HK1179474A - Spot-on pesticide composition - Google Patents
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- HK1179474A HK1179474A HK13106632.6A HK13106632A HK1179474A HK 1179474 A HK1179474 A HK 1179474A HK 13106632 A HK13106632 A HK 13106632A HK 1179474 A HK1179474 A HK 1179474A
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Description
RELATED APPLICATIONS
The present application relates to and claims priority from U.S. provisional patent application No. 61/297,194 filed on 21/2010 and U.S. provisional patent application No. 61/244,788 filed on 22/9/2009, each of which is incorporated herein by reference in its entirety.
Technical Field
The present invention relates to a spot-on or pour-on insecticidal composition comprising fipronil and a pyrethroid for use in the treatment or prevention of insect, parasite or mite infestations in animals, especially mammals including dogs and cats. The invention also relates to a spot-on or pour-on insecticidal composition comprising fipronil, a pyrethroid and an insect growth regulator, said combination also being useful for the treatment and prevention of insect, parasite or mite infestations in animals, especially mammals. The invention also relates to a method of topical skin application of an insecticide composition comprising fipronil and a pyrethroid and an additional insect growth regulator.
Background
Traditional products for treating or preventing insect or parasite infestation of animals include shampoo treatments, insecticidal collars, oral ingestion treatments, compositions designed to treat the animal's environment, spot-on treatments, and the like. Different forms of treatment provide unique benefits and disadvantages; however, most have significant disadvantages. For example, shampoo treatments require that the treatment be applied over the entire surface of the animal and then rinsed, which is often unpleasant for both the animal and the owner and provides only a short-term, temporary treatment. Insecticidal collars require the animal to wear the collar for a period of time, typically for months, which is uncomfortable and heavy for the animal. In addition, orally administered treatments increase the likelihood of side effects and are more difficult to administer to animals. Alternatively, treatments to animal environments and habits are generally undesirable because they can cause discoloration of furniture, carpeting, bedding, and the like and can also produce undesirable odors. Thus, there is a need for a site-directed treatment that can be applied to an animal in smaller portions and that maintains therapeutic efficacy on the entire surface of the animal.
Previously developed site-directed compositions contain a number of insecticides. Common agents include arylpyrazole derivatives, insect growth factors, pyrethrins, nodulisporic acid derivatives, neonicotinoids, formamides, avermectins, and the like. All compounds listed herein have different mechanisms of action and thus treat and prevent infestation in different ways. Thus, each compound also has adverse effects associated with a variety of different treatments. The various agents may be combined in various concentrations. Generally, higher concentrations of active ingredients result in higher pesticidal rates and more successful treatments; however, the use of higher concentrations of active ingredients is more costly to manufacture and results in a greater likelihood of the animal suffering an adverse reaction to the treatment. Adverse effects of treatment include skin discoloration, local hair loss, itching, redness, excessive phlegm and salivation, and in some cases neurotoxicity.
Site-directed treatments known in the art typically have a long-term effect before the active ingredient is effective in eliminating the target pest. For example, insect growth regulators (i.e., juvenile hormone mimics) eliminate target pests by effectively inhibiting the development of immature pests so that they cannot reproduce. Although the insect growth regulator is effective in ultimately controlling pest infestation, additional time is required to kill all pests during which the animal host, as well as all other animals and humans, have to be subjected to the effects of the infestation. Even fast acting agents such as arylpyrazole derivatives known as fipronil which cause hyperexcitability of the pest leading to death require long-term action. Typically, a fast acting agent requires several hours to provide symptom relief to the host animal.
Thus, in view of the limitations of the prior art, there is a need for site-directed insecticidal therapy with low concentrations of known compounds to minimize the risk of adverse effects, produce high insecticidal efficiency and improve kill rates, preferably within the first hour of treatment.
Disclosure of Invention
The present invention relates to novel spot-on compositions for treating and preventing insect or mite infestations, and methods of killing pests comprising administering the compositions to a host animal, particularly a mammal. The spot-on pesticidal compositions of the present invention comprise low concentrations of the active components fipronil and pyrethroid and may additionally comprise an insect growth factor, wherein the active agents are each present in the composition at a concentration typically below 20% (w/w) of the total weight of the spot-on composition. The low concentration minimizes the risk of adverse effects. It has also been found that a novel combination of these active ingredients has a higher and faster rate of kill (such as fleas and mites) than treatment with fipronil and/or an insect growth regulator alone or without a pyrethroid. The compositions of the present invention also comprise an organic solvent and may optionally include an antioxidant.
One embodiment of the present invention is directed to a spot-on composition comprising from about 1% to about 20% (w/w) fipronil, from about 1% to about 20% (w/w) pyrethroid, from about 65% to about 85% (w/w) organic solvent, and from about 2% to about 10% (w/w) antioxidant. More specifically, this embodiment of the spot-on composition includes from about 5% to about 15% (w/w) fipronil, from about 2% to about 10% (w/w) pyrethroid, from about 70% to about 80% (w/w) organic solvent, and from about 3% to about 8% (w/w) antioxidant. Most particularly, the first embodiment of the present invention comprises from about 8% to about 11% (w/w) fipronil, from about 4% to about 6% (w/w) pyrethroid, from about 75% to about 80% (w/w) organic solvent, and from about 4% to about 6% (w/w) antioxidant.
A second embodiment of the invention is directed to a spot-on composition comprising from about 1% to about 20% (w/w) fipronil, from about 1% to about 20% (w/w) pyrethroid, from about 1% to about 20% (w/w) insect growth regulator, from about 55% to about 80% (w/w) organic solvent, and from about 2% to about 10% (w/w) antioxidant. More specifically, this embodiment of the composition includes about 5% to about 15% (w/w) fipronil, about 2% to about 10% (w/w) pyrethroid, about 4% to about 15% (w/w) insect growth regulator, about 60% to about 75% (w/w) organic solvent, and about 3% to about 8% (w/w) antioxidant. Most specifically, the spot-on compositions of the present invention comprise from about 8% to about 11% (w/w) fipronil, from about 4% to about 6% (w/w) pyrethroid, from about 7% to about 11% (w/w) insect growth regulator, from about 65% to about 70% (w/w) organic solvent, and from about 4% to about 6% (w/w) antioxidant.
A third embodiment of the present invention is directed to a spot-on composition comprising from about 1% to about 20% (w/w) fipronil, from about 1% to about 20% (w/w) pyrethroid, and from about 60% to about 85% (w/w) organic solvent. More specifically, this embodiment of the spot-on composition includes from about 5% to about 15% (w/w) fipronil, from about 8% to about 18% (w/w) pyrethroid, and from about 65% to about 80% (w/w) organic solvent. Most specifically, this embodiment of the invention includes from about 8% to about 11% (w/w) fipronil, from about 14% to about 16% (w/w) pyrethroid, and from about 70% to about 75% (w/w) organic solvent.
A fourth embodiment of the spot-on composition includes about 1% to about 20% (w/w) fipronil, about 1% to about 20% (w/w) pyrethroid, about 1% to about 20% (w/w) insect growth regulator, and about 55% to about 75% (w/w) organic solvent. More specifically, this embodiment of the composition includes about 5% to about 15% (w/w) fipronil, about 8% to about 18% (w/w) pyrethroid, about 5% to about 16% (w/w) insect growth regulator, and about 60% to about 70% (w/w) organic solvent. Most specifically, this embodiment of the spot-on composition includes from about 8% to about 11% (w/w) fipronil, from about 14% to about 16% (w/w) pyrethroid, from about 11% to about 14% (w/w) insect growth regulator, and from about 60% to about 65% (w/w) organic solvent.
A fifth embodiment of the spot-on composition includes from about 1% to about 20% (w/w) fipronil, from about 1% to about 20% (w/w) pyrethroid, from about 1% to about 20% (w/w) insect growth regulator, from about 65% to about 85% (w/w) organic solvent, and from about 2% to about 10% (w/w) antioxidant. More specifically, this embodiment of the composition includes about 5% to about 15% (w/w) fipronil, about 2% to about 10% (w/w) pyrethroid, about 2% to about 10% (w/w) insect growth regulator, about 70% to about 85% (w/w) organic solvent, and about 3% to about 8% (w/w) antioxidant. Most specifically, the spot-on composition of the present invention includes from about 8% to about 11% (w/w) fipronil, from about 4% to about 6% (w/w) pyrethroid, from about 3% to about 6% (w/w) insect growth regulator, from about 75% to about 80% (w/w) organic solvent, and from about 4% to about 6% (w/w) antioxidant.
A sixth embodiment of the spot-on composition includes from about 1% to about 20% (w/w) fipronil, from about 1% to about 20% (w/w) pyrethroid, from about 1% to about 20% (w/w) insect growth regulator, and from about 55% to about 80% (w/w) organic solvent. More specifically, this embodiment of the composition includes about 5% to about 15% (w/w) fipronil, about 8% to about 18% (w/w) pyrethroid, about 2% to about 10% (w/w) insect growth regulator, and about 60% to about 75% (w/w) organic solvent. Most specifically, this embodiment of the spot-on composition includes from about 8% to about 11% (w/w) fipronil, from about 14% to about 16% (w/w) pyrethroid, from about 3% to about 6% (w/w) insect growth regulator, and from about 65% to about 70% (w/w) organic solvent.
In addition, the present invention provides a method of eliminating and preventing pest infestation in an animal, particularly a dog, comprising topically applying a topical skin application of a spot-on composition of the invention between the shoulders of said animal in a volume sufficient to deliver a dose of the active ingredient in the range of from about 0.5mg/kg to about 10mg/kg of the animal's body weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs at the time of filing. If specifically defined, the definitions provided herein are superior to any dictionary or extrinsic definitions. Furthermore, unless otherwise provided herein, singular terms shall include the plural and plural terms shall include the singular. Herein, the use of "or" means "and/or" unless stated otherwise. All patents and publications mentioned herein are incorporated herein by reference.
Detailed Description
The compositions provided herein are spot-on pesticidal compositions which utilize certain combinations of active compounds to treat insect, parasite or mite infestations in animals, especially mammals (preferably dogs and cats), and also to prevent further infestations by a long-term therapeutic effect which can last up to 3 months. Thus, the composition eliminates existing pests and prevents these pests from surviving through development and reproduction. The composition interrupts the growth cycle and prevents the pest from incubating additional eggs. The compositions of the present invention are useful for treating a number of pests, especially fleas and mites found on domestic animals. The compositions include low concentrations of fipronil and pyrethroid, and may also include insect growth regulating compounds. Furthermore, the present invention is based in part on the following findings: treatment of the host animal with a composition comprising a combination of fipronil and a pyrethroid results in a significantly improved kill rate within the first 24 hours of treatment compared to treatment with fipronil and an insect growth regulator, alone or in combination, without the addition of a pyrethroid.
The spot-on composition of the present invention includes fipronil. Fipronil compounds are phenylpyrazole acaricides effective against a broad spectrum of mite species and were first disclosed in U.S. patent No. 5,232,940. Fipronil achieves its efficacy by disrupting the central nervous system by blocking chloride ion passage through components of the central nervous system, GABA receptors and glutamate-gated chloride channels (GluCl). This damage causes the affected nerves and muscles to be over-excited, eventually leading to death. The compounds are slow acaricides and thus can be used to target not only the host, but also other mites that come into contact with the host. Fipronil is also known as 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [ (1-R, S) (trifluoromethyl) sulfinyl ] -1H-pyrazole-3-carbonitrile, 5-amino-1- (2, 6-dichloro- α, α, α -trifluoro-p-tolyl) -4- [ (trifluoromethyl) sulfinyl ] pyrazole-3-carbonitrile and flucyanobenzazole [ CAS No. 120068-37-3 ]. Fipronil is generally available as a liquid or solid crystalline material or powder. Fipronil typically comprises from about 1% to about 20% (w/w) of the total weight of the spot-on composition. In some embodiments, fipronil comprises about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% (w/w) of the spot-on composition. For example, fipronil may be present in the spot-on composition in an amount of about 5% to about 15% (w/w), and preferably about 7% to about 12% (w/w) of the total composition. Most preferably, the amount of fipronil present in the spot-on composition may range from about 8% to about 11% (w/w) of the total composition. In an exemplary embodiment, fipronil is present in the composition in an amount of about 9.8% (w/w) of the total composition. The chemical structure of fipronil is given below.
The spot-on compositions of the invention also include pyrethroids. Generally, pyrethroids are a class of synthetic insecticides associated with naturally occurring pyrethrins. Pyrethroids are more potent and less toxic to mammals than natural pyrethrins. Pyrethroids are axitoxins that act by keeping the sodium channels in the neuronal membrane open. Sodium channels are composed of internal hydrophilic membrane proteins that allow sodium ions to enter and leave the membrane. While the sodium channels remain open, sodium ion influx causes hyperexcitability and the pest becomes trapped in paralysis. The pyrethroid typically comprises from about 1% to about 20% (w/w) of the total weight of the spot-on composition. In some embodiments, the pyrethroid comprises about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% (w/w) of the spot-on composition. For example, the pyrethroid may be present in the spot-on composition in an amount from about 1% to about 18% (w/w), and preferably from about 3% to about 16% (w/w) of the total composition. In another embodiment, the pyrethroid may be present in the spot-on composition in an amount from about 1% to about 10% (w/w) by weight of the total composition. In another embodiment, the pyrethroid may be present in the spot-on composition in an amount from about 4% to about 6% (w/w) of the total composition. In another embodiment, the pyrethroid may be present in the spot-on composition in an amount from about 10% to about 16% (w/w) of the total composition. In another embodiment, theThe pyrethroid may be present in the spot-on composition in an amount from about 14% to about 16% (w/w) of the total composition. Suitable non-limiting examples of pyrethroids include pyrethrin, cypermethrin, cyphenothrin, efenprox, fenvalerate, and cyfluthrin. In particular, cyphenothrin is classified as a pyrethroid insecticide. Cypermethrin is also known as (RS) -alpha-cyano-3-phenoxybenzyl (1RS, 3 RS; 1RS, 3SR) -2, 2-dimethyl-3- (2-methylpropylidene-1-enyl) cyclopropane carboxylate, d-trans-cyphenothrin, d-cyphenothrin, GokilahtTM(RS) -alpha-cyano-3-phenoxybenzyl- (1RS) -cis-trans-2, 2-dimethyl-3- (2-methylpropylidene-1-enyl) cyclopropanecarboxylate, (+ -) -alpha-cyano-3-phenoxybenzyl (+ -) -cis-trans-chrysanthemate, and cyano (3-phenoxyphenyl) methyl 2, 2-dimethyl-3- (2-methyl-1-propenyl) cyclopropanecarboxylate. Some commercially available Gokilaht on the marketTMThe product contains cyphenothrin and pyriproxyfen. It should be noted that the cyphenothrin product of the present invention may contain only the active compound pyriproxyfen in the formulation and no S-methoprene, since it was found that the incorporation of both S-methoprene and pyriproxyfen into the composition reduced efficacy and increased the likelihood of adverse effects. The chemical structure of cyphenothrin is given below.
In an exemplary embodiment, pyriproxyfen is present in the spot-on composition in an amount of 5.0% (w/w) of the total composition effective for treating pest infestation in dogs.
Efeprazole is also known as ethofenprox, kresoxim-methyl, 1-ethoxy-4- [ 2-methyl-1- [ [3- (phenoxy) phenyl ] methoxy ] prop-2-yl ] benzene 2- (4-ethoxyphenyl) -2-methylpropyl 3-phenoxybenzyl ester, 3-phenoxybenzyl 2- (4-ethoxyphenyl) -2-methylpropyl ester, c076840, 2- (4-ethoxyphenyl) -2-methylpropyl-3-phenoxybenzyl ester, 1- ((2- (4-ethoxyphenyl) -2-methylpropoxy) methyl) -3-phenoxybenzene, α - ((p-ethoxy- β, β -dimethylbenzyl) oxy) -m-phenoxytoluene. The CAS registry number for efeprister is 80844-07-1. Efepressin is known to be an effective pyrethroid for eliminating pests in cats. The chemical structure of efepristol is given below.
In an exemplary embodiment, the amount of efepressim present in the spot-on composition effective for treating pest infestation in a cat is 15.0% (w/w) of the total composition.
The spot-on pesticidal compositions of the present invention may additionally include an Insect Growth Regulator (IGR). IGR is not effective in killing already existing pests; it prevents reproduction and further infestation. IGRs are generally compounds that disrupt the growth and development of pest species, so that the pest cannot mature and reproduce. IGR typically constitutes less than about 20% (w/w) of the total weight of the spot-on composition. In some embodiments, IGR comprises about 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.1%, or 0% (w/w) of the spot-on composition. For example, the amount of IGR present in the spot-on composition may range from about 0% to about 20% (w/w) of the total composition weight, and preferably the IGR is from about 2% to about 15% (w/w) of the total composition. In another embodiment, the amount of IGR present in the spot-on composition may range from about 4% to about 12% (w/w) of the total composition. In another embodiment, the amount of IGR present in the spot-on composition may range from about 7% to about 14% (w/w) of the total composition. In another embodiment, the amount of IGR may range from about 8% to about 12% (w/w) of the total composition. In another embodiment, the amount of IGR may range from about 2% to about 9% (w/w) of the total composition. In another embodiment, the amount of IGR may range from about 3% to about 5% (w/w) of the total composition. IGRs may include, but are not limited to, juvenile hormone mimics, chitin synthesis inhibitors, and the like. Suitable non-limiting examples of insect growth regulators include bistrifluron, dicluron, chlorfluazuron, cyromazine, diflubenzuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, tefluazuron, triflumuron, juvenil ether (epofennane), fenoxycarb, hydroprotenone (hydroprene), propafenone (kinerene), methoprene, pyriproxyfen, methoprene, and combinations thereof. In a preferred embodiment, the insect growth regulator is S-methoprene. Typically, methoprene is a racemic mixture of the R-and S-enantiomers of the compound, however, only the S-enantiomer is the active juvenile hormone analogue. Juvenile hormone analogs exert therapeutic effects by mimicking the natural juvenile hormones found in pests. Pupae must be deprived of juvenile hormone for molting to be an adult, so that the nymph-treated larvae cannot successfully develop from pupae to adult. This action disrupts the natural life cycle of the pest, preventing its maturation and reproduction. S-methoprene is also known as isopropyl (2E, 4E, 7S) -11-methoxy-3, 7, 11-trimethyl-2, 4-dodecanedioate. S-methoprene is available from a variety of commercial products and is used to control long-term pest infestation, while other active ingredients are primarily effective in the immediate, short-term elimination of pests. The insecticidal time for S-methoprene treatment varies according to the general life span of the treated species. Unlike some other compounds, S-methoprene is generally considered non-toxic to humans, which makes it useful for treating good reservoirs and many food products, including meat, milk, mushrooms, peanuts, rice and cereals. In an exemplary embodiment, the concentration of S-methoprene present in a spot-on composition effective to treat an animal pest infestation is 8.8% (w/w).
In an alternative embodiment (i.e., an embodiment of the invention that does not contain S-methoprene), the insect growth regulator may be the juvenile hormone analog pyriproxyfen, also known as 4-phenoxyphenyl 2- (2-pyridyloxy) propyl ester and NylarTM. The chemical structure of pyriproxyfen is given below.
In an exemplary embodiment, pyriproxyfen is present in the spot-on composition in an amount of 2.0% (w/w) of the total composition effective to treat an animal pest infestation.
The non-aqueous spot-on compositions of the present invention also include an organic solvent. Generally, an organic solvent is defined as a carbon-containing compound that can dissolve solids, liquids, or gases. Although one skilled in the art will appreciate that a variety of solvents may be incorporated into the present invention, the solvents should generally have a dielectric constant of about 1-40, a low boiling point (less than 100 ℃), a density less than that of water (less than 1.0 at 20 ℃), and are generally soluble in water. In addition, the organic solvent should cause minimal skin irritation when applied to the skin of animals, including dogs or cats. Examples of suitable organic solvents include, but are not limited to, acetyl tributyl citrate, fatty acid esters such as dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol N-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, diethylene glycol monoethyl ether, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyethylene oxide glycol, propylene glycol, 2-pyrrolidones such as N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, ethoxydiglycol, or combinations thereof. In a preferred embodiment, the organic solvent comprises diethylene glycol monoethyl ether.
In addition, the organic solvent typically constitutes from about 55% to about 85% (w/w) of the spot-on composition. In some embodiments, the organic solvent comprises about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, or about 55% (w/w) of the total composition. For example, the amount of organic solvent present in the spot-on composition is preferably from about 60% to about 80% (w/w) of the total composition. In another embodiment, the amount of organic solvent present in the spot-on composition may range from about 60% to about 75% (w/w) of the total composition. In another embodiment, the amount of organic solvent in the spot-on composition is from about 70% to 80% (w/w) of the total composition. In another embodiment, the amount of organic solvent in the spot-on composition is about 60% to 70% (w/w).
The spot-on composition can also include an antioxidant. Antioxidants are generally defined as compounds that slow or prevent the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a starting material to an oxidizing agent. The oxidation reaction generates free radicals, which initiate a chain reaction that damages cells. Antioxidants interrupt these chain reactions by removing free radical intermediates and inhibit other oxidation reactions by oxidizing themselves. In the spot-on composition, the antioxidant acts as a stabilizer to prevent degradation of the various components by oxidative processes. In addition, it has been reported that many of the commercially available compositions containing pyrethroids, including cyphenothrin, cause the animal to suffer adverse effects, including paresthesia (skin sensations that typically include stinging, itching, and tingling). However, it has been shown that the inclusion of an antioxidant in the spot-on composition helps to prevent the adverse side effects associated with cyphenothrin-containing treatment regimens. It should be noted that the spot-on compositions of the present invention do not include a crystallization inhibitor.
The antioxidants included in the present invention should generally be miscible with the organic solvents described herein. The antioxidant should also not cause irritation to the skin of an animal, particularly a dog or cat, when applied to the skin of the animal. Furthermore, the antioxidant may be natural or synthetic. Soluble antioxidants include, but are not limited to, ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, unoxomer (anoxomer), N-acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid, anthranilic acid, p-aminobenzoic acid (PABA), Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), caffeic acid, canthaxanthin (canthaxanthin), alpha-carotene, beta-apo-carotene, carnosol, carvacrol, catechin, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3, 4-dihydroxybenzoic acid, N, N' -diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate, distearyl thiodipropionate, 2. 6-di-tert-butylphenol, dodecyl gallate, edetic acid, ellagic acid, erythorbic acid, sodium erythorbate, aesculetin, esculin, 6-ethoxy-1, 2-dihydro-2, 4-trimethylquinoline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferulic acid, flavonoids (such as catechin, epicatechin gallate, Epicatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavonoids (such as chrysin, luteolin, apigenin), flavonols (such as acorn, myricetin, daemofero), flavanone, cortex moutan, fumaric acid, gallic acid, gentian extract, gluconic acid, and alpha-hydroxy acid, Glycine, gum acacia, hesperetin, alpha-hydroxybenzylphosphonic acid, hydroxycinnamic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytyrosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, citric acid lecithin; r-alpha-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxytryptamine, methyl gallate and citric acid monoglyceride; mono-isopropyl citrate; morin, beta-naphthone, nordihydroguaiaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphate, phytic acid, nickel-chromium phytate (phytoubichromel), green pepper extract, propyl gallate, polyphosphate, quercetin, trans-resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, erucic acid, succinic acid, stearin citrate, syringic acid, tartaric acid, thymol, tocopherol (i.e., alpha-, beta-, gamma-and sigma-tocopherol), tocotrienol (i.e., alpha-, beta-, gamma-and sigma-tocotrienol), p-hydroxyphenylethanol, vanillic acid, 2, 6-di-tert-butyl-4-hydroxytoluene (i.e., noox) 100), 2. 4- (tri-3 ', 5 ' -di-tert-butyl-4 ' -hydroxybenzyl) -mesitylene (i.e., hypnone 330), 2, 4, 5-trihydroxybutyrophenone, ubiquinone, tert-butylhydroquinone (TBHQ), thiodipropionic acid, trihydroxybutyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivatives, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof. One skilled in the art will appreciate that the antioxidants (including those listed herein) contained in the compositions encompass all possible salt and ester forms of the antioxidants in addition to the pure compound form. The antioxidant preferably comprises vitamin E compounds such as tocopheryl acetate, tocopheryl linoleate, tocopheryl nicotinate, tocopheryl succinate, tocopheryl ascorbate phosphate, tocopheryl dioleyl silanol, tocoferol and tocopheryl linoleate/oleate. In an exemplary embodiment, the antioxidant comprises tocopherol nicotinate [ CAS number 43119-47-7 ].
In addition, antioxidants typically comprise less than about 10% (w/w) of the total spot-on composition. In some embodiments, the antioxidant comprises about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.1%, or 0% (w/w) of the total composition. For example, the amount of antioxidant present in the spot-on composition can be from about 2% to about 10% (w/w) of the total composition, and preferably the antioxidant is from about 3% to about 6% (w/w) of the total composition. In another embodiment, the amount of antioxidant present in the spot-on composition ranges from about 4% to about 6% (w/w) of the total composition. In an exemplary embodiment, the antioxidant is present in the composition in an amount of 5.3% (w/w).
The spot-on composition may also include an inactivation excipient added to the composition that incorporates the active ingredient of the subject. For example, the fipronil component of the composition may be provided in a 95% solution, i.e. 95% of the volume of the fipronil component is active fipronil compound and the remaining 5% is inactive excipients which are subsequently introduced into the composition, so the insecticide may not be a 100% pure concentrate and may be purchased with other components. One skilled in the art will recognize that the inactive excipients include, but are not limited to, binders, fillers, non-effervescent disintegrants, preservatives, diluents, lubricants, pH modifying agents, stabilizers, and the like. However, it is understood that the inactivating excipient is typically included as part of the active ingredient component and constitutes a minor percentage (typically less than 1%) of the total spot-on composition volume, typically without affecting the physical characteristics of the spot-on composition.
It is understood that the active ingredient of the site-directed composition may be provided in the dosage form as a pure concentrate (100% concentration) or as a diluted composition with additional excipients (i.e., the amount of active ingredient in the composition is less than or equal to 99.99%, with the remainder consisting of inactive excipients). One skilled in the art will appreciate that the volume of active ingredient added to the spot-on composition needs to be adjusted to effect dilution and to ensure that the final spot-on composition contains the appropriate final concentration of each active ingredient. It is also understood by those skilled in the art that the components of the spot-on composition can be provided in a variety of dosage forms including, but not limited to, powders, briquettes, liquid solutions or suspensions, pellets, emulsions, aerosols, creams, gels, salves, and the like.
In addition, the spot-on pesticidal compositions of the present invention can be produced by contacting the individual active ingredients of the spot-on composition with one another to produce a spot-on formulation suitable for application to the skin of an animal. It is to be understood that the present invention encompasses a variety of physical formulations; however, the spot-on compositions of the present invention are generally directed to liquid solutions and suspensions. The formulations of the present invention may be prepared by standard techniques known in the art. For example, in one embodiment where the desired spot-on formulation is a liquid solution, the composition is produced by contacting the fipronil and pyrethroid components with a solvent system and then gently heating and stirring the components until dissolved. In a preferred embodiment, the spot-on composition comprising fipronil, pyrethroid and solvent system is also contacted with an antioxidant and the combination is then stirred to produce the spot-on composition. One of ordinary skill in the art will appreciate that the components of the spot-on composition can be contacted and mixed with each other so long as the solution is well stirred and mixed.
The physical characteristics of the spot-on composition can vary depending on the physical characteristics desired. However, the spot-on composition should be capable of being applied to the skin of an animal and provide sufficient residence for the active components of the spot-on composition to be absorbed by the host animal. The spot-on compositions of the present invention preferably have low tack. Viscosity is a measure of the flow resistance due to friction within the fluid, measured in centistokes (cSt). Measurements of low cSt indicate that the fluid will flow with lower resistance because molecular friction within the fluid is minimal. The lower the viscosity, the faster the flow of fluid. Highly viscous substances are thick and gel-like slow-flowing liquids in nature. Low viscosity materials exhibit rapid flow, such as water at room temperature (water viscosity of about 1cSt at 20 c; 1cSt ═ 1 mm/sec). The spot-on compositions of the present invention generally have a viscosity of from about 0.01 square millimeters per second to about 100 square millimeters per second. In a more preferred embodiment, the spot-on composition has a tack of from about 1 mm/sec to about 30 mm/sec. In another preferred embodiment, the spot-on composition has a tack of from about 4 mm/sec to about 20 mm/sec.
The base spot-on composition of the invention includes fipronil at a concentration of about 1% to about 20% (w/w), pyrethroid at a concentration of about 1% to about 20% (w/w), and organic solvent at a concentration of about 55% to about 85% (w/w) of the total spot-on composition. For the base spot-on composition, it is preferred to use from about 8% to about 11% (w/w) fipronil, from about 3% to about 16% (w/w) pyrethroid, and from about 60% to about 80% (w/w) organic solvent, depending on the type of animal to be treated. The base site-directed composition may additionally include IGR at a concentration of from 1% to about 20% (w/w) of the total composition, preferably at a concentration of from about 2% to about 12% (w/w). More preferably, the IGR is present in the composition at a concentration of 4% to about 12% (w/w) of the total composition. In addition, the base spot-on composition may also include an antioxidant at a concentration of 0% to about 10% (w/w) of the total composition, preferably at a concentration of about 4% to about 6% (w/w) of the total composition.
In a preferred embodiment, the present invention provides a spot-on composition comprising 9.97% (w/w) fipronil, 5.3% (w/w) cyphenothrin, 79.43% (w/w) diethylene glycol monoethyl ether, and 5.3% (w/w) tocopherol nicotinate. The spot-on composition can be used to treat any mammal, but it is well suited for treating dogs.
Another preferred embodiment of the present invention includes a spot-on composition comprising 9.97% (w/w) fipronil, 5.3% (w/w) cyphenothrin, 9.21% (w/w) S-methoprene, 70.22% (w/w) diethylene glycol monoethyl ether, and 5.3% (w/w) tocopherol nicotinate. The spot-on composition can be used to treat any mammal, but it is well suited for treating dogs.
In another embodiment, the present invention provides a spot-on composition comprising 9.97% (w/w) fipronil, 15.89% (w/w) efenpres, and 74.14% (w/w) diethylene glycol monoethyl ether. The spot-on composition can be used to treat any mammal, but it is well suited for treating cats.
In another embodiment, the present invention provides a spot-on composition comprising 9.97% (w/w) fipronil, 15.89% (w/w) efenprox, 12.36% (w/w) S-methoprene, and 61.78% (w/w) diethylene glycol monoethyl ether. The spot-on composition can be used to treat any mammal, but it is well suited for treating cats.
In another embodiment, the present invention provides a spot-on composition comprising 9.97% (w/w) fipronil, 5.3% (w/w) cyphenothrin, 4% (w/w) pyriproxyfen, 75.43% (w/w) diethylene glycol monoethyl ether, and 5.3% (w/w) tocopherol nicotinate. The spot-on composition can be used to treat any mammal, but it is well suited for treating dogs.
In another embodiment, the present invention provides a spot-on composition comprising 9.97% (w/w) fipronil, 15.89% (w/w) efeprazole, 4.4% (w/w) pyriproxyfen, and 69.74% (w/w) diethylene glycol monoethyl ether. The spot-on composition can be used to treat any mammal, but it is well suited for treating cats.
In addition, the invention includes a method of killing pest pupae and adults on an animal comprising administering a spot-on composition comprising about 1% -20% (w/w) fipronil and about 1% -20% (w/w) pyrethroid to the topical skin between the shoulders of the animal. The method of using the composition of the present invention preferably comprises topically administering a base spot-on composition, preferably comprising 7% (w/w) to about 12% (w/w) fipronil and about 3% to about 16% (w/w) pyrethroid, and may additionally include IGR at a concentration preferably of about 4% to about 12% (w/w) of the total composition.
The compositions and methods of the present invention are intended for application to animals, particularly dogs and cats, and are generally applied by deposition onto the skin ("spot-on" or "pour-on" application). The treatment is usually contained in less than 10cm2Is applied topically, especially 5-10cm2. Typically, the spot-on composition is applied to an application area that the animal cannot lick, which would result in transient negative effects, such as excessive salivation. In particular, it is preferably applied at two points and preferably between the shoulders of the animal. After application of the spot-on composition, the composition spreads(particularly over the whole body of the animal) and then dried without crystallizing or otherwise altering the appearance (particularly without any white deposits or dust) or feel of the animal's fur. Furthermore, the methods of the present invention apply the spot-on composition to the skin of the animal for every four weeks to ensure continuous treatment and prevention of pest infestation. Typically, the active ingredients are applied together in a single formulation to the host animal.
In a preferred embodiment of the invention, a method of killing insect and pest pupae and adults on an animal comprises administering to the topical skin between the shoulders of the animal a spot-on composition comprising 9.97% (w/w) fipronil, 5.3% (w/w) cyphenothrin, 79.43% (w/w) diethylene glycol monoethyl ether, and 5.3% (w/w) tocopherol nicotinate. The present method can be used to treat any animal, but it is well suited for treating dogs.
Another preferred embodiment of the invention comprises a method of killing insect and pest pupae and adults on a dog or cat comprising administering to the topical skin between the shoulders of the animal a spot-on composition comprising 9.97% (w/w) fipronil, 5.3% (w/w) cyphenothrin, 9.21% (w/w) S-methoprene, 70.22% (w/w) diethylene glycol monoethyl ether, and 5.3% (w/w) tocopherol nicotinate. The present method can be used to treat any animal, but it is well suited for treating dogs.
In another preferred embodiment, the present invention provides a method of killing insect and pest pupae and adults on an animal comprising administering to the topical skin between the shoulders of the animal a spot-on composition comprising 9.97% (w/w) fipronil, 15.89% (w/w) efenix, 74.14% (w/w) tocopherol nicotinate. The present method can be used to treat any animal, but it is well suited for treating cats.
In another preferred embodiment, the present invention provides a method of killing insect and pest pupae and adults on an animal comprising administering to the topical skin between the shoulders of the animal a spot-on composition comprising 9.97% (w/w) fipronil, 15.89% (w/w) efenprox, 12.36% (w/w) S-methoprene, and 77.67% (w/w) diethylene glycol monoethyl ether. The present method can be used to treat any animal, but it is well suited for treating cats.
In another preferred embodiment, the present invention provides a method of killing insect and pest pupae and adults on an animal comprising administering to the topical skin between the shoulders of the animal a spot-on composition comprising 9.97% (w/w) fipronil, 5.3% (w/w) cyphenothrin, 4.0% (w/w) pyriproxyfen, 75.43% (w/w) diethylene glycol monoethyl ether, and 5.3% tocopherol nicotinate. The present method can be used to treat any animal, but it is well suited for treating dogs.
In another preferred embodiment, the present invention provides a method of killing insect and pest pupae and adults on an animal comprising administering to the topical skin between the shoulders of the animal a spot-on composition comprising 9.97% (w/w) fipronil, 15.89% (w/w) efenprox, 4.4% (w/w) pyriproxyfen, and 85.63% (w/w) diethylene glycol monoethyl ether. The present method can be used to treat any animal, but it is well suited for treating cats.
In another embodiment, the method of killing insects is performed such that the spot-on composition is applied in a volume sufficient to deliver a dose of the active ingredient fipronil of about 0.1mg/kg to about 40mg/kg body weight of the host animal. In a preferred embodiment, the dose of fipronil is from about 2mg/kg to about 20mg/kg of the body weight of the host animal. In a more preferred embodiment, the spot-on composition application comprises a volume sufficient to deliver a dose of fipronil ranging from about 5mg/kg to about 15mg/kg of the body weight of the host animal.
In another embodiment, the method of killing insects is performed such that the spot-on composition is applied in a volume sufficient to deliver a dose of the active pyrethroid component in the range of about 0.1mg/kg to about 40mg/kg of the body weight of the host animal. In a preferred embodiment, the dose of pyrethroid is from about 0.5mg/kg to about 20mg/kg of body weight of the host animal. In a more preferred embodiment, the spot-on composition application comprises a volume sufficient to deliver a dose of pyrethroid in the range of about 0.5mg/kg to about 10mg/kg of the body weight of the host animal.
In another embodiment, the method of killing insects is performed such that the spot-on composition further comprises an IGR and is applied in a volume sufficient to deliver a dose of insect growth regulating active ingredient of from about 0.1mg/kg to about 40mg/kg of the body weight of the host animal. In a preferred embodiment, the dose of insect growth regulator is from about 0.2mg/kg to about 20mg/kg of body weight of the host animal. In a more preferred embodiment, the spot-on composition application comprises a volume sufficient to deliver a dose of the insect growth regulator of from about 0.5mg/kg to about 10mg/kg of the body weight of the host animal.
Those skilled in the art will appreciate that the dosage ranges given above are approximate and may vary over a wide range. The dosage differences are due to the fact that in practice the spot-on composition will be administered to the animal in a certain weight range and in a defined dose and volume. Thus, the dose actually administered to an animal may vary by a factor of 0.1-10 from the preferred dose without affecting any additional risk of toxicity or efficacy decline.
Although the components of the composition are effective against a variety of pests and parasites, the composition has been specifically developed for the treatment of fleas, including catfleas (Ctenocephalides) species, and mites (rhipicephalus (rhipeocephalus), hard ticks (Ixodes), and nibble lice (trichodictyones) species). Furthermore, the frequency of application may vary according to the needs of the individual animal and the severity of the infestation. Treatment of fleas may be repeated as often as once a week or may be reserved for a one-time acute treatment of flea infestations or bursts. In one embodiment of the invention, flea treatment may be repeated about every four, five or six weeks. In another embodiment, the spot-on composition is applied to a host animal for single-use treatment of pest infestation. With respect to mite treatment, the application regimen of the spot-on composition varies depending on the type of mite being treated. It is generally recommended that treatment of the paralytic mite (hard tick (Ixodes) species) be more frequent than in other species. In an embodiment of the invention, the paralytic mites are treated at a frequency of 1-4 weeks, preferably every 2 weeks. The treatment regimen for other acarids is generally similar to that for flea infestations, preferably about 4-6 weeks. In another embodiment, the spot-on composition is applied on the basis of a single treatment of mite infestations.
While the invention described herein is susceptible to various modifications and alternative forms, specific embodiments thereof have been described above in detail. It should be understood, however, that the detailed description of the spot-on composition is not intended to limit the invention to the particular embodiments disclosed. But, on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
Definition of
The terms "about" and "approximately" as used herein refer to values within a statistically significant range. The range can typically be within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The terms "about" and "approximately" include the permissible deviations that depend on the particular system under study and are readily understood by one of ordinary skill in the art.
The term "w/w" as used herein refers to the phrase "weight ratio" and is used to describe the concentration of a particular substance in a mixture or solution.
The term "mL/kg" as used herein refers to milliliters of composition per kilogram of body weight.
The term "a.i." as used herein refers to an active ingredient.
As used herein, the terms "treat" or "treating" a condition, such as pest infestation, include inhibiting the presence of the condition or preventing its development; or ameliorating the condition or causing regression thereof. The term "preventing" or "prevention" of a condition, such as insect or pest infestation, includes significantly blocking or inhibiting the development or growth of the condition prior to its onset. The compositions for treating or preventing an insult herein preferably exhibit at least 90% efficacy.
As used herein, the term "pesticide" or "pesticidal" refers to an agent or composition comprising an agent that prevents, reduces or eliminates pest infestation. Preferred insecticides of the present invention include fipronil, cyphenothrin and efenprox.
The term "insect growth regulator" or "IGR" as used herein refers to an agent that is capable of interrupting or inhibiting the life cycle of a pest such that the pest no longer matures into an adult and becomes unable to reproduce. Preferred IGRs of the invention include S-methoprene and pyriproxyfen.
The term "animal" as used herein refers to mammals, particularly companion animals, including but not limited to dogs, cats, rabbits, ferrets, horses, and hamsters.
The terms "pest" and "insect" as used herein refer to any ectoparasite, including but not limited to fleas, mites, flies, kefir flies, mosquitoes and mites.
The following examples are intended to further illustrate and explain the present invention. Therefore, the present invention should not be limited to any of the details in these examples.
Example 1-Process for preparing a fipronil/cyphenothrin spot-on insecticide composition for dogs
| Components | Amount in 1000L |
| Fipronil raw material (as 100%) | 98kg (99.7kg as 98.3%) |
| Cypermethrin (as 100%) | 50kg (53kg as 94.4%) |
| Nicotinic acid tocopherol | 53kg |
| Diethylene glycol monoethyl ether | Adding to 1000L (about 794.3kg) |
Diethylene glycol monoethyl ether and tocopherol nicotinate were added to the vessel and heated to 50 ℃ (about 1 hour). Once heated, fipronil and cyphenothrin were added to the vessel and all components were mixed until a homogeneous solution was formed (about 1 hour).
Example 2-Process for preparing fipronil/S-methoprene/cyphenothrin spot-on insecticide composition for dogs
| Components | Amount in 1000L |
| Fipronil raw material (as 100%) | 98kg (99.7kg as 98.3%) |
| S-methoprene (as 100%) | 88kg (92.1kg as 95.5%) |
| Cypermethrin (as 100%) | 50kg (53kg as 94.4%) |
| Nicotinic acid tocopherol | 53kg |
| Diethylene glycol monoethyl ether | To 1000L (about 702.2kg) |
Diethylene glycol monoethyl ether and tocopherol nicotinate were added to the vessel and heated to 50 ℃ (about 1 hour). Once heated, fipronil, cyphenothrin and S-methoprene were added to the vessel and all the components were mixed until a homogeneous solution was formed (about 1 hour).
Example 3-Process for preparing fipronil/efenpres site-directed insecticidal composition for cats
| Components | Amount in 1000L |
| Fipronil raw material (as 100%) | 98kg (99.7kg as 98.3%) |
| Epipristal (as 100%) | 150kg (158.9kg as 94%) |
| Diethylene glycol monoethyl ether | Adding to 1000L (about 741.4kg) |
Diethylene glycol monoethyl ether was added to the vessel and heated to 50 deg.C (about 1 hour). Once heated, fipronil and efepristox were added to the vessel and all components were mixed until a homogeneous solution was formed (about 1 hour).
Example 4-Process for preparing fipronil/efenprox/S-methoprene fixed-Point insecticide composition for cats
| Components | Amount in 1000L |
| Fipronil raw material (as 100%) | 98kg (99.7kg as 98.3%) |
| Epipristal (as 100%) | 150kg (158.9kg as 94%) |
| S-methoprene (as 100%) | 88kg (123.6kg as 95.5%) |
| Diethylene glycol monoethyl ether | Adding to 1000L (about 617.8kg) |
Diethylene glycol monoethyl ether was added to the vessel and heated to 50 deg.C (about 1 hour). Once heated, fipronil, efenix and S-methoprene were added to the vessel and all the components were mixed until a homogeneous solution was formed (about 1 hour).
Example 5-efficacy evaluation of the Spot composition containing fipronil and Cypermethrin for the treatment of fleas and mites on dogs
A double-blind, controlled study was conducted to demonstrate the difference in kill rate for treatment of mites and fleas between a spot-on composition containing fipronil and cyphenothrin prepared in a similar manner to example 1 and a composition containing fipronil alone.
A total of 18 dogs were randomized into one of three treatment groups. Group a was a control group, did not receive any treatment against fleas and mites and served as a control point for the active treatment regimen. Group B included the active treatment group receiving treatment with a fipronil/cyphenothrin spot-on composition of 8.38% (w/w) fipronil in combination with 4.76% (w/w) cyphenothrin. The final group C included the active treatment group receiving only 8.8% (w/w) fipronil treatment. For all active treatments, the method according to the invention was applied site-specifically and to dogs. All dogs involved in the experiment were first considered to be infested with fleas and mites. The experiment was designed so that all treatment groups were given the appropriate treatment and then observed at 1 and 4 hours post-application. During post-application observation, a defined area of the dog's body was contacted with a test piece of paper for a defined time. The paper was designed so that dead mites and fleas would attach it, and the number of dead mites and fleas was counted in comparison to group a (control), to determine the reduction of pests after treatment. In addition, the number of mites and fleas remaining in the observation area on the dog was also counted.
Dogs in each group (groups a, B and C) were infested with fleas and mites on day-1, and then both active treatment groups (groups B and C) received treatment on day 0. The experimental protocol was designed to test the efficacy of both treatments for subsequent infestation after the initial treatment with the active site-directed composition. After the initial infestation, dogs were again infested with fleas at 4 intervals the first day of the week (days 7, 14, 21 and 28) over a period of about 4 weeks, and monitoring continued until day 30. For each subsequent infestation, the dogs of each treatment group were monitored to determine the kill rate of fleas (fleas Ctenophalides felis)) and mites (Rhipicephalus sanguineus) 1 hour after infestation, 4 hours after infestation, 1 day (24 hours) after infestation, 2 days (48 hours) after infestation. The values in tables 1 and 2 represent the average percent reduction in the numbers of mites and fleas on dogs in each treatment group after subsequent infestation, comparing the treatment results for group B (fipronil and cyphenothrin) and group C (fipronil).
Table 1 group efficacy means against mites
Table 1 provides the average mite kill rate information for the two treatment groups. Dogs in group B were treated with a combination of 8.38% fipronil and 4.76% cyphenothrin, which showed significantly higher average mite kill rates after treatment (day 0) and 1 and 4 hours after all re-infesting periods (days 7, 14, 21 and 28) than in group C (8.8% fipronil treatment). Thus, table 1 illustrates that treatment with a combination of fipronil and cyphenothrin significantly increased the average kill rate and kill rate of mites at 1 hour and 4 hours after initial treatment and after subsequent re-infestation. Table 1 also illustrates that treatment with a combination of fipronil and cyphenothrin provides long-term efficacy in the treatment and prevention of mite infestations up to 30 days after application of the pesticide composition.
Table 2 group efficacy means against fleas
As seen in table 2, the dogs treated with the combination of 8.38% fipronil and 4.76% cyphenothrin (group B) had higher average flea kill rates at 1 hour and 4 hours after infestation and all subsequent infestation periods (days 7, 14, 21 and 28). The dogs treated with the combination of fipronil and cyphenothrin (group B) had a higher average reduction in the number of fleas present at 1 and 4 hours after re-infestation for all re-infestation intervals. Thus, the results of this example demonstrate that treatment with a combination of fipronil and cyphenothrin significantly increased the average kill rate and kill rate of fleas after treatment and 1 and 4 hours after subsequent re-infestation, and provided long-term efficacy of treatment for up to 30 days after treatment.
The empirical data of tables 1 and 2 demonstrate that treatment with the combination of fipronil and cyphenothrin significantly improved the average kill rate and speed of fleas and mites 1 and 4 hours after treatment compared to fipronil treatment alone. In addition, tables 1 and 2 show that the fipronil and cyphenothrin combination maintained a high kill rate for as long as 30 days after the initial application of the spot-on composition following four subsequent re-infestations of the host dog with fleas and mites.
EXAMPLE 6 efficacy evaluation of a site-directed composition containing fipronil and S-methoprene against a site-directed composition containing fipronil, S-methoprene and cyphenothrin for the treatment of fleas and mites in dogs
A double-blind, randomized, single-center, controlled study was conducted to demonstrate the efficacy of fipronil and S-methoprene spot-on compositions enhanced with cyphenothrin, prepared in a similar manner as example 2, in treating mites and fleas in dogs, as compared to fipronil and S-methoprene spot-on compositions enhanced without cyphenothrin.
The study was conducted on 13 groups of dogs, each group consisting of 6 dogs, for a total of 78 dogs. Dogs were ranked by weight and randomly placed into 4 individual reclassifications: a (4lbs-22.9lbs), B (23lbs-44.9lbs), C (45lbs-88.9lbs) and D (25lbs-35.9 lbs). Control dogs (group 1) were selected to represent low, medium and high body weights and had acceptable numbers of fleas and parasites without a bias towards high parasite numbers. In each weight category (A, B, C, D), dogs were randomly assigned to 2, 3, or 4 groups, thus forming 3 groups (2, 3, 4) in each weight category (A, B, C, D). 3 spot-on formulations were administered topically, one to each group of dogs (2, 3 and 4) as shown in Table 3. Fipronil and S-methoprene spot-on products (one reconfigured for testing and one commercially available) each contained 9.8% fipronil and 8.8% S-methoprene. The fipronil, S-methoprene and cyphenothrin spot-on products contained 9.8% fipronil, 8.8% S-methoprene and 5.0% cyphenothrin. The dose volume given to the treated dogs was consistent with the conventional dose (i.e., 0.67mL for dogs weighing less than 23lbs, 1.67mL for dogs weighing 23lbs-44.9lbs, and 2.68mL for dogs weighing 45lbs-88.9 lbs). A subgroup 4 of dogs (D) were treated with the test substance at a volumetric dose rate of 0.67mL/kg, which provided the calculated minimum active ingredient dose rate for dogs having an upper limit in the 89-132lbs weight group.
TABLE 3 grouping and treatment
| Group of | Weight (D) | Treatment of |
| 1 | 4lb-60lb | Is free of |
| 2A | 4lb-22.9lb | Reconfigured fipronil/S-methoprene |
| 2B | 23lb-44.9lb | Reconfigured fipronil/S-methoprene |
| 2C | 45lb-88.9lb | Reconfigured fipronil/S-methoprene |
| 2D | 25lb-35.9lb | Reconfigured fipronil/S-methoprene |
| 3A | 4lb-22.9lb | fipronil/S-methoprene/cyphenothrin |
| 3B | 23lb-44.9lb | fipronil/S-methoprene/cyphenothrin |
| 3C | 45lb-88.9lb | fipronil/S-methoprene/cyphenothrin |
| 3D | 25lb-35.9lb | fipronil/S-methoprene/cyphenothrin |
| 4A | 4lb-22.9lb | Retail fipronil/S-methoprene |
| 4B | 23lb-44.9lb | Retail fipronil/S-methoprene |
| 4C | 45lb-88.9lb | Retail fipronil/S-methoprene |
| 4D | 25lb-35.9lb | Retail fipronil/S-methoprene |
Three active treatments were applied to separate groups at the beginning of the study (day 0). Dogs were infested with fleas (cat fleas) and mites (rhipicephalus rubripes, rhipicephalus americanus (dermalis variabilis), and Haemaphysalis ovalis (Haemaphysalis ellipsotica) at 5 intervals (days-1, 7, 14, 21, and 28) over a period of about 4 weeks, and were monitored for 30 days post-treatment. For each subsequent infestation, dogs of each treatment group were monitored to determine the kill rate of mites 1 hour post-infestation, 4 hours post-infestation, 1 day post-infestation (24 hours), 2 days post-infestation (48 hours). Mites were found by direct observation along the skin and palpation of various areas of the test animals (i.e. outside the hind leg including the foot, tail and anus areas, border areas excluding the shoulders, abdominal area from the chest to the inside of the hind leg, forelegs and shoulders including the foot, all neck and head areas, and back from the shoulder blades to the root of the tail). The efficacy (%) of each mite treatment at 24 and 48 hours after treatment/re-infestation and at 1 and 4 hours after treatment/re-infestation is shown in tables 4 and 5.
Flea counts were only performed 48 hours after treatment (i.e. day 2) and 48 hours after each reinfection (i.e. days 9, 16, 23 and 30). Fleas are recovered from animal hair by a fine comb. The grooming method was performed by stroking each area of the test animal several times with a comb (i.e. outside the hind leg including the foot, tail and anus areas, border areas excluding the shoulders, abdominal area from the chest to the inside of the hind leg, forelegs and shoulders including the foot, all neck and head areas, and back from the shoulder blade to the root of the tail). Each dabbing comb was performed in the same direction of the fur structure. The movement from one part of the animal hair to the next is performed by the flicks overlapping each other so that no hair area is missed. The efficacy of fleas treatment is shown in table 6.
TABLE 4 group mean efficacy against mites 24 and 48 hours after treatment/re-infestation
DV ═ infestation with american dog ticks (d.variabilis); RS ═ infestation with rhipicephalus rubrus (r.sanguineus); HE ═ infestation with haemaphysalis (h
As shown in table 4, the efficacy of all tested substances against existing mites (day-1 infestation) was irregular at 24 and 48 hours after the initial treatment. In summary, a higher average mite kill rate against both mites was observed for the cyphenothrin-enhanced treatment recorded at 24 hours post-infestation in all dog weight categories (3A, 3B, 3C, and 3D groups). Of the different dog weight classifications treated according to the dose range, the effectiveness of cyphenothrin-enhanced fipronil treatment against mites was > 90% or only slightly below 90% 48 hours after treatment. Table 4 also illustrates that treatment with a combination of fipronil/IGR and cyphenothrin provides long-term efficacy in the treatment and prevention of mite infestations up to 30 days after application of the composition.
TABLE 5 group mean immediate efficacy against mites 1 and 4 hours after treatment/re-infestation
DV ═ infestation with american dog ticks (d.variabilis); RS ═ infestation with rhipicephalus rubrus (r.sanguineus); HE ═ infestation with haemaphysalis (h
Table 5 illustrates that the enhanced spot-on compositions consistently provided better immediate efficacy against the new mites, especially when compared to the phenothrin-free compositions (groups 2 and 4). Efficacy of killing/repelling mites was observed at 1 and 4 hours after re-infestation on days 7 and 21 for both mites, and at day 28 for rhipicephalus rhynchophyllus. Thus, table 5 illustrates that treatment with a combination of fipronil and cyphenothrin significantly increased the average kill rate and kill rate of mites after 1 hour and 4 hours after initial treatment and after subsequent re-infestation.
TABLE 6 group mean efficacy against fleas 24 and 48 hours after treatment/re-infestation
Table 6 illustrates that the efficacy of the cyphenothrin-enhanced composition throughout the study (i.e., until day 30) was 100% by weight in all dogs, whereas the retail fipronil/IGR composition failed to maintain 100% efficacy in the mid weight range of dogs.
In summary, the efficacy of the enhanced formulation against fleas measured 48 hours after treatment and re-infestation was 100%. Cyphenothrin enhanced formulations are generally more effective than commercial fipronil/IGR formulations without cyphenothrin. The residual efficacy against new mite infestation 30 days after treatment was well above 90% in all weight groups, but the commercial product was well below 90% in half the body recombination in the last week of the study. The enhancement of the formulation with 5% cyphenothrin improved the immediate efficacy against new mites (american dog tick and haemaphysalis ovaliformis) on days 7 and 21 and against rhipicephalus rubrus on day 28. Comparison of the enhanced formulation with the two fipronil only test substances shows that the enhanced test substance provides statistically better anthelmintic effect 1 and 4 hours after re-infestation.
Example 7-Spot composition containing fipronil/S-methoprene and Spot composition containing fipronil/S-methoprene/Epfenprox for efficacy assessment on the treatment of fleas and mites on cats
A double-blind, randomized, single-center, controlled study was conducted to demonstrate the efficacy of fipronil/IGR site-directed compositions enhanced with efepruse in treating mites and fleas in cats, as compared to fipronil/IGR site-directed compositions enhanced without efepruse. The experimental spot-on formulation containing 9.8% fipronil and 11.8% S-methoprene was enhanced by the addition of 15% efenprox. The efficacy of the enhanced composition and the two fipronil/S-methoprene formulations, enhanced without efention, against existing fleas and mites, was evaluated.
The study was conducted on 7 groups of cats, each group consisting of 6 cats, totaling 42 cats. Cats were randomly assigned to 7 groups. Efepristol active prodrug (97% a.i.) was added at a ratio of 15% to a base fipronil-methoprene formulation (9.8% fipronil, 11.8% S-methoprene) to provide an enhanced formulation. Two efenix-methoprene formulations without efenix contained 9.8% and 11.8% S-methoprene. A fipronil/methoprene formulation was reconstituted for testing, a commercially available formulation, which served as a positive control for this study. The enhanced formulation was applied to a group of 6 cats treated at a 0.50mL unit dose (group 2A). The non-enhanced formulation was applied to 6 cats in two groups each (groups 3A and 4A) at a 0.50mL unit dose. Three further groups of 6 cats were treated by applying the test substance at the minimum dose rate, corresponding to a cat weighing 20lb (about 0.055mL/kg) treated with a dose volume of 0.5 mL. The enhanced formulation was administered to group 2B at this dose and the non-enhanced formulation was administered to groups 3B and 4B at this dose. The weight specification for all treated cats was 10lb +/-5 lb. Group 7 of 6 cats (group 1) served as untreated controls. Table 7 shows the groups, treatments and doses of cats in this study.
TABLE 7 grouping, treatment and dosing
| Group of | Weight (D) | Dosage form | Treatment of |
| 1 | 5lb-15lb | Is free of | Is free of |
| 2A | 5lb-15lb | 0.5mL/cat | fipronil/S-methoprene/efeprazole |
| 2B | 5lb-15lb | 0.055mL/kg | fipronil/S-methoprene/efeprazole |
| 3A | 5lb-15lb | 0.5mL/cat | Reconfigured fipronil/S-methoprene |
| 3B | 5lb-15lb | 0.055mL/kg | Reconfigured fipronil/S-methoprene |
| 4A | 5lb-15lb | 0.5mL/cat | Retail fipronil/S-methoprene |
| 4B | 5lb-15lb | 0.055mL/kg | Retail fipronil/S-methoprene |
Cats were infested with 100 fleas (cat fleas) and 50 mites (Rhipicephalus appendiculatus (Rhipicephalus turanicus) on days-1, 7, 14, 21 and 28, day 7, american dog ticks on days-1, 21 and 28, and haemaphysalis on day 14) over a period of about 4 weeks, and monitored for 30 days post-treatment. Mite counting without disturbing or removing mites was performed similarly after 1 and 4 hours after application of the test substance on the treatment day (day 0) and after re-infestation on days 8, 15, 22 and 28, to determine the kill rate as evidence of repellency. Mite counts were also performed 24 and 48 hours after treatment and each reinfection. Mites were found by direct observation along the skin and palpation of various areas of the test animals (i.e. outside the hind leg including the foot, tail and anus areas, border areas excluding the shoulders, abdominal area from the chest to the inside of the hind leg, forelegs and shoulders including the foot, all neck and head areas, and back from the shoulder blades to the root of the tail). The efficacy (%) of each mite treatment after treatment and 24 and 48 hours after re-infestation is shown in table 8. The efficacy (%) of each mite treatment after treatment and 1 and 4 hours after re-infestation is shown in table 9.
TABLE 8 group mean efficacy against mites 24 and 48 hours after treatment/re-infestation
DV ═ infestation with american dog ticks (d.variabilis); RT ═ infestation with rhipicephalus appendiculatus (r. turanicus); HE ═ infestation with haemaphysalis (h
Bold indicates up to/over 90% (unless increased to 90% by rounding)
As shown in table 8, a complete marker dose (0.5mL) of all 3 test substances similarly achieved a killing/repelling efficacy of up to/over 90% at 48 hours post-treatment and re-infestation. Almost exclusively for the group receiving the full marker dose, it also showed occasionally sufficient efficacy (> 90%) against mites 24 hours after treatment or re-infestation. The minimum dose rate treatment groups (groups 2B, 3B and 4B) achieved 90% efficacy or slightly less than 90% efficacy (i.e., at least 85% -95%) against fleas at 48 hours, except for the positive control group at the fourth week (group 4B).
TABLE 9 group mean efficacy against mites 1 and 4 hours after treatment/re-infestation
DV ═ infestation with american dog ticks (d.variabilis); RT ═ infestation with rhipicephalus appendiculatus; HE ═ infestation with haemaphysalis (h
Bold indicates up to/over 90%
Table 9 illustrates that the killing/repellent efficacy at 1 and 4 hours after treatment and re-infestation did not show the immediate efficacy improvement resulting from the enfenprox boost of the basic fipronil-methoprene formulation. Only 3 cases (4 hour counts) showed sufficient (> 90%) immediate efficacy against mites, and these 3 events did not appear to correlate consistently with the formulation or dose rate.
TABLE 10 group mean efficacy against fleas 24 and 48 hours after treatment/re-infestation
Bold indicates up to/over 90%
Table 10 illustrates that all 3 treatments given to cats at a minimum dose of 0.055mL/kg had more than 90% immediate efficacy against fleas and > 90% sustained efficacy for four weeks (groups 2B and 3B) and three weeks (group 4B). Table 10 also demonstrates that all 3 treatments given to the cat at a dose of 0.50 ml/cat had > 90% immediate (day 2) and four weeks of efficacy against fleas.
In summary, test substances that provided 90% or better efficacy against fleas at the end of the study at full and minimum dose rates when given only at full marker dose rates (groups 2A and 4A) were enhanced fipronil-methoprene (group 2) and a positive control test (group 4). Both provided sufficient efficacy against fleas and mites at study week 4.
Example 8: fipronil and S-methoprene compositions were tested against enhanced fipronil, S-methoprene and phenothrin compositions
A double-blind, controlled study was conducted to demonstrate the difference in kill rates for mites and fleas between a spot-on composition containing fipronil and S-methoprene and an enhanced spot-on composition containing fipronil, S-methoprene and cyphenothrin prepared in a similar manner to example 2.
A total of 18 dogs were randomized into three treatment groups. Group a was a control group and received no treatment. Group B included the active treatment group receiving an enhanced combination therapy of 9.8% fipronil, 8.8% S-methoprene and 5% cyphenothrin. Group C included the active treatment group receiving a combination treatment of 9.8% fipronil and 8.8% S-methoprene. For all treatments, the method according to the invention was applied topically and to dogs. All dogs involved in the experiment were first considered to be infested with fleas and mites. The experiment was designed so that all treatment groups were given the appropriate treatment and then observed at 1 and 4 hours post-application. During post-application observation, a defined area of the dog's body was contacted with a test piece of paper for a defined time. The paper was designed so that dead mites and fleas would attach it, and the number of dead mites and fleas was counted in comparison to the control group (group a), thereby determining the reduction of pests due to the treatment. In addition, the number of mites and fleas remaining in the observation area on the dog was also counted. The results of this experiment are shown in Table 11.
Table 11: killing data for treatment of mites and fleas
As shown in table 11, group B (including treatment with cyphenothrin) killed a much lower number of mites and fleas within the first hour of treatment than group C (without treatment with cyphenothrin). Using group a as the average baseline for the numbers of mites and fleas present on the infested dogs, the average numbers of mites and fleas present on the skin of the dogs in group B were reduced by 87.6% and 75.5% after 1 hour, respectively. Whereas the average numbers of mites and fleas present on the skin after 1 hour were only reduced by 8.4% and 12.3% in the dogs in group C, respectively.
In addition, the numbers of mites and fleas remaining on the skin of the animals in group B dogs dropped on average by 96.4% and 95.9% at 4 hour intervals, respectively. The dogs in group C had an average drop of 94.6% and 76.3%. Thus, the average reduction of mites on animals was similar, but the average reduction of fleas on dog skin was significantly higher (95.9% for group B versus 76.3% for group C). Finally, group B died more mites and fleas dead on the paper than group C. The B-treated group produced a total average kill rate of 44.5 mites and 59.5 fleas during the 4 hour interval compared to 29.7 mites and 49.0 fleas for the C-treated group. Thus, the combination of fipronil, S-methoprene and cyphenothrin produced a significantly improved average kill rate after 1 hour and maintained a higher average kill rate for mites and fleas 4 hours after treatment.
All of the compositions and methods described and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described with reference to preferred embodiments, it will be apparent to those of skill in the art that various changes may be made in the compositions and methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
Claims (48)
1. A spot-on pesticidal composition comprising 8% to 11% (w/w) fipronil, 3% to 16% (w/w) pyrethroid, and 60% to 80% (w/w) organic solvent.
2. The spot-on pesticidal composition of claim 1, comprising 8% to 11% (w/w) fipronil, 4% to 6% (w/w) pyrethroid, and 70% to 80% (w/w) organic solvent.
3. The spot-on pesticidal composition of claim 2, wherein the pyrethroid is cyphenothrin.
4. The spot-on pesticidal composition of claim 1, comprising 8% to 11% (w/w) fipronil, 14% to 16% (w/w) pyrethroid, and 60% to 75% (w/w) organic solvent.
5. The spot-on pesticidal composition of claim 4, wherein the pyrethroid is efeprazole.
6. The spot-on pesticidal composition of claim 1, wherein the organic solvent is diethylene glycol monoethyl ether.
7. The spot-on pesticidal composition of claim 1, further comprising an antioxidant.
8. The spot-on pesticidal composition of claim 7, wherein the antioxidant is present in the composition at a concentration of 4% to 6% (w/w).
9. The spot-on pesticidal composition of claim 7, wherein the antioxidant is tocopherol nicotinate.
10. The spot-on composition of claim 1, further comprising an insect growth regulator.
11. The spot-on composition of claim 10, wherein the insect growth regulator is present in the composition at a concentration of 2% to 15% (w/w).
12. The spot-on composition of claim 10, wherein the insect growth regulator is present in the composition at a concentration of 3% to 5% (w/w).
13. The spot-on composition of claim 12, wherein the insect growth regulator is pyriproxyfen.
14. The spot-on composition of claim 10, wherein the insect growth regulator is present in the composition at a concentration of 8% to 12% (w/w).
15. The spot-on composition of claim 14, wherein the insect growth regulator is S-methoprene.
16. A spot-on insecticide composition comprising 8% to 11% (w/w) fipronil, 3% to 16% (w/w) pyrethroid, 2% to 15% (w/w) insect growth regulator and 60% to 80% (w/w) organic solvent.
17. A spot-on pesticidal composition, the composition comprising:
8-11% (w/w) fipronil;
4% -6% (w/w) cyhalothrin;
c.75-80% (w/w) organic solvent; and
4% -6% (w/w) antioxidant.
18. A spot-on pesticidal composition, the composition comprising:
8-11% (w/w) fipronil;
4% -6% (w/w) cyhalothrin;
c.8% -12% (w/w) S-methoprene;
d.65% -70% (w/w) organic solvent; and
e.4% -6% (w/w) antioxidant.
19. A spot-on pesticidal composition, the composition comprising:
8-11% (w/w) fipronil;
14% -16% (w/w) efeprazole; and
c, 70-75% (w/w) of organic solvent.
20. A spot-on pesticidal composition, the composition comprising:
8-11% (w/w) fipronil;
14% -16% (w/w) efeprazole;
c, 11-13% (w/w) S-methoprene; and
60% -65% (w/w) of organic solvent.
21. A spot-on pesticidal composition, the composition comprising:
8-11% (w/w) fipronil;
4% -6% (w/w) cyhalothrin;
c.3% -5% (w/w) pyriproxyfen;
75-80% (w/w) organic solvent; and
e.4% -6% (w/w) antioxidant.
22. A spot-on pesticidal composition, the composition comprising:
8-11% (w/w) fipronil;
14% -16% (w/w) efeprazole;
c.3% -5% (w/w) pyriproxyfen; and
d, 65-70% (w/w) of organic solvent.
23. A method of killing insect and pest pupae and adults on an animal comprising applying to the topical skin between the shoulders of the animal a spot-on composition comprising 8% to 11% (w/w) fipronil, 3% to 16% (w/w) pyrethroid, and 60% to 80% (w/w) organic solvent.
24. The method of claim 23, wherein the spot-on composition comprises 4% to 6% (w/w) pyrethroid.
25. The method of claim 23, wherein the animal is a mammal.
26. The method of claim 25, wherein the mammal comprises a dog or cat.
27. The method of claim 23, wherein the spot-on composition additionally comprises an insect growth regulator.
28. The method of claim 27, wherein the insect growth regulator is present in the composition at a concentration of 2% to 15% (w/w).
29. The method of claim 23, wherein the spot-on composition additionally comprises 4% to 6% (w/w) antioxidant.
30. A method of killing insect and pest pupae and adults on an animal comprising administering to the animal a topical skin application between the shoulders a spot-on composition comprising 8% to 11% (w/w) fipronil, 3% to 16% (w/w) pyrethroid, 2% to 15% (w/w) insect regulator, and 60% to 80% (w/w) organic solvent.
31. A method of killing insect and pest pupae and adults on an animal comprising applying a spot-on composition to the topical skin between the shoulders of the animal, the spot-on composition comprising:
8-11% (w/w) fipronil;
4% -6% (w/w) cyhalothrin;
c, 70-80% (w/w) of organic solvent; and
4% -6% (w/w) antioxidant.
32. The method of claim 31, wherein the organic solvent is diethylene glycol monoethyl ether.
33. The method of claim 31, wherein the composition further comprises 3% to 5% (w/w) pyrethroid.
34. The method of claim 31, wherein the composition further comprises 8% to 12% (w/w) S-methoprene.
35. The method of claim 31, wherein the antioxidant is tocopherol nicotinate.
36. A method of killing insect and pest pupae and adults on an animal comprising applying a spot-on composition to the topical skin between the shoulders of the animal, the spot-on composition comprising:
8-11% (w/w) fipronil;
4% -6% (w/w) cyhalothrin;
c.8% -12% (w/w) S-methoprene;
70-80% (w/w) of an organic solvent; and
e.4% -6% (w/w) antioxidant.
37. The method of claim 36, wherein the animal is a mammal.
38. The method of claim 37, wherein the mammal comprises a dog or cat.
39. A method of killing insect and pest pupae and adults on an animal comprising applying a spot-on composition to the topical skin between the shoulders of the animal, the spot-on composition comprising:
8-11% (w/w) fipronil;
4% -6% (w/w) cyhalothrin;
c.3% -5% (w/w) pyriproxyfen;
70-80% (w/w) of an organic solvent; and
e.4% -6% (w/w) antioxidant.
40. A method of killing insect and pest pupae and adults on an animal comprising applying a spot-on composition to the topical skin between the shoulders of the animal, the spot-on composition comprising:
8-11% (w/w) fipronil;
14% -16% (w/w) efeprazole; and
c, 60-75% (w/w) of organic solvent.
41. The method of claim 35, wherein the organic solvent is diethylene glycol monoethyl ether.
42. The method of claim 35, wherein said composition further comprises 2% to 15% (w/w) insect growth regulator.
43. The method of claim 42, wherein the insect growth regulator comprises pyriproxyfen or S-methoprene.
44. A method of killing insect and pest pupae and adults on an animal comprising applying a spot-on composition to the topical skin between the shoulders of the animal, the spot-on composition comprising:
8-11% (w/w) fipronil;
14% -16% (w/w) efeprazole;
c, 11-14% (w/w) S-methoprene; and
60% -75% (w/w) of organic solvent.
45. A method of killing insect and pest pupae and adults on an animal comprising applying a spot-on composition to the topical skin between the shoulders of the animal, the spot-on composition comprising:
8-11% (w/w) fipronil;
14% -16% (w/w) efeprazole;
c.3% -5% (w/w) pyriproxyfen; and
60% -75% (w/w) of organic solvent.
46. A method of preparing a spot-on insecticide composition comprising 8% to 11% (w/w) fipronil, 3% to 16% (w/w) pyrethroid, and 60% to 80% (w/w) organic solvent, the method comprising;
a. adding an organic solvent to the vessel and heating to about 50 ℃;
b. adding the fipronil and the pyrethroid to the solvent, and then mixing to produce a solution.
47. A method of preparing a spot-on insecticide composition comprising 8% to 11% (w/w) fipronil, 3% to 16% (w/w) pyrethroid, 2% to 15% (w/w) insect growth regulator and 60% to 80% (w/w) organic solvent, the method comprising:
a. adding an organic solvent to the vessel and heating to about 50 ℃;
b. adding the fipronil, the pyrethroid, and the insect growth regulator to the solvent, and then mixing to produce a solution.
48. A method of preparing a spot-on insecticide composition comprising 8% to 11% (w/w) fipronil, 3% to 16% (w/w) pyrethroid, 60% to 80% (w/w) organic solvent, and 4% to 6% (w/w) antioxidant, the method comprising;
a. adding an organic solvent and an antioxidant to a vessel and heating to about 50 ℃ to form a hot mixture;
b. adding the fipronil and the pyrethroid to the hot mix, and then mixing to produce a solution.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/244,788 | 2009-09-22 | ||
| US61/297,154 | 2010-01-21 | ||
| US12/888,136 | 2010-09-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1179474A true HK1179474A (en) | 2013-10-04 |
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