GB2464449A - A topical ectoparasiticide composition - Google Patents

A topical ectoparasiticide composition Download PDF

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Publication number
GB2464449A
GB2464449A GB0816306A GB0816306A GB2464449A GB 2464449 A GB2464449 A GB 2464449A GB 0816306 A GB0816306 A GB 0816306A GB 0816306 A GB0816306 A GB 0816306A GB 2464449 A GB2464449 A GB 2464449A
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composition according
composition
ether
insecticide
methoprene
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GB2464449B (en
GB0816306D0 (en
Inventor
Eddie O'gorman
Willy Blakely
Lillian Cromie
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Norbrook Laboratories Ltd
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Norbrook Laboratories Ltd
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Priority to GB0816306A priority Critical patent/GB2464449B/en
Publication of GB0816306D0 publication Critical patent/GB0816306D0/en
Priority to PCT/GB2009/002107 priority patent/WO2010026370A1/en
Priority to ARP090103425A priority patent/AR074974A1/en
Publication of GB2464449A publication Critical patent/GB2464449A/en
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    • 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
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom
    • 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
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • 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
    • A01N49/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds containing the group, wherein m+n>=1, both X together may also mean —Y— or a direct carbon-to-carbon bond, and the carbon atoms marked with an asterisk are not part of any ring system other than that which may be formed by the atoms X, the carbon atoms in square brackets being part of any acyclic or cyclic structure, or the group, wherein A means a carbon atom or Y, n>=0, and not more than one of these carbon atoms being a member of the same ring system, e.g. juvenile insect hormones or mimics thereof
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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

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

Abstract

A topical ectoparasiticide composition comprising: i) an Insect Growth Regulator (IGR) and/or a phenyl pyrazole insecticide; and/or a chloronicotinyl insecticide; ii) glycol ether; and iii) butanol and/or dimethylsulfoxide (DMSO). The preferred IGRs include hydroprene, s- hydroprene, kinoprene, s-kinoprene, fenoxycarb, pyriproxifen, cyromazine, dimilin and novaluron, especially methoprene or s-methoprene. The preferred phenyl pyrazole insecticide is fipronil. Preferably, the chloronicotinyl insecticide is imidacloprid and/or thiacloprid. The preferred glycol ether is diethylene glycol monoethyl ether. The composition may also comprise a crystallization inhibitor and/or a surfactant and/or an antioxidant and/or a propellant. The composition is useful for the treatment for the reduction or inhibition of juvenile ectoparasite maturation from the skin of an animal.

Description

A topical ectoparasiticide composition The present invention relates to an ectoparasiticide composition for topical application comprising an Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chloronicotinyl insecticide, and its use in a method of treatment for the reduction or inhibition of the maturation of ectoparasites. In particular, the topical composition may be used in a method of treatment for reduction or inhibition of the maturation of fleas and ticks from infested animals.
Insect growth regulators (IGRs) like methoprene, hydroprene, kinoprene, fenoxycarb, pyriproxifen, cyromazine, dimilin and novaluron are a class of insecticides that inhibit chitin synthesis or the development of parasites from immature stages, like eggs and larvae, into the adults. Common ectoparasiticides which may be treated with insect growth regulators include fleas and ticks, for example the Siphonaptera order and Ctencephalides Fells and Ctencephalides Canis, human fleas like Pulex Irritans, rat fleas like Xenopsylla Cheopis and ticks like those of cattle (e.g. oophilus Microplus) and of dog (Rhipicephali Sanguineus) . Examples of formulations containing methoprene which are effective against ticks include US-5,194,264 which describes an aqueous/polar solvent methoprene composition.
US-6,492,419 discloses a composition with an Insect Growth Regulator (IGR) in a vehicle comprising a suspending agent, an anionic surfactant, a non-ionic surfactant or mixtures thereof, and an aqueous carrier.
Compositions comprising phenyl pyrazole, and in particular formulations of 5-amino-i--(2, 6-dichioro-4-trifluoromethylphenyl) -3--cyano-4-trifluoromethyl suiphinyl pyrazole, which is commonly known as Fipronil, are known to be used for the eradication or reduction of ectoparasites from the skin of an animal. A number of publications indicate that a crystallisation inhibitor is required in order for the phenyl pyrazole, and in particular fipronil, to remain in solution and not crystallise out on the skin surface of an animal. For example the Frontline� product (EP0881881 Bi) comprises polyvinylPyrrolidone (PVP) which acts as a crystailisation inhibitor. Other known crystallisation inhibitors for topical fipronil compositions are described in the prior art and include, sorbitol lecithin, anionic surfactants, cationic surfactants, amine salts, non-ionic surfactants and amphoteric surfactants.
The known formulations typically require the presence of one or more of adjuvants and/or crystallisation inhibitors in order to provide stable compositions in which the active (Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chioronicotinyl insecticide) is prevented from crystallising out on the skin surface of the treated animal.
It is an object of the present invention to provide a stable topical composition for application to humans or animals comprising an Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chloronicotinyl insecticide, especially methoprene and/or fipronil, which preferably does not require the presence of adjuvants and/or crystallisation inhibitors, and still provides efficacious levels of insecticide activity over the surface of the human or animal treated for a number of weeks.
In a first aspect of the present invention there is provided a topical ectoparasiticide composition comprising: (i) an Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chioronicotinyl insecticide; (ii) glycol ether; and (iii) butanol and/or DMSO.
In the second aspect of the present invention there is provided a topical ectoparasiticide composition consisting of: (i) an Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chioronicotinyl insecticide; (ij_) glycol ether; (iii) optionally butanol and/or DMSO; (iv) optionally a crystallisation inhibitor; (v) optionally a surfactant; (vi) optionally an antioxidant; and (v) optionally a propellant.
In a third aspect of the present invention there is provided a composition as described herein for use in a method of treatment of the human or animal body by therapy.
In a fourth aspect of the present invention there is provided a composition as described herein for use in a method of treatment for the reduction or inhibition of juvenile ectoparasite maturation from the skin of an animal, wherein the composition is applied topically to the skin of the animal.
In a fifth aspect of the present invention there is provided the use of a composition as described herein for the reduction or inhibition of juvenile ectoparasite maturation from the skin of an animal or from the environment of an animal.
The present inventors have surprisingly found that by using a topical ectoparasiticide composition consisting of glycol ether as a solvent or compositions comprising solvents of glycol ether and butanol and/or DM50 that stable topical compositions may be produced without the need to include additional adjuvants or further crystallisation inhibitors.
The formation of stable topical compositions without the need for crystallisation inhibitors is advantageous because the product is easier, faster and cheaper to make, whilst still providing an efficient and effective topical composition for the reduction or elimination of ectoparasites. It has surprisingly been found that such compositions, even without the presence of additional crystallisation inhibitors, do not crystallise on the skin of an animal after application. These compositions have also been found to have good storageability. Furthermore these compositions do not cause, or cause reduced skin irritation at the site of application.
Advantageously, by providing topical ectoparasiticide compositions comprising glycol ether as solvent, and preferably at least 50% (w/v) of glycol ether based on the total composition, then combinations of actives can be combined into a stable formulation, for example an Insect Growth Regulator and/or a phenyl pyrazole insecticide may be combined within the same composition. Advantageously, such formulations do not require the presence of additional crystallisation inhibitors, although these may be present as well.
Although topical ectoparasiticide compositions and in particular those comprising Insect Growth Regulators and/or phenyl pyrazole insecticides using mixtures of solvents are known in combination with the need for additional adjuvants or further crystallisation inhibitors the use of a topical ectoparasiticide compositions consisting of glycol ether as a solvent or compositions comprising solvents of glycol ether and butanol and/or DMSO are not known.
Each aspect as defined herein may be combined with any other aspect or aspects unless clearly indicated to the contrary.
In particular any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
Preferably, the Insect Growth Regulator is selected from methoprene, s-methoprene, hydroprene, s-hydroprene, kinoprene, s-kinoprene, fenoxycarb, pyriproxif en, cyromazine, dimilin, novaluron, pharmaceutically or veterinarily acceptable derivatives or prodrugs thereof and mixtures of two or more thereof. Most preferably the Insect Growth Regulator is s-methoprene or methoprene, pharmaceutically or veterinarily acceptable derivatives or prodrugs thereof and mixtures of two or more thereof.
Preferably the phenyl pyrazole insecticide has the formula (I) R4 (Y)p formula (I) in which: Rj is a halogen atom, CN or methyl; R2 is S(O)R3 or 4,5-dicyanoimidazol-2--yl or haloalkyl; R3 is alkyl or haloalkyl, for example lower haloalkyl; R4 represents a hydrogen or halogen atom; or a radical NR5R6, S(O)mR7, C(O)R7 or C(O)0R7, alkyl, haloalkyl or OR8 or a radical -N-C(R9) (R10) R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, S(O)rCF3, acyl or alkoxycarbonyl radical; or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms such as oxygen or sulphur; R7 represents an alkyl or haloalkyl radical; R8 represents an alkyl or haloalkyl radical or a hydrogen atom; R9 represents an alkyl radical or a hydrogen atom R10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -0-alkyl, -S-alkyl, cyano or alkyl; Y represents a halogen atom or a haloalkyl or haloalkoxy radical, for example a lower haloalkoxy radical, or an SF5 radical, with the possibility that: Y is CN or NO2 in positions 2 and 6 (with reference to the carbon of the phenyl ring which is attached to the pyrazole ring and designated 1); the carbon in position 2 of the phenyl ring is replaced by a trivalent nitrogen atom; Y is S(O)qCF3 in position 4 on the phenyl ring, but preferably haloalkyl, haloalkoxy or SF5; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; p is an integer equal to 1, 2, 3, 4 or 5, preferably equal to 1, 2 or 3, in particular 3; with the proviso that when R1 is methyl, then either R3 is haloalkyl, R4 is NH2, p is 2, Y in position 6 is Cl, Y in position 4 is CF3 and the carbon in position 2 of the phenyl is replaced by N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, p is 3, Y in position 6 is Cl, Y in position 4 is CF3 and the carbon in position 2 of the phenyl is replaced by =C-Cl.
As used herein the term lower haloalkoxy radicals preferably refers to haloalkoxy radicals having C1-C4 carbon atoms.
Preferably the insecticide of formula (I) is 1-[2,6-Cl2 4- CF3 phenyl] 3-CN 4-[SO-CF3I 5-NH2 pyrazole, (also known as 5- amino-i-(2, 6-dichloro-4-trifluoromethyiphenyl) -3-cyano- 4-trifluorornethyl suiphinyl pyrazole) whose common name is fipronil. Pharmaceuticaliy or veterinarily acceptable derivatives or prodrugs of fipronil may also be used.
The compounds of formula (I) may be prepared, for example, according to one of the processes described in, for example, patent application WO-A-87/3781.
Preferably the the chioronicotinyl insecticide is selected from imidacloprid and/or thiacloprid or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
The Insect Growth Regulator and/or phenyl pyrazole insecticide; and/or a chioronicotinyl insecticide may be present from 0.1% to 100% (weight/volume) w/v, preferably it is present between from 1 to 40% w/v, more preferably from 5 to 20% most preferably from 8 to 15% w/v, even more preferably it is present at 12% w/v based on the total composition.
Preferably, the glycol ether is selected from ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, ethylene ylycol monomethyl ether, diethylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol monoethyl ether, propylene glycol rnonomethyl ether, dipropylene glycol monomethyl ether and mixtures of two or more thereof. The glycol ether may also be, for example, dipropylene glycol n-butyl ether, dipropylene glycol methyl ether, dipropylene glycol ethyl ether. More preferably the glycol ether is selected from diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol mononiethyl ether and mixtures of two or more thereof.
Most preferably the glycol ether is selected from diethylene glycol monoethyl ether, and/or ethylene glycol monoethyl ether.
Preferably, the composition comprises at least 35%(w/v), at least 40% (w/v), at least 50% (w/v), more preferably at least 60% (w/v) of glycol ether based on the total composition. More preferably still, the composition comprises at least 70% (w/v) of glycol ether based on the total composition. Most preferably, the composition comprises at least 80% (w/v) or at least 90% (w/v) of glycol ether based on the total composition. The composition may comprise up to 99% (w/v) of glycol ether based on the total composition.
In the first aspect of the present invention the composition comprises butanol and/or DMSO in addition to glycol ether.
In the second aspect of the present invention the composition preferably comprises butanol and/or DMSO in addition to glycol ether.
The butanol may one of more of n-butanol, sec-butanol, isobutanol and tert-butanol. Preferably the butanol is n-butanol.
Preferably, the composition comprises less than 30% (w/v) of butanol based on the total composition. More preferably, the composition comprises less than 20% (w/v), less than 15% (w/v) or less than 10% (w/v) of butanol based on the total composition.
Preferably, the composition comprises less than 30% (w/v) of DMSO based on the total composition. Preferably, the -10 -composition comprises less than 20% (w/v), less than 15% (w/v) or less than 10% (w/v) of DMSO based on the total composition. it is advantageous for the amount of DMSO in the composition to be low, because otherwise the active goes through the skin, and the action of the active is systemic, rather than topical.
Preferably the composition of the present invention is a non-aqueous composition. Preferably the composition comprises less than 1% (w/v), more preferably less than 0.5% (w/v) water based on the total composition. Most preferably the composition does not comprise any water.
Other suitable solvents may be present in the topical composition of the first aspect of the present invention.
Suitable other solvents include, but are not limited to acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, ethanol, isopropanol, I monomethylacetamide, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone, ethylene glycol, diethyl phthalate, and mixtures of two or more thereof. The preferred additional solvents are ethanol, isopropanol, or benzyl alcohol.
Preferably the composition of the present invention is free of crystallisation inhibitors. This has the advantage that the composition may be made more cheaply and efficiently, whilst still being effective.
Advantageously, the composition of the present invention comprises less than 25% (w/v) of crystallisation inhibitor, -11 -more preferably less than 10% (w/v), more preferably still less than 1% (w/v) based on the total composition.
As used herein the term "crystallisation inhibitor" may be used to mean an agent or substance which inhibits crystal formation of the insect growth inhibitor in the composition.
The crystallisation inhibitor preferably corresponds to a test in which lOml of the composition comprising 10% (w/v) of inhibitor is placed in a glass slide at 20°C for 24 hours. The slide is then observed with the naked eye.
Acceptable inhibitors are those whose addition provides few or no crystals, and in particular less than 10 crystals, preferably less than 5 crystals, more preferably 0 crystals.
In an alternative embodiment, the composition of the present invention may comprise at least one crystallisation inhibitor. Suitable crystallisation inhibitors are known in the art and include, but are not limited to polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose; acrylic derivatives such as methacrylates and the like, alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecy].benzenesulphonate, sodium dioctylsuiphosuccinate; cationic surfactants such as water-soluble quaternary ammonium salts of formula NR'R' R' R' Y in which the radicals R are hydrocarbon radicals, optionally hydroxylated, and Y is an anion of a strong acid such as halide, sulphate and sulphonate anions; cetyltrimethylammoniurn bromide is among the cationic -12 -surfactants which can be used, amine salts of formula NR'R' R''' in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used, nonionic surfactants such as optionally polyoxyethylenated sorbitan esters, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as lauryl-substituted betaine compounds, or preferably a mixture of at least two of these crystallization inhibitors. Preferably the crystallisation inhibitor is polyvinylpyrrolidone, polyvinyl alcohols, polyethylene glycol, benzyl alcohol and/or lecithin.
The composition may comprise anti-oxidants. Suitable antioxidants include, but are not limited to butylated hydroxyanisole (BHA), butylated hydroxytoluene, ascorbic acid, alpha, beta or gamma tocopherol, sodium metabisuiphite, propyl gallate, sodium thiosuiphate, and mixtures of two or more thereof. Preferred antioxidants are butylated hydroxyanisole (BHA) and butylated hydroxytoluene.
Addition of antioxidants may be advantageous in extending the shelf-life of the compositions.
Preferably in the composition anti-oxidants are present in a concentration of from 0.005 to 1% (w/v) based on the total composition, more preferably from 0.01 to 0.05% (w/v) The composition of the present invention may include additional active agents which help to enable the -13 -composition to be sprayed, squirted, or rubbed on to the skin. These include, for example, conventional propellent gases required for spray cans, such as propane, butane, dimethyl ether, C02, or halogenated lower alkyl gases (for example, halogenated C1-C4 alkyls), and mixtures of two or more thereof.
As outlined above in the second aspect of the present invention there is provided a topical ectoparasiticide composition consisting of: (i) an Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chioronicotinyl insecticide; (ii) glycol ether; (iii) optionally butanol and/or DMSO; (iv) optionally a crystallisation inhibitor; (v) optionally a surfactant; (vi) optionally an antioxidant; and (v) optionally a propellant.
Preferably, in this second aspect, the composition consists of at least 50% (w/v), more preferably at least 60% (w/v) of glycol ether based on the total composition. More preferably still, the composition consists of at least 70% (w/v) of glycol ether based on the total composition. Most preferably, the composition consists of least 80% (w/v) of glycol ether based on the total composition. The composition may consist of up to 99% (w/v) of glycol ether based on the total composition.
Each of the preferred features as outlined herein are applicable to both the first and second aspect of the -14 -present invention, unless explicitly stated to the contrary.
In the second aspect of the present invention the presence of butanol and/or DMSO is optional.
In one embodiment the composition consists of (i) methoprene and/or fipronil; (ii) diethylene glycol monoethyl ether; (iii) butanol; (iv) polyvinylpyrrolidone; (v) polysorbate 80; and (vi) butylated hydroxyanisole and/or butylated hydroxytoulene.
The present inventors have found that this embodiment is particularly stable whilst providing good skin tolerance, and good parasiticide properties.
The compositions according to the invention are usually prepared by simply mixing the constituents as defined above.
Advantageously, to begin with, the an Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chloronicotinyl insecticide is mixed into the main solvent, and the other ingredients or adjuvants are subsequently added.
The compositions according to the invention are typically intended for pets, in particular cats and dogs, and are generally applied by deposition on the skin ("spot on" or "pour on" application) . This is generally a localized application to a region with a surface area of less than 10 -15 -cm2, typically between 5 and 10 cm2. The composition may, for example, by applied at one, two or more points and is preferably localized between the animal's shoulders. After deposition, the composition diffuses, in particular over the animal's entire body, and then dries, without crystallizing or changing the appearance (in particular there is an absence of any whitish deposit or of any dusty appearance) or the feel of the coat. The composition of the present invention may be a spot-on or a spray-on formulation.
The composition of the present invention may be in the form of a concentrated emulsion, microemulsion, suspension, or solution for spot-on application to an animal. In less preferred embodiments the composition may be in the form of a spray, an emulsion, microemulsion, suspension, or solution of the pour-on-type, an oil, a cream, an ointment, or any other fluid formulation for topical administration.
The compositions according to the present invention are particularly advantageous on the grounds of their efficacy, their speed of action and the pleasant appearance of the animal's hair after application and drying.
It is preferable that the composition of the present invention is administered every 4 weeks or even more preferably every B or 12 weeks on small animals, such as cats and dogs.
The volume applied to a dog is typically from 0.25 to 3m1 and to a cat is typically from 0.25 to lml.
-16 -The composition of the present invention may be used to treat insect infestation on humans, large and small animals, birds and reptiles. Preferably the animal to be treated is a human, cow, horse, bird or small animal. Most preferably it is a cat or a dog. The larger the animal to be treated, the larger the dose volume of the composition to be applied.
The composition of the present invention is especially suitable for administration to dogs and cats.
The composition of the present invention is preferably administered in order to provide doses of from 1 to 30 mg/kg of the insect growth regulator per kg of animal body weight, more preferably from S to 25 mg/kg, more preferably still from 10 to 20 mg/kg.
The composition of the present invention may be used to improve the appearance and texture of an animal's coat by elimination or reduction of mature entoparasites therefrom and any consequential irritation caused, however slight, to the infected animal. One object of the present invention is to provide a non-therapeutic method of cleaning animal hairs and skin by the reduction or elimination of mature parasites which are present in the animal hair or skin. The treated animals have hair that has a more pleasant look and feel.
Additionally, the compositions of the current invention may be used prophylactically in order to inhibit or reduce maturation of juvenile ectoparasites like fleas or even ticks. The compositions may be used such that the treated animal are used as vectors in order to eradicate or reduce insects (for example ticks) from the animals environment, e.g. like bedding, carpet, floors and walls.
-17 -In one embodiment, the present invention provides a therapeutic treatment, and the composition may be used in a method of treatment for the inhibition of juvenile S ectoparasite maturation from the skin of an animal, wherein the composition is applied topically to the skin of the animal. The process described herein may be used to control ectoparasites, and in particular ticks.
In one aspect of the present invention there is provided the use of a composition as described herein in the manufacture of a medicament for the inhibition or reduction of juvenile ectoparasite maturation from the skin of an animal.
In further embodiment the present invention provides a method for the inhibition or reduction of juvenile ectoparasite maturation from the skin of an animal, the method comprising applying the topical composition as defined herein to the skin of an animal. Preferably the topical composition is in the form of a spot-on composition.
Preferably the composition is applied between the shoulders of the animal. Preferably the animal is a dog or a cat.
Preferably, the composition comprises methoprene and/or fipronil. Preferably the composition is applied in unit dosage form.
The present invention will be further illustrated with reference to the following non-limiting Examples.
q.s. as used herein means quantity sufficient.
-18 -
Example 1
Fipronil 10%w/v S-methoprene 12%w/v Diethylerie Glycol Monoethyl Ether q.s. 100%
Example 2
Fipronil 10%w/v Butanol 1O%w/v PVP 5%w/v Polysorbate 80 5%w/v Butylated Hydroxyanisole 0.02%w/v Butylated Hydroxytoluene O.01%w/v Diethylene Glycol Nonoethyl Ether q.s. 100%v/v
Example 3
For cats S-Methoprene 12%w/v Butanol 10%w/v PVP 5%w/v Polysorbate 80 5%w/v Eutylated Hydroxyanisole 0.02%w/v Butylated Hydroxytoluene 0.01%w/v Diethylene Glycol Monoethyl Ether q.s. 100%v/v -19 -
Example 4
For dogs S-Methoprene 9%w/v Butanol l0%w/v PVP 5%w/v Polysorbate 80 5%w/v Butylated Hydroxyanisole 0.02%w/v Butylated Hydroxytoluene 0.01%w/v Diethylene Glycol Monoethyl Ether q.s. 100%v/v Skin Tolerance Test: Clinical trials were carried out using the above formulations on 3 cats and 3 dogs.
Skin tolerance tests were carried out these animals after 2h, 4hr, 1 day, 2 days 5 days and 7 days.
No Irritation was observed. No skin reaction, swelling or reddening was observed. No clinical reactions, for example convulsions or hypersalivation, were observed.
No Crystallisation Observed.

Claims (34)

  1. -20 -CLAIMS1. A topical ectoparasiticide composition comprising: (1) an Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chioronicotinyl insecticide; (ii) glycol ether; and (iii) butanol and/or IJMSO.
  2. 2. The composition according to claim 1 comprising of least 60% (w/v) of glycol ether based on the total composition.
  3. 3. The composition according to claim 2 consisting of at least 80% (w/v) of glycol ether based on the total composition.
  4. 4. The composition according to claim 1 wherein the glycol ether is selected from ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol monoethyl ether, propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and mixtures of two or more thereof.
  5. 5. The composition according to any one of the preceding claims wherein the Insect Growth Regulator is selected from methoprene, s-methoprene, hydroprene, s-hydroprene, kinoprene, s-kinoprene, fenoxycarb, pyriproxiferi, cyromazine, dimilin, novaluron, pharmaceutically or -21 -veterinarily acceptable derivatives or prodrugs thereof and mixtures of two or more thereof.
  6. 6. The composition according to claim 5 wherein the Insect S Growth Regulator is s-methoprene or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
  7. 7. The composition according to any one of the preceding claims wherein the phenyl pyrazole insecticide is fipronil or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
  8. 8. The composition according to any one of the preceding claims wherein the Insect Growth Regulator is present in a concentration of from 0.1 to 40% (w/v) based on the total composition.
  9. 9. The composition according to any one of the preceding claims wherein the phenyl pyrazole insecticide is present in a concentration of from 0.1 to 40% (w/v) based on the total composition.
  10. 10. The composition according to any one of the preceding claims comprising an Insect Growth Regulator and a phenyl pyrazole insecticide.
  11. 11. The composition according to claim 10 comprising s-methoprene and fipronil.
  12. 12. The composition according to any one of the preceding claims wherein the chloronicotinyl insecticide is selected -22 -from imidacloprid and/or thiacloprid or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
  13. 13. The composition according to any one of the preceding claims comprising less than 20% (w/v) of butanol and/or DMSO based on the total composition.
  14. 14. The composition according to any one of the preceding claims comprising a crystallisation inhibitor.
  15. 15. The composition according to any one of the preceding claims comprising an antioxidant.
  16. 16. A topical ectoparasiticide composition consisting of: (i) an Insect Growth Regulator and/or a phenyl pyrazole insecticide; and/or a chloronicotinyl insecticide; (ii) glycol ether; (iii) optionally butanol and/or DMSO; (iv) optionally a crystallisation inhibitor; (v) optionally a surfactant; (vi) optionally an antioxidant; and (v) optionally a propellant.
  17. 17. The composition according to claim 16 consisting of least 60% (w/v) of glycol ether based on the total composition.
  18. 18. The composition according to claim 17 consisting of at least 80% (w/v) of glycol ether based on the total composition.
    -23 -
  19. 19. The composition according to any one of claism 16 to 19 wherein the glycol ether is selected from ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol monoethyl ether, propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and mixtures of two or more thereof.
  20. 20. The composition according to any one of the preceding claims wherein the Insect Growth Regulator is selected from methoprene, s-methoprene, hydroprene, s-hydroprene, kinoprene, s-kinoprene, fenoxycarb, pyriproxif en, cyromazine, dimilin, novaluron, pharmaceutically or veterinarily acceptable derivatives or prodrugs thereof and mixtures of two or more thereof.
  21. 21. The composition according to claim 20 wherein the Insect Growth Regulator is s-methoprene or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
  22. 22. The composition according to any one of claims 16 to 21 wherein the phenyl pyrazole insecticide is fipronil or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
  23. 23. The composition according to any one of claims 16 to 22 wherein the Insect Growth Regulator is present in a concentration of from 0.1 to 40% (w/v) based on the total composition.
    -
  24. 24 - 24. The composition according to any one of claims 16 to 23 wherein the phenyl pyrazole insecticide is present in a concentration of from 0.1 to 40% (w/v) based on the total composition.
  25. 25. The composition according to any one of claims 16 to 24 comprising an Insect Growth Regulator and a phenyl pyrazole insecticide.
  26. 26. The composition according to claim 25 comprising s-methoprene and fipronil.
  27. 27. The composition according to any one of claims 16 to 25 wherein the chioronicotinyl insecticide is selected from imidacloprid and/or thiacloprid or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
  28. 28. The composition according to any one of the preceding claims consisting of less than 20% (w/v) of butanol and/or DMSO based on the total composition.
  29. 29. The composition according to any one of the preceding claims consisting of (i) methoprene and/or fipronil; (ii) diethylene glycol monoethyl ether; (iii) butanol; (iv) polyvinylpyrrol idone; (v) polysorbate 80; and (vi) butylated hydroxyanisole and/or butylated hydroxytoulene.
    -25 -
  30. 30. The composition according to any one of claims 16 to 28 consisting of fipronil, methoprene and diethylene glycol monoethyl ether.
  31. 31. The composition according to any one of the preceding claims which is in the form of a spot-on or spray-on formulation for an animal.
  32. 32. A composition as defined in any one of the preceding claims for use in a method of treatment of the human or animal body by therapy.
  33. 33. A composition as defined in any one of claims 1 to 31 for use in a method of treatment for the reduction or inhibition of juvenile ectoparasite maturation from the skin of an animal, wherein the composition is applied topically to the skin of the animal.
  34. 34. Use of a composition as defined in any one of claims 1 to 31 in the manufacture of a medicament for the reduction or inhibition of juvenile ectoparasite maturation from the skin of an animal.
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