WO2006039079A2 - Formulations endoparasiticides et ectoparasiticides topiques - Google Patents

Formulations endoparasiticides et ectoparasiticides topiques Download PDF

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Publication number
WO2006039079A2
WO2006039079A2 PCT/US2005/031983 US2005031983W WO2006039079A2 WO 2006039079 A2 WO2006039079 A2 WO 2006039079A2 US 2005031983 W US2005031983 W US 2005031983W WO 2006039079 A2 WO2006039079 A2 WO 2006039079A2
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WO
WIPO (PCT)
Prior art keywords
formulation
group
topical formulation
animal
topical
Prior art date
Application number
PCT/US2005/031983
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English (en)
Other versions
WO2006039079A3 (fr
Inventor
Ian William Cottrell
Albert Ahn
Richard Fisher
Original Assignee
Summit Vetpharm, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/181,344 external-priority patent/US20050245582A1/en
Application filed by Summit Vetpharm, Llc filed Critical Summit Vetpharm, Llc
Priority to CA2579844A priority Critical patent/CA2579844C/fr
Priority to EP05795973A priority patent/EP1796463A4/fr
Priority to MX2007002832A priority patent/MX2007002832A/es
Priority to JP2007531327A priority patent/JP5622218B2/ja
Publication of WO2006039079A2 publication Critical patent/WO2006039079A2/fr
Publication of WO2006039079A3 publication Critical patent/WO2006039079A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N51/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds having the sequences of atoms O—N—S, X—O—S, N—N—S, O—N—N or O-halogen, regardless of the number of bonds each atom has and with no atom of these sequences forming part of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • This invention relates generally to topical formulations that can have significant parasiticidal activity as insecticides, endoparasites, ectoparasiticides and acaricides in animal health, such as one suitable to use on house pets such as dogs and cats.
  • animal health such as one suitable to use on house pets such as dogs and cats.
  • the infestation of companion animals with endoparasites and/or ectoparasites such as heartworms, roundworms, hookworms, whipworms, fleas, ticks, flies, mites and the like is highly undesirable and as such, it is beneficial to include multiple pharmaceutical drugs in the same formulation in order to target a wider variety of parasites. Additionally, it has become common to administer both topical and internal insecticides to livestock and pets. Topical applications can be desirable since many formulations are acceptably safe when used topically, but not when used internally.
  • topical pharmaceutical formulations have drawbacks. Some formulations require a large volume to be applied to the animal. This can cause considerable ' mess and can lead to an unpleasant smell. Additionally, if the dosage of a topical formulation is in a large volume, it can be easily shaken off by the animal thereby reducing the effectiveness of the formulation. Also, when the animal is a house pet, there is a further complication in that the formulation should be safe for human contact. It should also not lead to staining of furniture, carpeting and the like. Finally, even if safe, topical formulations should not be irritating or lead to rashes, hair loss or exhibit other unpleasant side effects.
  • a topical pharmaceutical formulation comprising a macrocyclic lactone, together with a neo-nicotinoid and/or an insect growth regulator, particularly one for use on cats and dogs, is provided.
  • Formulations in accordance with the invention can be safe to use and avoids many common deleterious side effects of conventional topical formulations.
  • the invention provides a topical formulation that contains a combination of insecticides and insect growth regulators, which can be effective to kill endoparasites and ectoparasites such as heartworm, fleas, flea eggs, flea larvae, ticks, tick eggs, tick larvae, tick nymphs, mites and mosquitoes.
  • endoparasites and ectoparasites such as heartworm, fleas, flea eggs, flea larvae, ticks, tick eggs, tick larvae, tick nymphs, mites and mosquitoes.
  • the selection of the combination of insecticides and insect growth regulators produces a composition having high parasitical activity, thereby providing broad protection against a variety of endoparasites and ectoparasites with a single application of the topical formulation.
  • the compositions derived herein can also be useful to improve the speed of result and decrease the reoccurrence, compared to other formulations.
  • the invention provides a topical formulation that contains a combination of a first active ingredient comprising a macrocyclic lactone and a second active ingredient comprising a neo-nicotinoid.
  • the topical formulation further contains an insect growth regulator (IGR).
  • IGR insect growth regulator
  • the macrocyclic lactone in the composition comprises at least one of ivermectin, selamectin, doramectin, moxidectin or eprinomectin.
  • the neo-nicotinoid can comprise a (tetrahydro-3-furanyl) methylamine derivative of formula (1), as identified below.
  • the neo-nicotinoid comprises a chloronicotinyl insecticide, preferably acetamiprid.
  • the insect growth regulator (IGR) preferably comprises pyriproxyfen and/or methoprene.
  • IGR insect growth regulator
  • the identification of an active ingredient, e.g., ivermectin, is intended to also refer to other pharmaceutically active forms of the active ingredient, such as esters, salts, hydrochlorides, acid or base forms, isomers and so forth.
  • the topical formulation also contains a pyrethroid such as permethrin or phenothrin in order to provide additional acaricide efficacy and to repel and kill mosquitoes.
  • a pyrethroid such as permethrin or phenothrin in order to provide additional acaricide efficacy and to repel and kill mosquitoes.
  • topical formulation also contains an IGR, which may be packaged with either the first or second formulation or in yet another container.
  • the first and second formulations are advantageously produced and packaged in a manner so that the first and second formulations can be prevented from interacting prior to application of the formulation to the animal.
  • the first and second formulations can be stored separately from each other in a package or container having two associated, preferably attached, but individual chambers to prevent the mixing of the first and second formulations prior to administration of the first and second formulation to the animal.
  • the first and second formulations can be advantageously packaged in a container or chamber that is opaque in order to prevent the photodegradation of the active ingredients in the formulations.
  • the packages containing the first and second formulations in their respective separate chambers are opened, and the first and second formulations are dispensed simultaneously or at least at about the same time, to the animal.
  • Another object of the invention is to provide a method for controlling parasites.
  • Another object of the invention is to provide a topical formulation that works more rapidly and/or more permanently than other topical formulations.
  • Another object of the invention is to provide an improved method of making an insecticide.
  • Another object of the invention is to provide a new insecticide packaging system.
  • insecticidal compositions which contain a combination of a macrocyclic lactone, a neo-nicotinoid and preferably, an insect growth regulator, that are effective against endoparasites and ectoparasites such as heartworm, fleas, flea eggs, ticks, and mites.
  • the combination of active ingredients produces topical formulations that provides broad protection against endoparasites and ectoparasites using a single application of the formulation.
  • insecticidal compositions of the invention comprise a first active ingredient comprising a macrocyclic lactone such as ivermectin, selamectin, doramectin moxidectin or eprinomectin, combined with a second active ingredient comprising a neo- nicotinoid such as dinotefuran or acetamiprid, in a suitable solvent solution.
  • a solvent comprising ethyl lactate and water should not be utilized. Rather, it has been determined that an effective solvent for the solubilization of high concentrations of dinotefuran and acetamiprid comprises ethanol.
  • the topical formulation further comprises an insect growth regulator (IGR).
  • IGR insect growth regulator
  • the first component in the formulation comprises a macrocyclic lactone such as ivermectin, selamectin, doramectin, moxidectin or eprinomectin
  • the second component is dinotefuran or N-((6-chloro-3- pyridinyl)methyl)-N'-cyano-N-methyl-ethanimidamide (acetamiprid)
  • the IGR is
  • the macrocyclic lactone in the formulation comprises at least one of ivermectin, selamectin, doramectin, moxidectin and eprinomectin
  • the neo-nicotinoid comprises a (tetrahydro-3-furanyl)methylamine derivative of following formula (1)
  • the IGR comprises pyriproxyfen and/or methoprene.
  • the (tetrahydro- 3-furanyl)methylamine derivatives of the formula (1) have an excellent insecticidal activity even in the absence of a pyridylmethyl group or a thiazolylmethyl group in their molecular structure.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 each represent each a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms
  • R 1 represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, an alkenyl group having 3 carbon atoms, a benzyl group, an alkoxyalkyl group having from 2 to 4 carbon atoms (in its whole group), an alkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxy carbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms, an alkenylcarbonyl group having from 2 to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoyl group, a benzoyl group substituted by alkyl group(s) having from 1 to 4 carbon atoms, a benzoyl
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 each represent each a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;
  • R 10 represents an alkyl group having from 1 to 5 carbon atoms or a benzyl group; and
  • R 11 represents an alkyl group having from 1 to 5 carbon atoms or a benzyl group.
  • alkyl group for X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 in the above formulae (1) and (2) include a methyl group, an ethyl group, an n-propyl group, an iso- propyl group, a tert-butyl group, and the like, preferably a methyl group.
  • alkyl group for R 1 examples include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n- butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and the like.
  • alkenyl group for R 1 examples include a 1-propenyl group, a 2- propenyl group, and the like.
  • alkoxyalkyl group for R 1 include a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, an iso-propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, and the like.
  • alkyloxycarbonyl group for R 1 examples include a methyloxycarbonyl group, an ethyloxycarbonyl group, an n-propyloxycarbonyl group, an iso- propyloxycarbonyl group, and the like.
  • alkylcarbonyl group for R 1 include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-propylcarbonyl group, an n- butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and the like.
  • alkenylcarbonyl group for R 1 examples include a vinylcarbonyl group, a 1-methylvinylcarbonyl group, and the like.
  • cycloalkylcarbonyl group for R 1 examples include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, and the like.
  • benzoyl group substituted by alkyl group(s) for R 1 include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a 4-methylbenzoyl group, a 4-tert- butylbenzoyl group, and the like.
  • benzoyl group substituted by halogen atom(s) for R 1 include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a 4-chlorobenzoyl group, a 3,4- dichloro-benzoyl group, a 4- fiuorobenzoyl group, and the like.
  • R 1 can take various substituents as described above, it is preferably a hydrogen atom, an alkylcarbonyl group having from 1 to 4 carbon atoms or a cyclopropylcarbonyl group.
  • alkylamino group for R 2 examples include a methylamino group, an ethylamino group, an n-propyl-amino group, an iso-propylamino group, an n-butylamino group, an iso-butylamino group, a sec-butylamino group, a tert-butylamino group, an n- pentylamino group, and the like, preferably a methylamino group.
  • di-substituted alkylamino group for R 2 include a dimethylamino group, a diethylamino group, an N-methyl-N-ethylamino group, an N-methyl-N- n-propylamino group, an N-methyl-N-n-butylamino group, and the like, preferably a dimethylamino group.
  • alkenylamino group for R 2 include a 1-propenylamino group, a 2-propenylamino group, and the like.
  • alkynylamino group for R 2 include a propargylamino group, and the like.
  • alkoxyalkylamino group for R 2 examples include a methoxymethylamino group, an ethoxymethylamino group, an n-propoxymethylamino group, an iso-propoxymethylamino group, a methoxyethylamino group, an ethoxyethylamino group, and the like.
  • alkyloxycarbonyl group denoted by Y 1 for R 2 include a methyloxycarbonyl group, an ethyloxy-carbonyl group, an n-propyloxycarbonyl group, an iso- propyloxy-carbonyl group, and the like.
  • alkylcarbonyl group denoted by Y 1 for R 2 include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso- propylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a sec-butyl- carbonyl group, a tertbutylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and the like, preferably a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonyl group and a tert-butylcarbonyl group.
  • alkenylcarbonyl group denoted by Y 1 for R 2 include a vinylcarbonyl group, a 1-methyl-vinylcarbonyl group, and the like.
  • cycloalkylcarbonyl group denoted by Y 1 for R 2 include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclo- hexylcarbonyl group, and the like, preferably a cyclopropyl-carbonyl group.
  • Y 1 for R 2 include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and the like.
  • benzoyl group substituted by halogen atom(s) denoted by Y 1 for R 2 include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a 4-chlorobenzoyl group, a 3,4-dichlorobenzoyl group, a 4-fluoro benzoyl group, and the like.
  • alkyl group denoted by Y 2 for R 2 include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and the like, preferably a methyl group.
  • the macrocyclic lactone comprises at least one ivermectin, selamectin, doramectin, moxidectin or eprinomectin
  • the neo-nicotinoid comprises l- ⁇ (tetrahydro-3-furanyl)methyl ⁇ -2-nitro-3-methylguanidine (dinotefuran)
  • the insect growth regulator preferably comprises pyriproxyfen or methoprene.
  • Dinotefuran is an insecticide that kills adult fleas
  • pyriproxyfen and methoprene are insect growth regulators that kill flea larvae and prevent flea eggs from hatching. Accordingly, the combination of dinotefuran and an IGR such as pyriproxyfen or methoprene provides for an effective flea control system since only about 5% of the existing fleas on an animal are adults and the other
  • dinotefuran is dissolved in the formulation to a concentration of approximately 50 to 150 mg/ml, more preferably 100 to 150 mg/ml, and most preferably, approximately 150 mg/ml.
  • Dinotefuran may be dissolved in particularly effective solvent systems such as a combination of water and ethanol or isopropanol, as disclosed in pending U.S. S.N. 10/242,552, or in phenyl methanol or ethanol, as disclosed in U.S. Patent 6,588,374, or in ethyl lactate and water combinations.
  • solvent systems such as a combination of water and ethanol or isopropanol, as disclosed in pending U.S. S.N. 10/242,552, or in phenyl methanol or ethanol, as disclosed in U.S. Patent 6,588,374, or in ethyl lactate and water combinations.
  • solvent systems such as a combination of water and ethanol or isopropanol, as disclosed in pending U.S. S.N. 10
  • the treatment of different endoparasites and ectoparasites are targeted by including particular macrocyclic lactones specific for the target endoparasite or ectoparasite in the topical formulation.
  • the combination of the macrocyclic lactone and neo-nicotinoid with an insect growth regulator preferably results in a topical formulation having effective insecticidal and parasiticidal activity against a variety of endoparasites and ectoparasites.
  • the topical formulation comprises a pyrethroid such as 2,2-Dimethyl-3 -(2 -methyl- l-propenyl)cyclopropanecarboxylic acid, (3-phenoxyphenyl)methyl ester (phenothrin) or cyclopropanecarboxylic acid, 3 -(2,2- dichlorethenyl)-2,2-dimethyl- (3-phenoxyphenyl)methyl ester (permethrin) in order to provide additional acaricide efficacy and to repel and kill mosquitoes.
  • Compositions containing permethrin in accordance with the invention are particularly advantageous for use on dogs, compared to their use on cats.
  • the topical formulation further comprises an IGR, which can be included in the first or second formulation or even separately in yet another container.
  • the first and second formulations are produced and packaged in a manner so that the first and second formulations are not permitted to interact prior to application of the total formulation to the animal.
  • the first and second formulations are stored separately from each other in a package or container having two associated, preferably attached, but individual chambers to prevent the mixing of the first and second formulations prior to administration of the first and second formulation to the animal.
  • the percentage of an active ingredient provided is the percentage of that active ingredient in a single solution.
  • 1 to 2% pyriproxyfen is the concentration of pyriproxyfen contained in the formulation in a single chamber rather than the concentration of pyriproxyfen in the total formulation of the combined chambers.
  • Macrocyclic lactones can be unstable in both acidic and basic solutions. For example, ivermectin is hygroscopic and therefore tends to be undesirably unstable.
  • the first active ingredient of the composition comprises ivermectin
  • the first and second formulations are stored in an opaque package or container to prevent the photodegradation of ivermectin during storage of the formulation.
  • the formulation will further comprise an antioxidant such as 2,6 ditertiarybutyl-4- methyl phenol (BHT) to prevent the oxidative degradation of ivermectin during storage of the formulation for a reasonable amount of time.
  • BHT 2,6 ditertiarybutyl-4- methyl phenol
  • the packages containing the first and second formulations in their respective separate chambers are opened, and the first and second formulations are dispensed simultaneously or at least at about the same time to the animal.
  • the first and second formulations can be packaged in a container having two associated, preferably attached, but individual, chambers to prevent the mixing of the formulations prior to the administration of the first and second formulations to the animal.
  • the container Prior to administration, the container can be opened and the first and second formulations can be dispensed simultaneously or nearly simultaneously to the
  • the insecticide composition of the invention can be packaged in a single dose package.
  • Single dose containers make storage and disposal more convenient for animal owners.
  • the composition is packaged in a container encompassing two associated, preferably attached but individual chambers, which are separated by a barrier, preferably plastic, plastic coated paper or metal, such as aluminum foil.
  • the first chamber and the second chamber are plastic tubes that are separate but fused together.
  • the first and second chambers are comprised of opaque plastic in order to prevent the photodegradation of the actives in the formulation.
  • the first formulation preferably comprising a macrocyclic lactone such as ivermectin, selamectin, doramectin, moxidectin or eprinomectin and a neo- nicotinoid, preferably dinotefuran or acetamiprid
  • the second formulation preferably comprising permethrin or phenothrin can be placed in the second chamber.
  • the topical formulation further comprises an IGR such as pyriproxyfen or methoprene, which may be included in the first or second formulation or in yet another container.
  • the first and second chambers can be separated by a barrier that prevents the interaction of the first and second formulations.
  • the entire container containing the first and second formulations in separate chambers is sealed, preferably with a tab or top, for use in opening the container prior to administration. After the container is sealed, the topical formulation can be safely stored in the container until administration of the formulation to the animal.
  • the container Prior to administration of the formulation to the animal, the container is opened by removing the tab or top. In one embodiment of the invention, the container is opened by twisting the tab thereby resulting in breaking or tearing of the barrier separating the two chambers, thereby allowing the first and second formulations to mix prior to administration of the insecticide formulation to the animal. After the two formulations are mixed, the two formulations are dispensed by squeezing or collapsing the body of the container either simultaneously or sequentially. In another embodiment of the invention, a dual plunger system can be employed to administer the formulation onto the animal.
  • first and second formulations need not be mixed together prior to administration of the topical formulation to the animal. Accordingly, in another embodiment of the invention, opening of the dual-chamber container does not result in the mixing of the first and second formulations. Rather, after the container is opened, the first and second formulations are dispensed onto the animal by squeezing or collapsing the container or containers, either simultaneously or sequentially.
  • the formulation is packaged with instructions, advising to mix the formulations.
  • the instructions will direct the user not to mix the formulation upon application.
  • compositions in accordance with preferred embodiments of the invention can be formulated with a relatively high concentration of active ingredients, a relatively small application of a spot or line on the animal can effectively prevent and control endoparasite and ectoparasite infestation on the animal for approximately one to four weeks post-administration.
  • the topical formulation is non-toxic and does not irritate the animal's skin.
  • the volume of total insecticide formulation applied onto a companion pet is in the range of about 0.5 to 10 ml, preferably about 2 to 5 ml, and most preferably, about 3 ml.
  • the volume of total insecticide formulation applied onto a small cat or kitten is in the range of about 0.5 to 1.5 ml. It should be noted that the total insecticide formulation contains solvents and other additives in addition to active ingredients and therefore, the volume of total insecticide formulation applied onto the animal does not comprise only actives.
  • the dosages of active ingredients in a single application of the topical formulation comprise approximately 0.16 to 4.80 mg of a macrocyclic lactone and approximately 90 to 1350 mg dinotefuran plus solvent, and preferably approximately 0.32 to 3.2 mg of a macrocyclic lactone and approximately 180 to 900 mg dinotefuran plus solvent.
  • the formulation further comprises an IGR such as pyriproxyfen or methoprene.
  • the dosage of pyriproxyfen in the total volume of a single application of the formulation is approximately 3.5 to 45 mg, and preferably, approximately 7 to 30 mg.
  • the dosage of methoprene in the total volume of a single application of the formulation is approximately 10 to 135 mg, and preferably, approximately 20 to 90 mg.
  • the insecticide formulation comprises ivermectin, dinotefuran and pyriproxyfen for the treatment of endoparasites and/or ectoparasites on cats and dogs. It should of course be understood that the actual amount of ivermectin in the formulation will vary depending on the size of the dog or cat. In a preferred embodiment the ivermectin ranges approximately 0.2 to 1.75 mg per ml of formulation.
  • up to 8 ml of the total insecticide composition can be administered to a dog weighing 55 to 120 pounds, and preferably, up to 6 ml.
  • composition will preferably comprise at least about 1.6 to 4.8 mg of ivermectin, at least about 450 to 1350 mg dinotefuran, and at least about 15 to 45 mg of pyriproxyfen. Even more preferably, the composition will comprise approximately 3.2 mg of ivermectin, approximately 900 mg dinotefuran, and approximately 30 mg of pyriproxyfen. In embodiments where the IGR is methoprene, the composition comprises at least about 45 to 180 mg methoprene.
  • approximately 6 to 8 ml of the total composition can be administered to a 55 to 120 Ib dog, which advantageously comprises approximately 675 to 2025 mg of permethrin or approximately 2015 to 5050 mg of phenothrin in order to provide additional acaricide efficacy and to repel and kill mosquitoes.
  • up to 4 ml of insecticide can be administered to a dog weighing 22 to 55 pounds.
  • Such composition will preferably comprise at least about 1.0 to 3.0 mg of ivermectin, at least about 300 to 900 mg dinotefuran, (and at least about 10 to 30 mg of pyriproxyfen. Even more preferably, the composition will comprise approximately 2.0 mg of ivermectin, approximately 600 mg dinotefuran, and approximately 20 mg of pyriproxyfen.
  • the composition comprises at least about 30 to 90 mg methoprene.
  • the composition further comprises approximately 450 to 1350 mg of permethrin or approximately 1115 and 3345 mg of phenothrin in order to provide additional acaricide efficacy and to repel and kill mosquitoes.
  • up to 2.1 ml of insecticide can be administered to an animal weighing 9 to 22 pounds.
  • Such composition will preferably comprise at least about 0.4 to 1.2 mg of ivermectin, at least about 225 to 675 mg dinotefuran, and at least about 5 to 15 mg of pyriproxyfen. Even more preferably, the composition will comprise approximately 0.8 mg of ivermectin, approximately 450 mg dinotefuran, and approximately 10 mg of pyriproxyfen.
  • composition further comprises at least about
  • the composition comprises at-leastabout 15 to-45-mg methoprene.
  • up to 1.5 ml of-insecticide can be administered to animals weighing 9 pounds or less.
  • Such composition will preferably comprise at least about 0.15 to 0.60 mg of ivermectin, at least about 90 to 270 mg dinotefuran, and at least about 3.5 to 12 mg of pyriproxyfen.
  • the composition will comprise approximately 0.32 mg of ivermectin, approximately 180 mg dinotefuran, and approximately 7 mg of pyriproxyfen.
  • the composition comprises at least about 10 to 30 mg methoprene.
  • the composition further comprises at least about 150 to 450 mg permethrin or about 475 to 1425 mg phenothrin in order to provide additional acaricide efficacy and to repel and kill mosquitoes. It should be noted that formulations containing permethrin are for application for dogs only.
  • the insecticide formulation comprises selamectin, dinotefuran and pyriproxyfen for the treatment of endoparasites and/or ectoparasites on cats and dogs. It has been determined that an effective dosage for selamectin contained in insecticide formulations according to the invention is approximately 3 to 6 mg per pound of animal body weight . Therefore, the actual amount of selamectin in the insecticide formulation will vary depending on the size of the dog or cat (for example, approximately 30 to 210 mg per ml of formulation).
  • the insecticide formulation comprises moxidectin, dinotefuran and pyriproxyfen for the treatment of endoparasites and/or ectoparasites on cats and dogs. It has been determined that an effective dosage for moxidectin contained in insecticide formulations according to the invention is approximately 0.2 mg per pound of animal body weight. Therefore,- the actual amount of moxidectin in the- insecticide formulation will vary depending on the size of the dog or cat.
  • the insecticide formulation comprises doramectin, dinotefuran and pyriproxyfen for the treatment of endoparasites and/or ectoparasites on cats and dogs. It has been determined that an effective dosage for doramectin contained in insecticide formulations according to the invention is approximately 0.02 mg per pound of animal body weight. Therefore, the actual amount of doramectin in the insecticide formulation will vary depending on the size of the dog or cat. [0079] In the preparation of a formulation for use on animals, there are several parameters that should be considered. These are:
  • the formulation should be stable for six months at 40 ° F and 75% relative humidity, room temperature and -10 F. This helps ensure that the formulation remains stable under the conditions that it could meet in commerce.
  • insecticidal formulations of the invention can contain an enzyme inhibitor or a synergist such as piperonyl butoxide, N- octylbicycloheptenedicarboximide, or triphenyl phosphate, which can increase the efficacy of the formulation.
  • the topical formulations also contain one or more compounds to increase the efficacy and to reduce the irritation of pyrethroid insecticides to the skin of animals.
  • the formulation can advantageously contain spreading agents such as n-octyl pyrrolidone and dioctylsulfosuccinimide, fragrances, and/or antioxidants.
  • additives to the insecticidal composition include but are not limited to fragrances, surfactants and spreading agents to increase performance such as polyoxyethylene (20) sorbitan monolaurate (commerically available as polysorbate 20 or Tween ® 20) and polyoxyethylene (20) sorbitan monooleate (commerically available as polysorbate 80 or Tween ® 80), and isopropyl myristate.
  • Polymers such as agar, gelatin, alginate, and cationic polymers such as cationic guar, cationic cellulose, cationic acrylates, and polyoxymethylene urea may also be added to provide enrobing of the insecticide Io improve safety and adhesion to skin and hair.
  • an effective amount of the insecticidal compositions as described herein may be applied to a companion animal, preferably a dog or a cat, as a foaming shampoo, dip, aerosol spray, pump spray, powder, lotion, emulsifiable concentrate, aqueous or liquid flowable, suspension concentrate and by any other methods suitable for administering topical compositions to animals.
  • Formulations containing permethrin cannot be applied to cats.
  • a mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol, 29. 5 g of trifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml of dichloromethane was stirred for an hour at room temperature. Water was poured into the reaction solution to separate the organic layer, which was washed with 1 N hydrochloric acid, water and a saturated saline solution, dried, and concentrated to obtain 20 g of 3-tetrahydro-furanylmethyl triflate.
  • Ivermectin (0.05 g) was dissolved in ethanol in a clean container with stirring until it was completely dissolved. This solution was added to a chamber in the package in the appropriate volume based on the dosage required.
  • a second solution containing dinotefuran was prepared by adding 25 g of dinotefuran to 100 ml phenyl methanol with stirring until it dissolved. This solution was added to the other chamber in the package in the appropriate volume based on the dosage required.
  • Example 2 placed in a chamber in the package in the appropriate volume based on the dosge required.
  • Example 4 Preparation of Compositions Containing Ivermectin, Dinotefuran and Methoprene [0089] A solution containing ivermectin was prepared using the methodology of
  • Example 2 placed in a chamber in the package in the appropriate volume based on the dosage required.
  • Methoprene (Lg) and Mackernium KP (1 g) were added to a clean container, and gently heated. Water (27.6 g) was added with stirring, followed by the addition of ethyl lactate (55.4 g). Dinotefuran (15 g) was added and the solution was mixed and heated at 50 degrees C until the dinotefuran dissolved. The solution was cooled to room temperature and the pH adjusted to 5.5 by the addition of sodium carbonate (0.15 g of a 25% aqueous solution). This solution containing dinotefuran and methoprene was added to the other chamber in the package in the appropriate volume based on the dosage required.
  • Example 5 Preparation of Compositions Containing; Ivermectin, Dinotefuran, Permethrin and Pyriproxyfen
  • Ivermectin (0.05 g) was added to this solution with stirring until it was completely dissolved.
  • Permethrin or phenothrin is preferably added to insecticide formulations according to the present invention in order to kill ticks and repel flies and mosquitoes.
  • This solution containing permethrin and ivermectin was added to one of the chambers in the package in the appropriate volume based on the dosage required.
  • Phenothrin (6.5 g) was dissolved in ethanol in a clean container with stirring.
  • Ivermectin (0.05 g) was added to this solution with stirring until it was completely dissolved.
  • Permethrin or phenothrin is preferably added to insecticide formulations according to the present invention in order to kill ticks and repel flies and mosquitoes. This solution containing phenothrin and ivermectin was added to one of the chambers in the package in the appropriate volume based on the dosage required.
  • an insecticide formulation containing moxidectin and dinotefuran was prepared using the methodology described in Example 3.
  • the total volume of the formulation is approximately 6 ml, comprises
  • moxidectin 11 to 24 mg of moxidectin and approximately 15% dinotefuran, which is approximately 900 mg dinotefuran for the treatment and prevention of fleas, prevention of heartworm, the control of roundworm, hookworms, and whipworms in dogs and cats.
  • the prevention of a specific parasite implies that the active ingredient precludes the parasite from having an effect, i.e., the active ingredient prevents the parasites from infesting the animal because the parasites are killed as soon as they enter the animal.
  • controlling a parasites implies that the active ingredient kills the parasites in an already infested animal.
  • the formulation further comprises approximately 10 mg/ml pyriproxyfen or approximately 30 mg/ml methoprene to kill flea larvae and prevent flea eggs from hatching. Even more preferably, the formulation also includes permethrin or phenothrin to kill ticks and repel mosquitoes and flies.
  • Example 8 Selamectin/Dinotefuran Compositions
  • an insecticide composition containing selamectin and dinotefuran was prepared using the methodology described in Example 2.
  • the total volume of the formulation applied to the companion animal is approximately 6 ml, which comprises approximately 8% to 15% dinotefuran and 2.6 to 12% selamectin.
  • the formulation comprises approximately 480 to 900 mg dinotefuran and 155 to 720 mg selamectin dissolved in solvent, which is effective in killing fleas, preventing flea eggs from hatching, preventing heartworm, controlling and treating ear mites, sacroptic mange and controlling tick infestation due to Dermacentor variabilis in dogs.
  • the formulation advantageously further comprises approximately 60 mg (10 mg/ml) pyriproxyfen or approximately 180 mg (30 mg/ml) methoprene, which provides additional efficacy against flea eggs.
  • Example 9 Compositions Containing Selamectin, Dinotefuran, Permethrin and Pyriproxyfen [00100]
  • permethrin (489.1 g) was dissolved in safflower oil (435.9g) in a clean container with stirring.
  • Selamectin (75 g) was added to this mixture with stirring until it was completely dissolved.
  • Permethrin or phenothrin is preferably added to insecticide formulations according to the present invention for additional acaricide efficacy and for the treatment of mosquitoes and flies. This solution containing permethrin and selamectin was added to one of the chambers in the package in the appropriate volume based on the dosage required.

Abstract

L'invention concerne une formulation topique présentant une activité parasiticide considérable, efficace contre des endoparasites et/ou des ectoparasites, notamment des filaires de chiens, des acariens, des puces, des tiques, des mouches. Cette formulation est inoffensive et permet d'éviter plusieurs effets secondaires nocifs communs des formulations topiques classiques. Les formulations topiques de l'invention comprennent une combinaison de lactose macrocyclique, un néo-nicotinoïde, et éventuellement, un régulateur de croissance d'insecte. La formulation topique peut être conditionnée avec ces substances ou conditionnée de sorte que le lactone macrocyclique et le néo-nicotinoïde soient stockés séparément, avant l'administration de la formulation insecticide topique à l'animal.
PCT/US2005/031983 2004-09-08 2005-09-07 Formulations endoparasiticides et ectoparasiticides topiques WO2006039079A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA2579844A CA2579844C (fr) 2004-09-08 2005-09-07 Formulations endoparasiticides et ectoparasiticides topiques
EP05795973A EP1796463A4 (fr) 2004-09-08 2005-09-07 Formulations endoparasiticides et ectoparasiticides topiques
MX2007002832A MX2007002832A (es) 2004-09-08 2005-09-07 Formulaciones topicas endoparasiticidas y ectoparasiticidas.
JP2007531327A JP5622218B2 (ja) 2004-09-08 2005-09-07 局所用殺内部寄生虫及び殺外部寄生虫製剤

Applications Claiming Priority (4)

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US60790004P 2004-09-08 2004-09-08
US60/607,900 2004-09-08
US11/181,344 2005-07-14
US11/181,344 US20050245582A1 (en) 2002-09-12 2005-07-14 High concentration topical insecticides containing pyrethroids

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WO2006039079A3 WO2006039079A3 (fr) 2007-07-05

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EP2015636A2 (fr) * 2006-04-28 2009-01-21 Summit Vetpharm, LLC Insecticides topiques à concentration élevée contenant des pyréthroïdes
WO2009059435A1 (fr) * 2007-11-08 2009-05-14 Ceapro Inc. Compositions contenant de l'avénanthramide
WO2017009219A1 (fr) * 2015-07-10 2017-01-19 Ceva Sante Animale Combinaisons de néonicotinoïde et de pyréthrinoïde pour lutter contre la propagation de dirofilariose
WO2019166649A1 (fr) * 2018-03-01 2019-09-06 Ceva Sante Animale Compositions vétérinaires pour lutter contre les moustiques
US11134685B2 (en) 2015-07-24 2021-10-05 Ceva Santé Animale Compositions and uses thereof for controlling ectoparasites in non-human mammals
CN117084254A (zh) * 2023-08-02 2023-11-21 湖北省疾病预防控制中心（湖北省预防医学科学院） 一种适用于动物及环境杀蜱虫组合物及其制备方法和应用

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US20050245582A1 (en) 2002-09-12 2005-11-03 The Hartz Mountain Corporation High concentration topical insecticides containing pyrethroids
WO2007127959A2 (fr) * 2006-04-28 2007-11-08 Summit Vetpharm, Llc Insecticide topique très concentré contenant un produit de régulation de la croissance des insectes

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US5942525A (en) 1995-05-11 1999-08-24 Ecto Development Corporation Spot treatment of animals with pyriproxyfen and an insecticide
EP0976328A2 (fr) 1998-07-27 2000-02-02 Sumitomo Chemical Company, Limited Agent pour lutter contre les ectoparasites sur des animaux
DE10207241A1 (de) 2002-02-21 2003-09-04 Bayer Cropscience Ag Synergistische insektizide Mischungen
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2015636A2 (fr) * 2006-04-28 2009-01-21 Summit Vetpharm, LLC Insecticides topiques à concentration élevée contenant des pyréthroïdes
EP2015636A4 (fr) * 2006-04-28 2013-04-10 Summit Vetpharm Llc Insecticides topiques à concentration élevée contenant des pyréthroïdes
WO2009059435A1 (fr) * 2007-11-08 2009-05-14 Ceapro Inc. Compositions contenant de l'avénanthramide
WO2017009219A1 (fr) * 2015-07-10 2017-01-19 Ceva Sante Animale Combinaisons de néonicotinoïde et de pyréthrinoïde pour lutter contre la propagation de dirofilariose
CN107921016A (zh) * 2015-07-10 2018-04-17 法国诗华大药厂 用于控制恶丝虫病传播的新烟碱和拟除虫菊酯的组合
RU2732965C1 (ru) * 2015-07-10 2020-09-25 Сева Санте Анималь Комбинация неоникотиноидного и пиретроидного соединений для контроля распространения дирофиляриоза собак сердечной формы
US10952988B2 (en) * 2015-07-10 2021-03-23 Ceva Santé Animale Methods for controlling the spread of dirofilariosis
AU2016292816B2 (en) * 2015-07-10 2021-08-26 Ceva Sante Animale Combinations of a neonicotinoid and a pyrethroid for controlling the spread of dirofilariosis
US11134685B2 (en) 2015-07-24 2021-10-05 Ceva Santé Animale Compositions and uses thereof for controlling ectoparasites in non-human mammals
WO2019166649A1 (fr) * 2018-03-01 2019-09-06 Ceva Sante Animale Compositions vétérinaires pour lutter contre les moustiques
CN117084254A (zh) * 2023-08-02 2023-11-21 湖北省疾病预防控制中心（湖北省预防医学科学院） 一种适用于动物及环境杀蜱虫组合物及其制备方法和应用
CN117084254B (zh) * 2023-08-02 2024-05-07 湖北省疾病预防控制中心（湖北省预防医学科学院） 一种适用于动物及环境杀蜱虫组合物及其制备方法和应用

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EP1796463A2 (fr) 2007-06-20
WO2006039079A3 (fr) 2007-07-05
JP2008512478A (ja) 2008-04-24
CA2579844C (fr) 2013-07-02
CA2579844A1 (fr) 2006-04-13
EP1796463A4 (fr) 2012-09-19
JP5622218B2 (ja) 2014-11-12

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