glycerol, soya-bean oil, polyethylene glycol such as Macrogol 3350, vegetable oil, or an approved pharmacopeia excipient.
  • Pharmacopeia excipient promotes stability and uniform mixing with the active ingredient.
  • An approved pharmacopeia excipient can be an approved excipient from US Pharmacopoeia (USP).
  • US Pharmacopoeia US Pharmacopoeia
  • an approved pharmacopeia excipient of the present disclosure includes a non-GMO dextrose such as Emdex®.
  • Excipients such as carriers in a composition or medicated fish feed can help consumption of the feed in fish. Such carriers include fish oil, fish meal, shrimp meal, krill meal, krill oil, poultry meal, protein concentrate, select amino acids, and/or water.
  • the protein concentrate can be processed protein concentrate such as processed corn protein concentrate or processed soybean protein concentrate, for example, at 80%, 85%, 90%, 95% or 99% protein, on a dry weight basis, and/or with less than 1% starch on a dry weight basis.
  • the carrier can be processed corn protein concentrate having at least 75.0% crude protein, at least 2.0% fat, at most 2.5% fiber and at most 1.0% starch, on a dry weight basis.
  • the carrier comprises fish oil, fish meal, shrimp meal, krill meal, krill oil, poultry meal, protein concentrate, select amino acids, water or combinations thereof.
  • the carrier comprises a fish oil, optionally further comprises a krill meal.
  • references to a kg of fish should be understood as references to a kg of fish biomass.
  • References to “fish” should be understood as references to a population of fish, except where the context indicates that a single fish is intended.
  • the present inventors disclose that using or administering isoxazoline such as fluralaner is effective in preventing or treating parasite infestations (e.g . sea lice infections) in fish.
  • the isoxazoline can be fed to the fish in pure form, in a composition comprising at least one excipient, or in a medicated fish feed that has fish feed coated or mixed with the isoxazoline-containing composition.
  • feeding isoxazoline such as fluralaner to fish in pure form or in a form of a suitable medicated fish feed decreases parasite infestations and maintains good food uptake.
  • pure does not require absolute purity, but rather it is intended as a relative definition, and can include isoxazoline that is highly purified or isoxazoline that are only partially purified, as those terms are understood by those of skill in the relevant art and within acceptable level of tolerance, for example, when it contains no other chemicals that might interfere with its action.
  • isoxazoline which has a purity of 100%, or at least 99.999%, 99.99%, 99.9%, 99%, 95%, or 90% by weight or greater is contemplated.
  • the present disclosure includes a method of preventing or treating parasite infection in a plurality of fish, comprising administering to the fish an effective amount of an isoxazoline such as fluralaner, a composition comprising an isoxazoline such as fluralaner and at least one excipient, or a medicated fish feed comprising fish feed granules or pellets coated or mixed with a composition comprising an isoxazoline such as fluralaner and at least one excipient, wherein the isoxazoline, composition, or medicated fish feed is administered at a daily dose comprising at least about 0.005 mg isoxazoline (e.g. fluralaner)/kg offish, up to about 5 mg isoxazoline ( e.g .
  • the present disclosure also includes a use of an isoxazoline, composition, or medicated fish feed described herein for preventing or treating parasite infection in a plurality of fish, wherein the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising at least about 0.005 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 5 to 15 days.
  • a daily dose comprising at least about 0.005 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 5 to 15 days.
  • the present disclosure further includes a use of an isoxazoline, composition, or medicated fish feed described herein for the preparation of a medicament for preventing or treating parasite infection in a plurality of fish, , wherein the medicament is for use at a daily dose comprising at least about 0.005 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 5 to 15 days.
  • a daily dose comprising at least about 0.005 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 5 to 15 days.
  • the present disclosure yet further includes an isoxazoline, composition, or medicated fish feed described herein for use for preventing or treating parasite infection in a plurality of fish, wherein the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising at least about 0.005 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 5 to 15 days.
  • the total dose over a 10-day total treatment period would typically be 0.1 to 10 mg of isoxazoline such as fluralaner per kg of fish.
  • the total isoxazoline such as fluralaner daily dose is optionally fed to the fish once a day.
  • the total isoxazoline such as fluralaner daily dose is optionally fed to the fish as a series of divided daily doses optionally comprising at least 2, 3, 4 or 5 feedings per day.
  • the fish are typically held in the pen until isoxazoline residue decreases to a level that the fish are suitable for human consumption, e.g. less than 0.65ppm in the fish.
  • the method or use disclosed herein is effective to prevent or treat the parasite (e.g. sea lice) infection. Treatment typically achieves at least 90% removal for significant control of parasite (e.g. sea lice), however, optionally 100% removal of the parasite (e.g. sea lice) is achieved and it represents complete control of the parasite.
  • Isoxazolines are a class of inhibitors of gamma-aminobutyric acid (GABA)- and glutamate-gated chloride channels in the nervous system of invertebrates.
  • GABA gamma-aminobutyric acid
  • Fluralaner is an isoxazoline approved by the U.S. Food and Drug Administration (FDA) for treatment of flea and tick infestations in terrestrial animals. Fluralaner is sold under the tradename BravectoTM for the treatment and prevention of flea infestations, and the treatment and control of tick infestations, in cats and dogs.
  • Fluralaner is also referred to as 4-[(5RS)-5-(3,5- Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-1 ,2-oxazol-3-yl]-N-[2-oxo-2- (2,2,2-trifluoroethylamino)ethyl]-o-toluamide and Chemical Abstracts Service (CAS) Registry Number S864731-61-3.
  • Isoxazoline afoxolaner is the active ingredient of the veterinary medicinal products NexGardTM which is indicated for the treatment and prevention of flea infestations, and the treatment and control of tick infestations in dogs and puppies.
  • Afoxolaner is also referred to as 4-[(5RS)-5-(5-Chloro-a,a,a- trifluoro-/77-tolyl)-4,5-dihydro-5-(trifluoromethyl)-1 ,2-oxazol-3-yl]-/ ⁇ /-[2-oxo-2- (2, 2, 2-trifluoroethylamino)ethyl]naphthalene-1 -carboxamide and CAS Registry Number 1093861-60-9.
  • Isoxazoline lotilaner (tradename CredelioTM) is a veterinary drug used to control fleas and ticks in dogs. Lotilaner is also referred to as 5-[(5S)-4,5- Dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2- oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide and CAS Registry Number 1369852-71-0.
  • the isoxazoline comprises, consists essentially of, or consists of fluralaner, afoxolaner, lotilaner, or a veterinary acceptable salt of any of the foregoing.
  • the isoxazoline is fluralaner or a veterinary acceptable salt.
  • the isoxazoline is afoxolaner or a veterinary acceptable salt.
  • the isoxazoline is lotilaner or a veterinary acceptable salt.
  • the excipient can, for example, promote stability and uniform mixing with the active ingredient, or improve flavor and palatability and thus increase consumption of a medicated feed.
  • the excipient comprises pork liver flavour, sucrose, maize starch, sodium lauryl sulfate, disodium embonate monohydrate, magnesium stearate, aspartame, glycerol, soya-bean oil, polyethylene glycol such as Macrogol 3350, vegetable oil, or an approved pharmacopeia excipient.
  • the excipient comprises one, two, three, or four approved pharmacopeia excipients.
  • the approved pharmacopeia excipient comprises dextrose.
  • the dextrose is a non-GMO dextrose.
  • the non- GMO dextrose is Emdex®.
  • Excipients such as carriers in composition or medicated fish feed can help consumption of the composition or feed in fish.
  • the excipient comprises a carrier described herein.
  • a person skilled in the art can readily determine how much isoxazoline to mix an excipient such as a carrier to provide a pre-mix composition having a particular percentage of active isoxazoline. For example, in an embodiment, the activity level of isoxazoline is first determined then the isoxazoline is mixed with an excipient described herein, to give a pre-mix comprising 40 wt% active isoxazoline which is 400 grams of active isoxazoline per kilogram of pre-mix composition.
  • the concentration of active isoxazoline in the composition is 10-90 wt%, 75-90 wt%, or 30-50 wt%, optionally 35-45 wt%, optionally at least 10 wt%, based on the total weight of the composition. In an embodiment, the concentration of active isoxazoline in the composition is 40 wt%.
  • Medicated feed for fish can be prepared based on the amount of feed that the fish are consuming each day or over the course of treatment. For example, 10 mg of 40 wt% isoxazoline (e.g . fluralaner) per kg of fish dosage divided over 10 days of feeding, if used in a sea cage site, would use 1 mg of active isoxazoline (e.g.
  • fluralaner per day for 10 days for 1 kg of fish.
  • a total biomass of 100,000 kg multiplied by 10 mg is 1 ,000,000 mg of active isoxazoline (e.g . fluralaner) required over 10 days. This equals 1 kg of active isoxazoline (e.g. fluralaner) used.
  • one kg of pre-mix composition may provide 400 grams of isoxazoline (e.g. fluralaner), 2.5 kg of pre-mix is added to the fish feed.
  • the present disclosure provides feeding regimes that result in decreases sea lice infection and maintain good food uptake.
  • an effective amount of the isoxazoline, composition, or medicated fish feed is administered to the fish, optionally in a single administration, or preferably comprising a series of administrations.
  • the isoxazoline, composition, or medicated fish feed is administered to the fish over a dosage period of 5 to 15 days.
  • Multiple feedings in fish i.e. a divided daily dose
  • Multiple dosages per day over a number of days can be used to keep isoxazoline (e.g. fluralaner) levels high in the fish to kill the parasite (e.g.
  • the dose is administered once per day. It will be appreciated by a person skilled in the art that a higher spike of medication can be obtained from such an administration.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 1 , 2, 3, 4, or 5 times daily, for 5 to 15 days.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 1 time daily, for 5 to 15 days.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 1 time daily, for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days. In an embodiment, the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 2 times daily, for 5 to 15 days. In an embodiment, the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds dose 2 times daily, for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds dose twice daily, for 10 days. In an embodiment, the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 3 times daily, for 5 to 15 days. In an embodiment, the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 3 times daily, for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 4 times daily, for 5 to 15 days.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 4 times daily, for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 5 times daily, for 5 to 15 days.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds 5 times daily, for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days.
  • the daily dose comprises 0.01 mg isoxazoline (e.g . fluralaner)/kg of fish, up to about 2.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the daily dose comprises about 0.07 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 0.7 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the daily dose comprises about 0.025 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 1 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises about 0.025 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 0.75 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises about 0.05 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 0.5 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises about 0.1 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 0.25 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the daily dose comprises about 0.025 mg isoxazoline (e.g. fluralaner
  • the skilled person can adjust dosage as necessary, for example adjusting on a per kilogram basis so the desired dose is measured and administered on an amount per kilogram offish.
  • 0.1 to 1 mg isoxazoline (e.g. fluralaner)/kg fish such as 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, or 1 mg isoxazoline (e.g. fluralaner)/kg of fish, is administered per day.
  • the daily dose comprises about 0.005, 0.006, 0.007, 0.008, 0.009, 0.01 , 0.02, 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 , 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21 , 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31 , 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41 , 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1 , 2.2, 2.3,
  • the daily dose comprises about 0.01 , 0.07, 0.1 , 0.5, 0.7, 0.75, or 1 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises about 0.01 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises about 0.07 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises about 0.1 mg isoxazoline (e.g. fluralaner)/kg offish. In an embodiment, the daily dose comprises about 0.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the daily dose comprises about 0.7 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises about 0.75 mg isoxazoline (e.g. fluralaner)/kg of fish. In an embodiment, the daily dose comprises about 1 mg isoxazoline (e.g. fluralaner)/kg offish. In an embodiment, the daily dose comprises about 0.01 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.07 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • the daily dose comprises about 0.07 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • the daily dose comprises about 0.1 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.11 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.12 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.13 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • isoxazoline e.g. fluralaner
  • the daily dose comprises about 0.14 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.15 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.16 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.17 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • the daily dose comprises about 0.14 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.15 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally
  • the daily dose comprises about 0.17 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.18 mg isoxazoline ( e.g . fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.19 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.2 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • isoxazoline e.g. fluralaner
  • the daily dose comprises about 0.21 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.22 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.23 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.24 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • isoxazoline e.g. fluralaner
  • the daily dose comprises about 0.25 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.26 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.27 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.28 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • isoxazoline e.g. fluralaner
  • the daily dose comprises about 0.29 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.3 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.31 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.32 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • isoxazoline e.g. fluralaner
  • the daily dose comprises about 0.33 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.34 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.35 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.36 mg isoxazoline ( e.g . fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • isoxazoline e.g. fluralaner
  • the daily dose comprises about 0.37 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.38 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.39 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.4 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • isoxazoline e.g. fluralaner
  • the daily dose comprises about 0.41 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.42 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.43 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.44 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • isoxazoline e.g. fluralaner
  • the daily dose comprises about 0.45 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.46 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.47 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.48 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • the daily dose comprises about 0.45 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.46 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally
  • the daily dose comprises about 0.49 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.5 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.4 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.5 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days.
  • the daily dose comprises about 0.49 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.5 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally
  • the daily dose comprises about 0.7 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 0.75 mg isoxazoline (e.g. fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the daily dose comprises about 1 mg isoxazoline ( e.g . fluralaner)/kg of fish, for up to 10 days, optionally for 10 days. In an embodiment, the isoxazoline, composition, or medicated fish feed is for use at a total dose of about 0.025 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a total dose of about 0.05 mg isoxazoline (e.g. fluralaner)/kg offish, up to about 25 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a total dose of about 0.1 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 10 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a total dose of about 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 , 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1 , 1.05 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1 .9, 2, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16,
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 0.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 0.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 0.7 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 0.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 0.9 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 1.1 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 1.2 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10,
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 1.4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 ,
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 1.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 1.7 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 1.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 1.9 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 2 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 2.1 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 2.2 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 2.3 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 2.4 mg isoxazoline ( e.g . fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 2.5 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 2.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 2.7 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 2.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 2.9 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 3 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 3.1 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 3.2 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 3.3 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 3.4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 3.5 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 3.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 3.7 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 3.8 mg isoxazoline ( e.g . fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 3.9 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 4.1 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 4.2 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 4.3 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 4.4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 4.5 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 4.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 4.7 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 4.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 days, for a total dose of about 4.9 mg isoxazoline (e.g. fluralaner)/kg offish.
  • the isoxazoline, composition, or medicated fish feed is for use for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, for a total dose of about 5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising at least about 0.005 mg isoxazoline ( e.g . fluralaner)/kg of fish, up to about 5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 5 to 15 days, for a total dose of about 0.025 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising at least about 0.01 mg isoxazoline (e.g. fluralaner)/kg of fish, up to about 5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.1 mg to about 50 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.005 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.05 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.01 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.02 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.2 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.03 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.3 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.04 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.05 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.06 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.07 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.7 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.08 mg isoxazoline (e.g . fluralaner)/kg of fish, for 10 days, for a total dose of about 0.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.09 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 0.9 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.1 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.11 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.12 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.2 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.13 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.3 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.14 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.15 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.16 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.17 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.7 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.18 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.19 mg isoxazoline ( e.g . fluralaner)/kg of fish, for 10 days, for a total dose of about 1.9 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.2 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.21 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.22 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.2 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.23 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.3 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.24 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.25 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.26 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.27 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.7 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.28 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.29 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.9 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.3 mg isoxazoline (e.g . fluralaner)/kg of fish, for 10 days, for a total dose of about 3 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.31 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.32 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.2 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.33 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.3 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.34 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 34 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.35 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.36 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.37 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.7 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.38 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.39 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.9 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.4 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.41 mg isoxazoline ( e.g . fluralaner)/kg of fish, for 10 days, for a total dose of about 4.1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.42 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.2 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.43 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.3 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.44 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.4 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.45 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.46 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.6 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.47 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.7 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.48 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.8 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.49 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.9 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.5 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.2 mg isoxazoline (e.g. fluralaner)/kg of fish, for 5 days, for a total dose of about 1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.167 mg isoxazoline (e.g . fluralaner)/kg of fish, for 6 days, for a total dose of about 1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.143 mg isoxazoline (e.g. fluralaner)/kg of fish, for 7 days, for a total dose of about 1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.125 mg isoxazoline (e.g. fluralaner)/kg of fish, for 8 days, for a total dose of about 1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.111 mg isoxazoline (e.g. fluralaner)/kg of fish, for 9 days, for a total dose of about 1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.1 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.091 mg isoxazoline (e.g. fluralaner)/kg of fish, for
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.083 mg isoxazoline (e.g. fluralaner)/kg of fish, for
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.077 mg isoxazoline (e.g. fluralaner)/kg of fish, for
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.071 mg isoxazoline (e.g. fluralaner)/kg of fish, for
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.067 mg isoxazoline (e.g. fluralaner)/kg of fish, for
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.11 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.1 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.12 mg isoxazoline ( e.g .
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.13 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.3 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.14 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.15 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 1.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.2 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.25 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 2.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.3 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.35 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 3.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.4 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.45 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 4.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.5 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.55 mg isoxazoline ( e.g . fluralaner)/kg of fish, for 10 days, for a total dose of about 5.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.6 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.65 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 6.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.7 mg isoxazoline (e.g.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 0.75 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 7.5 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for use at a daily dose comprising about 1 mg isoxazoline (e.g. fluralaner)/kg of fish, for 10 days, for a total dose of about 10 mg isoxazoline (e.g. fluralaner)/kg of fish.
  • the isoxazoline, composition, or medicated fish feed is for oral use by feeding a divided dose in a plurality of feeds once every 1 to 4 days for up to 15 days.
  • the isoxazoline, composition, or medicated fish feed disclosed herein can be used to treat or prevent parasite, e.g. sea lice infection in a fish, including any economically important fish such as salmonid.
  • the fish is carp, eel, trout, whitefish, salmon, bream, roach, rudd, chub, sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanese eel (Anguilla japonica), red sea bream (Pagurus major), sea bass (Dicen trarchus labrax), grey mullet (Mugilus cephalus), pompano, giltbread sea bream (Sparus auratus), Tilapia species, East Atlantic peacock wrasse (Symphodus tinea), cichlid species, such as, for example, plagioscion, channel catfish.
  • the fish is salmonid.
  • the salmonid is a salmon or trout.
  • the salmonid is Salmo salar, Oncorhynchus tshawytscha, Oncorhynchus kisutch, Oncorhynchus keta, Oncorhynchus gorbuscha, Oncorhynchus nerka, or Oncorhynchus mykiss.
  • each salmonid has an average mass of less than or equal to 5 kg, optionally an average mass of from 25 g to 5 kg.
  • the isoxazoline, isoxazoline-containing composition, or isoxazoline-containing medicated fish feed can treat parasites, e.g. sea lice infections.
  • the parasite is Copepodae (cyclops; fish-lice) with the genera Ergasilus , Bomolochus , Chondracanthus , Caligus(e.g. Caligus curtus), Lepeophtheirus (e.g. L. salmonis), Elythrophora , Dichelesthium , Lamproglena , Hatschekia , Leposphilus , Pseudocycnus, Lernaea , Lernaeocera, Pennella , Achtheres, Basanistes , Salmincola , Brachiella , Epibrachiella , PseudotracheUastes, Argulus, and Ceratothoa (e.g. Ceratothoa gaudichaudii).
  • the parasite is a sea louse.
  • the life cycle of sea lice begins at the nauplius stage when these planktonic nauplii cannot swim directionally against the water current but drift passively.
  • the free swimming nauplii then moult into the infective copepodid stage.
  • the copepodid has the ability to clasp onto the host tissue, and then it undergoes a moult to the immobile chalimus stages in the life cycle.
  • the sea lice are attached to the fish before becoming pre adults or mobile stage.
  • the sea lice are able to move around on the surface of the fish and can also swim in the water.
  • the sea louse is at any stage of life-cycle.
  • the sea louse is pre-adult sea lice, copepodites, chalimus, adult sea lice, or gravid female lice.
  • the sea louse is pre-adult sea louse.
  • the sea louse is copepodites.
  • the sea louse is chalimus.
  • the sea louse is adult sea lice.
  • the sea louse is gravid female lice.
  • the sea louse is Lepeophtheirus or Caligus
  • the Lepeophtheirus is Lepeophtheirus salmonis
  • the Caligus is Caligus clemensi, Caligus eiongatus, or Caligus rogercresseyi.
  • the fish are held in a pen prior to harvesting for the minimum time necessary for the isoxazoline residue (optionally fluralaner residue) to be reduced to a level that the fish is suitable for human consumption, optionally until residue testing on fish determines that the isoxazoline residue in the fish is below 0.65 parts per million.
  • the fish are harvested, optionally wherein the fish are harvested 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 21 , 22, 23, 24, or 25 days after the use is completed, optionally when isoxazoline residue (optionally fluralaner residue) in the fish is below 0.65 parts per million.
  • the present disclosure also includes a medicated fish feed comprising fish feed granules or pellets coated or mixed with a composition comprising an isoxazoline and at least one excipient.
  • the present disclosure also includes a pre-mix composition for medicated fish feed comprising an isoxazoline and at least one excipient.
  • a suitable means to mix the isoxazoline and the excipient can be made by a person skilled in the art. Then, for example, to formulate and administer the composition, a suitable amount (e.g . 5 kilograms) of the isoxazoline (e.g. fluralaner) containing pre-mix composition is mixed with a suitable amount (e.g. 5,000 kilogram) of fish feed and fed to the fish as the sole diet for, for example, 10 days.
  • a dry pre-mix composition is mixed in fish oil then applied to the fish feed, optionally in a vacuumed fat applicator.
  • a vacuumed fat applicator is a commonly used apparatus in large fish feed making plants.
  • the fish feed granules or pellets can be any suitable fish feed granules or pellets, the selection of which can be made by a person skilled in the art.
  • the method or use further comprises, after administration or use, holding the fish in a pen prior to harvesting for the minimum time necessary for the isoxazoline residue (optionally fluralaner residue) to be reduced to a level that the fish is suitable for human consumption, optionally until residue testing on fish determines that the isoxazoline residue in the fish is below 0.65 parts per million.
  • the method or use further comprises harvesting the fish, optionally 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 21 , 22, 23, 24, or 25 days after the administration or use is completed, optionally when isoxazoline residue (optionally fluralaner residue) in the fish is below 0.65 parts per million.
  • residue levels acceptable for harvest and therefore holding times may vary between different countries. It will also be appreciated that lower water temperatures typically increase excretion times of medications in fish (i.e. at lower water temperatures fish typically excrete lower amounts of medication per day) so longer holding periods would be expected at lower temperatures. The selection of suitable holding times and residue levels can be made by a skilled person.
  • the present inventor discloses that feeding isoxazoline (e.g . fluralaner) to fish in the form of a suitable medicated fish feed decreases parasite infestations (e.g. sea lice infections) and maintains good food uptake at doses of 0.01 to 0.1 mg isoxazoline (e.g. fluralaner)/kg fish per day.
  • the medicated fish feed used in the studies of the present disclosure was prepared by mixing feed pellet with powder formulation of fluralaner, and sealed with fish oil to help coat it onto the pellets of the salmon feed.
  • the present disclosure also includes medicated fish feed comprising fish feed granules or pellets coated or mixed with a composition comprising an isoxazoline and a carrier. It will be appreciated by a person skilled in the art that embodiments relating, for example, to the isoxazoline and the carrier in the medicated fish feeds of the present disclosure can be varied as detailed herein for the methods and uses of the present disclosure.
  • the medicated fish feed further comprises krill meal.
  • Atlantic Salmon Salmo salar
  • Atlantic Salmon Salmo salar
  • the isoxazoline class of compounds include fluralaner, afoxolaner and lotilaner.
  • the test compound in this example was fluralaner, which was tested at 3 doses.
  • Experimental diets were prepared by top dressing 3 mm floating feed pellets with the powder formulation of fluralaner and sealed with fish oil, this medicated feed was fed to the fish twice daily for ten days. Uneaten medicated feed pellets were removed and counted each day to estimate average dosage received by the fish. Fish were examined for sea lice 5 days following the end of the treatment period.
  • the medicated feed of the present disclosure is useful to deliver other isoxazolines for example, for sea louse control in salmonid and other fish.
  • Other types of isoxazolines are useful in the formulations and doses described herein to prevent and treat parasite infection in fish.
  • Medicated fish feed containing fluralaner was prepared for dose rates of 0.2, 0.1 , and 0.05 mg fluralaner / kg of fish biomass per day with a 5% overage to account for loss.
  • Materials were prepared to be sufficient to feed 70 fish per group, with the fish having an average base weight of 433.7 g, thus the biomass of each group was 30.359 kg. Therefore, the expected daily 0.6% food consumption was estimated as 0.182 kg/day.
  • the target concentration of the active ingredient in the medicated feed pellets for the dosage to give 0.1 mg of fluralaner, per kilogram of fish per day, plus a 5% overage for anticipated loss in mixing was 17.5 mg of active in 1 ,000 g of medicated feed pellets.
  • Fish oil was included at 0.75% or 7.5 g oil / kg pellets.
  • Atlantic Salmon Salmo salar
  • Atlantic Salmon Salmo salar
  • sea lice Lepeophtheirus salmonis
  • Fluralaner was tested at 3 doses (0.2, 0.1 , 0.05 mg fluralaner / kg fish / per day and control with no fluralaner).
  • Medicated fish feed prepared above was fed to the fish twice daily for ten days. At 11 and 20 days following the end of the treatment period, fish were examined for sea lice counts. At 11 days after the end of the 10-day treatment period, the average mobile sea lice (i.e.
  • control group averaged 32.9 mobile preadult lice.
  • daily dose of at least 0.1 fluralaner / kg fish for over 10 days (or at least 1 mg fluralaner / kg fish per entire treatment) was effective in reducing sea lice infection on salmon.

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Abstract

L'invention concerne des méthodes de prévention ou de traitement d'une infection parasitaire chez une pluralité de poissons le nécessitant, ces méthodes consistant à administrer au poisson une quantité efficace d'une isoxazoline telle que le fluralaner, une composition comprenant une isoxazoline telle que le fluralaner et au moins un excipient, ou des aliments médicamenteux pour poissons, comprenant des granulés d'aliments pour poissons, enrobés ou mélangés avec une composition comprenant une isoxazoline telle que le fluralaner et au moins un excipient. Le poisson peut être un salmonidé et le parasite peut être le pou de mer.
PCT/CA2022/050663 2021-04-30 2022-04-29 Utilisation d'isoxazoline pour protéger des poissons contre des parasites Ceased WO2022226660A1 (fr)

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WO2024189101A1 (fr) * 2023-03-13 2024-09-19 Virbac Composés d'arylaminobenzamide ou d'isoxazoline destinés à être utilisés dans la lutte contre une infestation parasitaire chez un poisson
EP4512398A1 (fr) * 2023-08-25 2025-02-26 Bimeda Animal Health Limited Fluralaner pour utilisation dans les procédés de traitement et de prévention d'infestation de poux de mer dans des poissons
GB2633692A (en) * 2023-09-15 2025-03-19 Evah Atlantic Inc Dihydroisoxazole compound for use in reducing ectoparasite infestations on fish

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Publication number Priority date Publication date Assignee Title
WO2024189101A1 (fr) * 2023-03-13 2024-09-19 Virbac Composés d'arylaminobenzamide ou d'isoxazoline destinés à être utilisés dans la lutte contre une infestation parasitaire chez un poisson
EP4512398A1 (fr) * 2023-08-25 2025-02-26 Bimeda Animal Health Limited Fluralaner pour utilisation dans les procédés de traitement et de prévention d'infestation de poux de mer dans des poissons
WO2025045633A1 (fr) * 2023-08-25 2025-03-06 Bimeda Animal Health Limited Fluralaner destiné à être utilisé dans des méthodes de traitement et de prévention de l'infestation par les poux de mer chez les poissons
GB2633692A (en) * 2023-09-15 2025-03-19 Evah Atlantic Inc Dihydroisoxazole compound for use in reducing ectoparasite infestations on fish
WO2025054724A1 (fr) * 2023-09-15 2025-03-20 Evah Atlantic Inc. Composé de dihydroisoxazole destiné à être utilisé dans la réduction d'infestations par des ectoparasites chez des poissons
US12280040B2 (en) 2023-09-15 2025-04-22 Evah Atlantic Inc. Compositions and methods of a dihydroisoxazole compound that reduces ectoparasite infestations on fish
DK202470232A1 (en) * 2023-09-15 2025-05-16 Evah Atlantic Inc Dihydroisoxazole compound for use in reducing ectoparasite infestations on fish

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