CA2222675C - Direct pour-on skin solution for antiparasitic use in cattle and sheep - Google Patents
Direct pour-on skin solution for antiparasitic use in cattle and sheep Download PDFInfo
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- CA2222675C CA2222675C CA002222675A CA2222675A CA2222675C CA 2222675 C CA2222675 C CA 2222675C CA 002222675 A CA002222675 A CA 002222675A CA 2222675 A CA2222675 A CA 2222675A CA 2222675 C CA2222675 C CA 2222675C
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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
- 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
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
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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
- 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
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- Pest Control & Pesticides (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A solution for direct application on the skin to eliminate cattle and sheep parasites, particularly Boophilus microplus, including 0.05-25 %, preferably 0.05-10 % and particularly 0.1-2 % w/v, relative to the total solution, of a compound of formula (I), in a low-volume formulation designed to release the compound of formula (I) onto the skin and hair for contact activity against parasites.
Description
DIRECT POUR-ON SKIN SOLtJTION FOR 11N'1'IPARASITIC CSE IN
CATTLE AND sSEEP.
The present invention relates to a direct pour-on skin solution which contains an antiparasitic product and is intended to be applied topically to cattle and sheep.
The invention also relates to the use of antiparasitic compounds for the preparation of this skin solution, as well as to a treatment process rela:ing thereto.
Cattle and sheep are affected by a large number of parasites.
The main ones are ticks of the genus Boophilus, among which mention may be made of the i5 species microplus (cattle tick), decoloratus and anulatus.
The other main parasites of cattle and sheep are indicated in order of decreasing importance:
- myiases such as Dermatobia hominis (known as Berne in Brazil) and Cochlyomia hominivorax (greenbottle); sheep myiases such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa). These are flies whose larva constitutes the animal parasite.
- flies proper, namely those whose adult constitutes the parasite, such as Haematobia irritans (horn fly).
- lice such as Linognathus vitulorum, etc.
- galls such as Sarcoptes scabiei and Psoroptes ovis.
Ticks, in particular Boophilus microplus, are very closely attached to the pasture in which they live and are particularly difficult to control.
There is at the present time no truly effective method for controlling ticks, and less still an effective way of controlling the, set of parasites indicated above.
WO-A-87/3781, EP-A-295,117 and EP-A-500,209 describe a class of insecticides which are N-phenyl-pyrazole derivatives. These compounds are given as having activity against a very large number of parasites, including Boophilus microplus, in'fields as varied as agriculture, public health and veterinary medicine. The general teaching of these documents indicates that these insecticidal compounds may be 1.0 administered via different routes; oral, parenteral, percutaneous and topical routes. Topical administration comprises, in particular, oral formulations, baits, dietary supplements, skin solutions (pour-on), solutions for spraying (sprays), baths, showers, jets, powders, i5 greases, shampoos, creams, etc. The pour-on type skin solutions are designed for percutaneous administratiori.
Example 9 of EP-A-295,117 and Example 291 of EP-A-500,209 describe a pour-on type skin solution containing 15% insecticide and 85% dimethyl sulphoxide, for 20 percutaneous administration of_the insecticide.
EP-A-296,381 also describes pyrazole compounds having insecticidal activity in the field of agriculture, public health and veterinary medicine.
Boophilus microplus is one of the very many targets 25 mentioned. There are very many forms of administration here also, and these include, for example, solutions, emulsions, suspensions, powders, pastes, granules and aerosols.
The problem which is posed is to find an 30 effective means which is entirely suitable for controlling the parasites of cattle and sheep, in particular ticks, most particularly Boophilus microplus in cattle and in particular lice and blowfly in sheep, under the conditions in which these animals are reared.
33 The Applicant has found that it is possible to effectively control Boophilus microplus for cattle using a specific topical formulation. The Applicant has also found that this formulation is effective against sheep lice and sheep flies known as "blowfly".
The object of the present invention is thus to provide a novel composition which is entirely effective against Boophilus microplus and also against all of the other parasites described above, in particular such as sheep lice and "blowfly", this composition being entirely suitable for controlling these parasites under the conditions in which these animals are reared.
The aim of the present invention is thus to i5 provide a novel composition which is entirely effective against Boophilus microplus and also against all of the other parasites described above such as, in particular, sheep lice and "blowfly", this composition being entirely suitable for controlling these parasites under the conditions in which these animals are reared.
Another aim of the invention is to provide such a formulation which has a long period of efficacy, preferably longer than or equal to two months.
Another aim of the invention is to provide such a formulation which is quick and easy to use and entirely compatible with use on herds or flocks contain-ing a large number of animals.
Another aim of the invention is to provide such a formulation which is particularly suitable for extensive pasture rearing and for use intended to pro-tect animals during the period of rounding up and finishing (Feed Lot in USA), namely the final period of rearing in which a large number of animals are herded into a small enclosure over an average period of two months preceding slaughter.
CATTLE AND sSEEP.
The present invention relates to a direct pour-on skin solution which contains an antiparasitic product and is intended to be applied topically to cattle and sheep.
The invention also relates to the use of antiparasitic compounds for the preparation of this skin solution, as well as to a treatment process rela:ing thereto.
Cattle and sheep are affected by a large number of parasites.
The main ones are ticks of the genus Boophilus, among which mention may be made of the i5 species microplus (cattle tick), decoloratus and anulatus.
The other main parasites of cattle and sheep are indicated in order of decreasing importance:
- myiases such as Dermatobia hominis (known as Berne in Brazil) and Cochlyomia hominivorax (greenbottle); sheep myiases such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa). These are flies whose larva constitutes the animal parasite.
- flies proper, namely those whose adult constitutes the parasite, such as Haematobia irritans (horn fly).
- lice such as Linognathus vitulorum, etc.
- galls such as Sarcoptes scabiei and Psoroptes ovis.
Ticks, in particular Boophilus microplus, are very closely attached to the pasture in which they live and are particularly difficult to control.
There is at the present time no truly effective method for controlling ticks, and less still an effective way of controlling the, set of parasites indicated above.
WO-A-87/3781, EP-A-295,117 and EP-A-500,209 describe a class of insecticides which are N-phenyl-pyrazole derivatives. These compounds are given as having activity against a very large number of parasites, including Boophilus microplus, in'fields as varied as agriculture, public health and veterinary medicine. The general teaching of these documents indicates that these insecticidal compounds may be 1.0 administered via different routes; oral, parenteral, percutaneous and topical routes. Topical administration comprises, in particular, oral formulations, baits, dietary supplements, skin solutions (pour-on), solutions for spraying (sprays), baths, showers, jets, powders, i5 greases, shampoos, creams, etc. The pour-on type skin solutions are designed for percutaneous administratiori.
Example 9 of EP-A-295,117 and Example 291 of EP-A-500,209 describe a pour-on type skin solution containing 15% insecticide and 85% dimethyl sulphoxide, for 20 percutaneous administration of_the insecticide.
EP-A-296,381 also describes pyrazole compounds having insecticidal activity in the field of agriculture, public health and veterinary medicine.
Boophilus microplus is one of the very many targets 25 mentioned. There are very many forms of administration here also, and these include, for example, solutions, emulsions, suspensions, powders, pastes, granules and aerosols.
The problem which is posed is to find an 30 effective means which is entirely suitable for controlling the parasites of cattle and sheep, in particular ticks, most particularly Boophilus microplus in cattle and in particular lice and blowfly in sheep, under the conditions in which these animals are reared.
33 The Applicant has found that it is possible to effectively control Boophilus microplus for cattle using a specific topical formulation. The Applicant has also found that this formulation is effective against sheep lice and sheep flies known as "blowfly".
The object of the present invention is thus to provide a novel composition which is entirely effective against Boophilus microplus and also against all of the other parasites described above, in particular such as sheep lice and "blowfly", this composition being entirely suitable for controlling these parasites under the conditions in which these animals are reared.
The aim of the present invention is thus to i5 provide a novel composition which is entirely effective against Boophilus microplus and also against all of the other parasites described above such as, in particular, sheep lice and "blowfly", this composition being entirely suitable for controlling these parasites under the conditions in which these animals are reared.
Another aim of the invention is to provide such a formulation which has a long period of efficacy, preferably longer than or equal to two months.
Another aim of the invention is to provide such a formulation which is quick and easy to use and entirely compatible with use on herds or flocks contain-ing a large number of animals.
Another aim of the invention is to provide such a formulation which is particularly suitable for extensive pasture rearing and for use intended to pro-tect animals during the period of rounding up and finishing (Feed Lot in USA), namely the final period of rearing in which a large number of animals are herded into a small enclosure over an average period of two months preceding slaughter.
The subject of the present invention is thus a direct pour-on skin solution, intended to eliminate parasites from cattle and sheep, most particularly ticks, especially Boophilus microplus in cattle and lice and blowfly in sheep, comprising from 0.05 to 25%
weight/volume, relative to the total solution, of a compound of formula (I) K
Ru ~X
ta (1) in which:
R1 is CN or methyl or a halogen atom;
R2 is S(0) aR, or 4, 5-dicyanoimidazol-2-yl or haloalkyl;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR5R,6, S(0)A, C(O)R7, C(0)O-R7, alkyl, haloalkyl or 0R@ or a radical -N=C (R9) (R10) ;
RS and Rs independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)sCF, radical; or RS 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;
R, represents an alkyl or haloalkyl radical;
N represents an alkyl or haloalkyl radical or a hydrogen atom;
R. represents an alkyl radical or a hydrogen atom;
Rlo 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;
Rl, and Rlg represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NOa ;
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(0)aCF3 or SFS group;
M. n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical C-R12, the other three valency positions -of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, either R3 is haloalkyl, R4 is NH2 , R11 is Cl, R13 is CF3 and X is N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is C1, Rll is Cl, R13 is CF3 and X is =C-Cl;
in a formulation at low volume, designed to release the compound (I) onto the skin and the hairs for a contact action against parasites.
Preferably, in formula (I), RI is CN or methyl;
R2 is S(0) aR3;
R. is alkyl or haloalkyl;
R. represents a hydrogen or halogen atom; or a radical 1vRSR6, S(O)õRõ C(0)R7, alkyl, . haloalkyl or ORe or a radical -N=C(R,) (Rlo) ;
RS and R. independently represent a hydrogen atom or an alkyl, haloalkyl, C(0)alkyl or S(0)=CF3 radi-cal; or Rs and R, 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;
weight/volume, relative to the total solution, of a compound of formula (I) K
Ru ~X
ta (1) in which:
R1 is CN or methyl or a halogen atom;
R2 is S(0) aR, or 4, 5-dicyanoimidazol-2-yl or haloalkyl;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR5R,6, S(0)A, C(O)R7, C(0)O-R7, alkyl, haloalkyl or 0R@ or a radical -N=C (R9) (R10) ;
RS and Rs independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)sCF, radical; or RS 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;
R, represents an alkyl or haloalkyl radical;
N represents an alkyl or haloalkyl radical or a hydrogen atom;
R. represents an alkyl radical or a hydrogen atom;
Rlo 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;
Rl, and Rlg represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NOa ;
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(0)aCF3 or SFS group;
M. n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical C-R12, the other three valency positions -of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, either R3 is haloalkyl, R4 is NH2 , R11 is Cl, R13 is CF3 and X is N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is C1, Rll is Cl, R13 is CF3 and X is =C-Cl;
in a formulation at low volume, designed to release the compound (I) onto the skin and the hairs for a contact action against parasites.
Preferably, in formula (I), RI is CN or methyl;
R2 is S(0) aR3;
R. is alkyl or haloalkyl;
R. represents a hydrogen or halogen atom; or a radical 1vRSR6, S(O)õRõ C(0)R7, alkyl, . haloalkyl or ORe or a radical -N=C(R,) (Rlo) ;
RS and R. independently represent a hydrogen atom or an alkyl, haloalkyl, C(0)alkyl or S(0)=CF3 radi-cal; or Rs and R, 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;
Ra represents an alkyl or haloalkyl radical or a hydrogen atom;
R9 represents an alkyl radical or a hydrogen atom;
Rlo 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;
R11 and R12 represent, independently of each other, a hydrogen or halogen atom;
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) qCF3 or SF5 group;
M. n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical C-R12, the other three valency positions of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, then R3 is haloalkyl, R4 is NH2, Rll is Cl, R13 is CF3 and X is N.
However, low concentrations of from 0.05 to 10%
weight/volume, more particularly from 0.1 to 2%, are preferred. Optimally, the value is between 0.25 and 1.5%, in particular in the region of 1%.
According to another aspect of the present invention, there is provided use of a composition comprising 0.05 to 25% weight/volume of a compound of formula (I):
- 6a -N
X
Rll C
(I) wherein:
Rl is CN or methyl;
R2 is S (O) R3i R3 is alkyl or haloalkyl;
R4 represents NH2;
R11 represents a halogen atom;
X is C-R12;
R12 represents a halogen atom;
R13 represents a haloalkyl;
n represents an integer equal to 0, 1 or 2;
for controlling ticks of the genus Boophilus in cattle or sheep, wherein the composition is adapted as a pour-on skin solution for application to the back of the cattle or sheep according to a schedule having no less than a once-monthly application interval.
- 6b -According to still another aspect of the present invention, there is provided a composition for controlling ticks of the genus Boophilus in cattle or sheep, the composition comprising from 0.05 to 25% weight/volume of a compound of formula (I):
N
Ra Rll X
/
(I) wherein:
R1 is CN or methyl;
R2 iS S (0) nR3i R3 is alkyl or haloalkyl;
R4 represents NH2;
R11 represents a halogen atom;
X is C-R12;
R12 represents a halogen atom;
R13 represents a haloalkyl;
n represents an integer equal to 0, 1 or 2;
and wherein the composition is adapted as a pour-on skin solution for administration to the back of the cattle or - 6c -sheep according to a schedule having no less than a once-monthly application interval.
According to yet another aspect of the present invention, there is provided a commercial package comprising a composition as described herein together with written matter describing instructions for the use thereof for controlling ticks of the genus Boophilus in cattle or sheep.
The expression pour-on skin solution is understood to refer to a ready-to-use solution intended to be applied topically and locally on the animal, preferably on the animal's back and at several points or along the line of the back, and applied in low volume, preferably of 5 to 20 ml per 100 kg, preferably about 10 ml per 100 kg, with a total volume of from 10 to 150 ml per animal, preferably limited to 50 ml.
The compound acts by simple contact, the parasite becoming impregnated with the compound on contact with the hair and the skin.
This thereby affords, in a noteworthy manner, a both perfect compatibility with the restrictions of use in extensive grazing, in terms of ease of use in particular, and a spectrum of activity and of efficacy, as well as a period of efficacy, which are suited to this type of rearing.
By working on the concentration of compound (I), in particular of compound A, solutions having note-worthy activities are obtained with, in particular, two months of efficacy against Boophilus microplus, this result never before having been achieved. Moreover, the solution according to the invention allows Boophilus microplus to be totally eliminated from an infested animal in less than 2 days.
As has been stated above, the solution according to the present invention is applied topically, in low volume, to the animal's back. The compound of formula (I) then diffuses out in a noteworthy'manner, this being reflected by a distribution of the compound over the animal's entire body. It has also been observed that the animals remained protected in the case of passage through water or exposure to rain.
The dose of compound of formula (I) is preferably between 0.1 and 2 mg/kg (animal weight), preferably between 0.25 and 1.5 mg/kg, and in particular about 1 mg/kg.
The compounds of formula (I) in which R1 is CN will be selected most particularly. The compounds in which R2 is S(0)4R,, preferably with n = 1, R, preferably being CF3 or alkyl, for example methyl or ethyl, or alternatively n = 0, R, preferably being CF3, as well as those in which X = C-R12, Rl, being a halogen atom, will also be selected. The compounds in which R11 is a halogen atom and those in which R33 is haloalkyl, preferably CF31 are also preferred. In the context of the present inven-tion, compounds combining two or more of these charac-teristics will advantageously be selected.
A preferred class of compounds of formula (I) consists of compounds such that R1 is CN, R3 is haloalkyl, preferably CF3, or ethyl, R4 is NH2, RI, and R12 are, independently of each other, a halogen atom, and/or R13 is haloalkyl.
The alkyl radicals of the definition of the compounds of formula (I) generally comprise from 1 to 6 carbon atoms. The ring formed by the divalent alkylene radical representing Rg ,and R6, as well as the nitrc%qen atom to which R. and R6 are attached, is generally a 5-, 6- or 7-membered ring.
A most particularly preferred compound of the formula (I) in the invention is i5 1-[2,6-C12 4-CF3phenyl]3-CN 4- [SO-CF,35-NH2pyrazole, referred to hereinbelow as compound A. This compound A
will be used in particular in a proportion of-from 0.1 to 2% by weight, more particularly about 1$, relative to the total solution.
Mention may also be made of the two compounds which differ from the above by the following characteristics:
1- n = 0, R] = CF]
2- n = 1,R3 = ethyl.
The compounds of formula (I) may be prepared according to one or other of the processes described in patent applications WO-A-87/3781, 93/6089, 94/21606 or European patent application EP-A-0,295,117, or any other process which falls within the competence of a specialist=skilled in the art of chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is considered as having at his or her disposal, inter alia, all the contents of "Chemical Abstracts" and the documents cited therein.
R9 represents an alkyl radical or a hydrogen atom;
Rlo 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;
R11 and R12 represent, independently of each other, a hydrogen or halogen atom;
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) qCF3 or SF5 group;
M. n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical C-R12, the other three valency positions of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, then R3 is haloalkyl, R4 is NH2, Rll is Cl, R13 is CF3 and X is N.
However, low concentrations of from 0.05 to 10%
weight/volume, more particularly from 0.1 to 2%, are preferred. Optimally, the value is between 0.25 and 1.5%, in particular in the region of 1%.
According to another aspect of the present invention, there is provided use of a composition comprising 0.05 to 25% weight/volume of a compound of formula (I):
- 6a -N
X
Rll C
(I) wherein:
Rl is CN or methyl;
R2 is S (O) R3i R3 is alkyl or haloalkyl;
R4 represents NH2;
R11 represents a halogen atom;
X is C-R12;
R12 represents a halogen atom;
R13 represents a haloalkyl;
n represents an integer equal to 0, 1 or 2;
for controlling ticks of the genus Boophilus in cattle or sheep, wherein the composition is adapted as a pour-on skin solution for application to the back of the cattle or sheep according to a schedule having no less than a once-monthly application interval.
- 6b -According to still another aspect of the present invention, there is provided a composition for controlling ticks of the genus Boophilus in cattle or sheep, the composition comprising from 0.05 to 25% weight/volume of a compound of formula (I):
N
Ra Rll X
/
(I) wherein:
R1 is CN or methyl;
R2 iS S (0) nR3i R3 is alkyl or haloalkyl;
R4 represents NH2;
R11 represents a halogen atom;
X is C-R12;
R12 represents a halogen atom;
R13 represents a haloalkyl;
n represents an integer equal to 0, 1 or 2;
and wherein the composition is adapted as a pour-on skin solution for administration to the back of the cattle or - 6c -sheep according to a schedule having no less than a once-monthly application interval.
According to yet another aspect of the present invention, there is provided a commercial package comprising a composition as described herein together with written matter describing instructions for the use thereof for controlling ticks of the genus Boophilus in cattle or sheep.
The expression pour-on skin solution is understood to refer to a ready-to-use solution intended to be applied topically and locally on the animal, preferably on the animal's back and at several points or along the line of the back, and applied in low volume, preferably of 5 to 20 ml per 100 kg, preferably about 10 ml per 100 kg, with a total volume of from 10 to 150 ml per animal, preferably limited to 50 ml.
The compound acts by simple contact, the parasite becoming impregnated with the compound on contact with the hair and the skin.
This thereby affords, in a noteworthy manner, a both perfect compatibility with the restrictions of use in extensive grazing, in terms of ease of use in particular, and a spectrum of activity and of efficacy, as well as a period of efficacy, which are suited to this type of rearing.
By working on the concentration of compound (I), in particular of compound A, solutions having note-worthy activities are obtained with, in particular, two months of efficacy against Boophilus microplus, this result never before having been achieved. Moreover, the solution according to the invention allows Boophilus microplus to be totally eliminated from an infested animal in less than 2 days.
As has been stated above, the solution according to the present invention is applied topically, in low volume, to the animal's back. The compound of formula (I) then diffuses out in a noteworthy'manner, this being reflected by a distribution of the compound over the animal's entire body. It has also been observed that the animals remained protected in the case of passage through water or exposure to rain.
The dose of compound of formula (I) is preferably between 0.1 and 2 mg/kg (animal weight), preferably between 0.25 and 1.5 mg/kg, and in particular about 1 mg/kg.
The compounds of formula (I) in which R1 is CN will be selected most particularly. The compounds in which R2 is S(0)4R,, preferably with n = 1, R, preferably being CF3 or alkyl, for example methyl or ethyl, or alternatively n = 0, R, preferably being CF3, as well as those in which X = C-R12, Rl, being a halogen atom, will also be selected. The compounds in which R11 is a halogen atom and those in which R33 is haloalkyl, preferably CF31 are also preferred. In the context of the present inven-tion, compounds combining two or more of these charac-teristics will advantageously be selected.
A preferred class of compounds of formula (I) consists of compounds such that R1 is CN, R3 is haloalkyl, preferably CF3, or ethyl, R4 is NH2, RI, and R12 are, independently of each other, a halogen atom, and/or R13 is haloalkyl.
The alkyl radicals of the definition of the compounds of formula (I) generally comprise from 1 to 6 carbon atoms. The ring formed by the divalent alkylene radical representing Rg ,and R6, as well as the nitrc%qen atom to which R. and R6 are attached, is generally a 5-, 6- or 7-membered ring.
A most particularly preferred compound of the formula (I) in the invention is i5 1-[2,6-C12 4-CF3phenyl]3-CN 4- [SO-CF,35-NH2pyrazole, referred to hereinbelow as compound A. This compound A
will be used in particular in a proportion of-from 0.1 to 2% by weight, more particularly about 1$, relative to the total solution.
Mention may also be made of the two compounds which differ from the above by the following characteristics:
1- n = 0, R] = CF]
2- n = 1,R3 = ethyl.
The compounds of formula (I) may be prepared according to one or other of the processes described in patent applications WO-A-87/3781, 93/6089, 94/21606 or European patent application EP-A-0,295,117, or any other process which falls within the competence of a specialist=skilled in the art of chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is considered as having at his or her disposal, inter alia, all the contents of "Chemical Abstracts" and the documents cited therein.
It is not departing from the scope of the present invention to incorporate other insecticides into the solution according to the present invention.
The solutions according to the invention, which are advantageously oily, generally comprise a diluent or vehicle and also a solvent (organic solvent) for the compound of formula (I) if the latter is not soluble in the diluent.
As organic solvent which can be used in the invention, mention may be made in particular of:
acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethyl-acetamide, dimethylformamide, dipropylene glycol n-butyl i5 ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
As vehicle or diluent, mention may be made in particular of:
plant oils such as soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (C8 to C12 in particular) triglycerides.
An emollient and/or spreading and/or film-forming agent will preferably be added, this agent being selected in particular from:
- polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, - ia -polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;
lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils, in particular polydimethylsiloxane (PDMS) oils, for example those containing silanol functionalities, or a 45V2 oil, - anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate;
sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate;
fatty acids, in particular those derived from coconut oil, s5 - cationic surfactants such as water-soluble quaternary ammonium salts of formula N'R'R"R"'R'", T
in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y' is an anion of a strong acid such as the halide, sulphate and sulphonate anions;
cetyl trimethyl ammonium bromide is among the cationic surfactants which can be used, - amine salts of formula N'R'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 sorbitan esters, which are optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, - amphoteric surfactants such as the substituted lauryl compounds of betaine;
or a mixture of at least two of these agents.
The solvent will be used in proportion with the concentration of the compound I and its solubility in this solvent.
For example, compound A has a solubility of 4.3% m/V in acetyl tributyl citrate. It will be sought to have the lowest possible volume.
The vehicle makes up the difference to 100%.
The emollient is preferably used in a proportion of from 0.1 to 10%, in particular from 0.25 to 5%, by volume.
The subject of the present invention is also iS a process for the elimination 'of parasites, in particular Boophilus microplus, from cattle and sheep using a direct pour-on skin solution according to the present invention, so as obtain long-lasting and broad-spectrum efficacy, the solution being applied to the animal's back, preferably along the line of the back at one or more points.
According to a first embodiment, the process consists in applying the solution to the animals in pasture and/or before they arrive in pasture, the application preferably being repeated every month, preferably every two months.
According to a second embodiment, the process consists in applying the solution to the animals before they arrive in the =feed Lot', it being possible for this application to be the final one before the animals are slaughtered.
Obviously, the process may also consist in combining these two embodiments, namely the first fol-lowed by the second.
In all cases, the efficacy advantageously makes it possible to stop any application 1 to 3 months before slaughter, in particular between 1.5 and 2.5 months, more particularly about two months before slaughter.
The solutions according to the invention may be applied using any means known per se, preferably using an applicator gun or a metering flask.
The aim of the method is not therapeutic and is, in particular, to cleanse the skin and the hairs of the animals by eliminating the parasites which are present thereon, as well as their residues and dejections. The result of this is that the animals are no longer stressed by the parasites and their bites, this having positive consequences, for example on their growth and on the use of their food ration.
Another subject of the invention is a therapeutic method using the external device according to the invention, intended for the treatment and prevention of parasitoses having pathogenic consequences.
The subject of the present invention is also the use of the compounds I, in particular compound A, for the manufacture of a direct pour-on skin solution comprising the compound (I) in a low volume and designed to release the compound (I) onto the skin and the hairs for a contact action against the parasites of cattle and sheep, in particular cattle ticks, such as Boophilus microplus, and sheep blowfly and lice.
The use according to the invention is directed towards producing skin solutions as described above.
The present invention will now be described in greater detail with the aid of non-limiting embodiment examples which demonstrate the activity of the solutions according.to the present invention, with reference to the attached drawings in which:
- Figure 1 is a graph showing the efficacy, against Boophilus microplus, of skin solutions according to the invention, with a 0.25%, 0.5% and 1% content, relative to a control, this graph including, on the x-axis, the time in days after application of the skin solutions, and, on the y-axis to the left, the number of ticks counted on the animals on which the skin solutions according to the invention are applied, and, on the y-axis to the right, the number of ticks counted in the controls;
- Figure 2 is a graph showing the population of ticks in animals which have received the placebo according to Example 2, with, on the x-axis, the time in days, and, on the y-axis, the number of ticks; and - Figure 3 compares the efficacy of a skin solution according to the invention containing" 1$ com-pound A (solid circles) with a skin solution containing 1% flumethrin (rings), with, on the x-axis, the time in days, and, on the y-axis, the number of ticks.
EXAIO=.E 1: Preparation ot the solntions accordin9 to tha invention.
InQredient Function Amount Compound A active substance x q polyoxypropylene 15 stearyl ether emollient 5 q acetyl tributyl citrate solvent 30 g soybean oil diluent qs 100 ml x= 0.25 g for 0.25% solution x= 0.5 g for 0.58 solution x= 1 g for 1% solution Compound A is dissolved in the solvent before being mixed with the other ingredients.
ER'AMPLE 21 Study of the efficacy of skin solut-ans according to the invention containing, respectively, 0.25, 0.50 and 1% compound A to combat Boophilus microplus.
The study was performed on 16 young male castrated Herefords (weight ranging between 114 and 172 kg).
Three skin solutions according to Example 1 were prepared:
1. 1% compound A
2. 0.5% compound A
3. 0.25% compound A
A placebo was prepared, which differed from the skin solutions according to the invention in that it contained no compound A.
In the studies, 1 ml of skin solution or of placebo were used per 10 kg of animal weight.
The dose volume was applied along the line of the animal's back, from the head to the base of the tail.
Between days -24 and -1, the animals were arti-ficially infested on 11 occasions with 2,500 Boophilus microplus larvae. The aim of 24-day infestation is to ensure that all of the stages of Boophilus microplus are present on the animal (eggs, larvae, adults).
On day 0, the animals receive one of the skin solutions or the placebo.
Before the skin solutions or the placebo are applied, the number of ticks present on the various animals in the different groups are counted.
The following table indicates the values recorded, the weight of the animals and the dose of skin solution or of placebo which will be applied to each of these animals.
Group Animal No. Number of Weight Dose (ml) ticks (in kg) 1.00% 94 588 134 13.4 43 470 140 14.0 47 300 154 15.4 39 =254 160 16.0 0.50% 34 706 145 14.5 99 452 143 14.3 48 375 114 11.4 45 201 153 15.3 0.25% 40 510 148 14.8 92 453 144 14.4 41 432 155 15.5 36 236 171 17.1 Placebo 96 627 150 15.0 44 482 144 14.4 93 315 140 14.0 97 292 172 17.2 The blood-engorged female ticks which become detached are included in the count. The results are indicated in Figure 1.
A dose-dependent effect is obtained with 100%
efficacy for the skin solution according to the inven-tion containing 1% compound A. The less-concentrated solutions nevertheless give noteworthy results.
The great rapidity of action of the solutions according to the invention is also noted, the 1%
solution allowing Boophilus microplus to be totally eliminated in less than 2 days.
:
Comparison of efficacy between a skin solution according to the invention containing 1% compound A and a skin solution containing 1% flumethrin.
Animals of the same breed as those in Example 1 were used.
On day 0, the groups are treated with:
- skin solution containing 1% compound A
- skin solution containing 1% flumethrin (mineral oil and ethylhexyl alcohol excipient) - placebo (excipient identical to the solution according to the invention) Table 2 below indicates, for each group, the weight of the animals, the dose of skin solution received and the dose of active substance applied.
- =18 -Group Animal No. Weight Dose (ml) Dose (mg/kg)) 18 719 141 14.1 1 Compound A 709 125 12.5 1 713 150 15.0 1 710 136 13.6 1 703 138 13.8 1 18 706 145 14.5 1 flumethrin 711 136 13.6 1 715 132 13.2 1 702 142 14.2 1 701 127 12.7 1 Placebo 717 133 13.3 0 707 133 13.3 0 704 134 13.4 .0 718 132 13.2 0 708 143 14.3 0 From day 2 to day 32, the animals receive 5,000 Boophilus microplus larvae three times a week. From day 18 to 64, the blood-engorged female ticks which become detached are collected and counted.
The results are indicated in Figures 2 and 3, which demonstrate the total efficacy of the skin solution according to the invention.
E]CAl4P2d! 4:
Study of efficacy over time.
Skin solutions according to the invention containing 0.25, 0.5 or 1% compound A where used in this example.
The composition of these solutions is the same as for the above examples.
The cattle were preinfested so as to have all of the stages of Boophilus microplus present (infestation with 5,000 larvae, 22 days, 15 days and 8 days before application of the skin solution).
After application of the skin solutions, the cattle are again infested with the larvae for 13 weeks, to determine the efficacy of the three concentrations.
The results are reported in Table 3 below:
Weeks of infestation Efficacy index for each after treatment concentration 0.25% 0.5% 1.0$
1 97.6 100 100 2 98.8 100 100 3 99.7 100 100 4 99.3 100 100 5 96.7 92.9 100 6 98.6 93.2 100 7 92.4 88.6 99.7 8 85.8 83.4 100 9 28.0 37.9 79.8 10 23.0 41.4 65.3 11 18.9 55.2 61.5 12 1.7 37.3 32.2 13 8.4 48.5 46.4 It is thus observed that noteworthy efficacy, which may last for two months or more, is obtained.
The solutions according to the invention, which are advantageously oily, generally comprise a diluent or vehicle and also a solvent (organic solvent) for the compound of formula (I) if the latter is not soluble in the diluent.
As organic solvent which can be used in the invention, mention may be made in particular of:
acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethyl-acetamide, dimethylformamide, dipropylene glycol n-butyl i5 ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
As vehicle or diluent, mention may be made in particular of:
plant oils such as soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (C8 to C12 in particular) triglycerides.
An emollient and/or spreading and/or film-forming agent will preferably be added, this agent being selected in particular from:
- polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, - ia -polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;
lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils, in particular polydimethylsiloxane (PDMS) oils, for example those containing silanol functionalities, or a 45V2 oil, - anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate;
sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate;
fatty acids, in particular those derived from coconut oil, s5 - cationic surfactants such as water-soluble quaternary ammonium salts of formula N'R'R"R"'R'", T
in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y' is an anion of a strong acid such as the halide, sulphate and sulphonate anions;
cetyl trimethyl ammonium bromide is among the cationic surfactants which can be used, - amine salts of formula N'R'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 sorbitan esters, which are optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, - amphoteric surfactants such as the substituted lauryl compounds of betaine;
or a mixture of at least two of these agents.
The solvent will be used in proportion with the concentration of the compound I and its solubility in this solvent.
For example, compound A has a solubility of 4.3% m/V in acetyl tributyl citrate. It will be sought to have the lowest possible volume.
The vehicle makes up the difference to 100%.
The emollient is preferably used in a proportion of from 0.1 to 10%, in particular from 0.25 to 5%, by volume.
The subject of the present invention is also iS a process for the elimination 'of parasites, in particular Boophilus microplus, from cattle and sheep using a direct pour-on skin solution according to the present invention, so as obtain long-lasting and broad-spectrum efficacy, the solution being applied to the animal's back, preferably along the line of the back at one or more points.
According to a first embodiment, the process consists in applying the solution to the animals in pasture and/or before they arrive in pasture, the application preferably being repeated every month, preferably every two months.
According to a second embodiment, the process consists in applying the solution to the animals before they arrive in the =feed Lot', it being possible for this application to be the final one before the animals are slaughtered.
Obviously, the process may also consist in combining these two embodiments, namely the first fol-lowed by the second.
In all cases, the efficacy advantageously makes it possible to stop any application 1 to 3 months before slaughter, in particular between 1.5 and 2.5 months, more particularly about two months before slaughter.
The solutions according to the invention may be applied using any means known per se, preferably using an applicator gun or a metering flask.
The aim of the method is not therapeutic and is, in particular, to cleanse the skin and the hairs of the animals by eliminating the parasites which are present thereon, as well as their residues and dejections. The result of this is that the animals are no longer stressed by the parasites and their bites, this having positive consequences, for example on their growth and on the use of their food ration.
Another subject of the invention is a therapeutic method using the external device according to the invention, intended for the treatment and prevention of parasitoses having pathogenic consequences.
The subject of the present invention is also the use of the compounds I, in particular compound A, for the manufacture of a direct pour-on skin solution comprising the compound (I) in a low volume and designed to release the compound (I) onto the skin and the hairs for a contact action against the parasites of cattle and sheep, in particular cattle ticks, such as Boophilus microplus, and sheep blowfly and lice.
The use according to the invention is directed towards producing skin solutions as described above.
The present invention will now be described in greater detail with the aid of non-limiting embodiment examples which demonstrate the activity of the solutions according.to the present invention, with reference to the attached drawings in which:
- Figure 1 is a graph showing the efficacy, against Boophilus microplus, of skin solutions according to the invention, with a 0.25%, 0.5% and 1% content, relative to a control, this graph including, on the x-axis, the time in days after application of the skin solutions, and, on the y-axis to the left, the number of ticks counted on the animals on which the skin solutions according to the invention are applied, and, on the y-axis to the right, the number of ticks counted in the controls;
- Figure 2 is a graph showing the population of ticks in animals which have received the placebo according to Example 2, with, on the x-axis, the time in days, and, on the y-axis, the number of ticks; and - Figure 3 compares the efficacy of a skin solution according to the invention containing" 1$ com-pound A (solid circles) with a skin solution containing 1% flumethrin (rings), with, on the x-axis, the time in days, and, on the y-axis, the number of ticks.
EXAIO=.E 1: Preparation ot the solntions accordin9 to tha invention.
InQredient Function Amount Compound A active substance x q polyoxypropylene 15 stearyl ether emollient 5 q acetyl tributyl citrate solvent 30 g soybean oil diluent qs 100 ml x= 0.25 g for 0.25% solution x= 0.5 g for 0.58 solution x= 1 g for 1% solution Compound A is dissolved in the solvent before being mixed with the other ingredients.
ER'AMPLE 21 Study of the efficacy of skin solut-ans according to the invention containing, respectively, 0.25, 0.50 and 1% compound A to combat Boophilus microplus.
The study was performed on 16 young male castrated Herefords (weight ranging between 114 and 172 kg).
Three skin solutions according to Example 1 were prepared:
1. 1% compound A
2. 0.5% compound A
3. 0.25% compound A
A placebo was prepared, which differed from the skin solutions according to the invention in that it contained no compound A.
In the studies, 1 ml of skin solution or of placebo were used per 10 kg of animal weight.
The dose volume was applied along the line of the animal's back, from the head to the base of the tail.
Between days -24 and -1, the animals were arti-ficially infested on 11 occasions with 2,500 Boophilus microplus larvae. The aim of 24-day infestation is to ensure that all of the stages of Boophilus microplus are present on the animal (eggs, larvae, adults).
On day 0, the animals receive one of the skin solutions or the placebo.
Before the skin solutions or the placebo are applied, the number of ticks present on the various animals in the different groups are counted.
The following table indicates the values recorded, the weight of the animals and the dose of skin solution or of placebo which will be applied to each of these animals.
Group Animal No. Number of Weight Dose (ml) ticks (in kg) 1.00% 94 588 134 13.4 43 470 140 14.0 47 300 154 15.4 39 =254 160 16.0 0.50% 34 706 145 14.5 99 452 143 14.3 48 375 114 11.4 45 201 153 15.3 0.25% 40 510 148 14.8 92 453 144 14.4 41 432 155 15.5 36 236 171 17.1 Placebo 96 627 150 15.0 44 482 144 14.4 93 315 140 14.0 97 292 172 17.2 The blood-engorged female ticks which become detached are included in the count. The results are indicated in Figure 1.
A dose-dependent effect is obtained with 100%
efficacy for the skin solution according to the inven-tion containing 1% compound A. The less-concentrated solutions nevertheless give noteworthy results.
The great rapidity of action of the solutions according to the invention is also noted, the 1%
solution allowing Boophilus microplus to be totally eliminated in less than 2 days.
:
Comparison of efficacy between a skin solution according to the invention containing 1% compound A and a skin solution containing 1% flumethrin.
Animals of the same breed as those in Example 1 were used.
On day 0, the groups are treated with:
- skin solution containing 1% compound A
- skin solution containing 1% flumethrin (mineral oil and ethylhexyl alcohol excipient) - placebo (excipient identical to the solution according to the invention) Table 2 below indicates, for each group, the weight of the animals, the dose of skin solution received and the dose of active substance applied.
- =18 -Group Animal No. Weight Dose (ml) Dose (mg/kg)) 18 719 141 14.1 1 Compound A 709 125 12.5 1 713 150 15.0 1 710 136 13.6 1 703 138 13.8 1 18 706 145 14.5 1 flumethrin 711 136 13.6 1 715 132 13.2 1 702 142 14.2 1 701 127 12.7 1 Placebo 717 133 13.3 0 707 133 13.3 0 704 134 13.4 .0 718 132 13.2 0 708 143 14.3 0 From day 2 to day 32, the animals receive 5,000 Boophilus microplus larvae three times a week. From day 18 to 64, the blood-engorged female ticks which become detached are collected and counted.
The results are indicated in Figures 2 and 3, which demonstrate the total efficacy of the skin solution according to the invention.
E]CAl4P2d! 4:
Study of efficacy over time.
Skin solutions according to the invention containing 0.25, 0.5 or 1% compound A where used in this example.
The composition of these solutions is the same as for the above examples.
The cattle were preinfested so as to have all of the stages of Boophilus microplus present (infestation with 5,000 larvae, 22 days, 15 days and 8 days before application of the skin solution).
After application of the skin solutions, the cattle are again infested with the larvae for 13 weeks, to determine the efficacy of the three concentrations.
The results are reported in Table 3 below:
Weeks of infestation Efficacy index for each after treatment concentration 0.25% 0.5% 1.0$
1 97.6 100 100 2 98.8 100 100 3 99.7 100 100 4 99.3 100 100 5 96.7 92.9 100 6 98.6 93.2 100 7 92.4 88.6 99.7 8 85.8 83.4 100 9 28.0 37.9 79.8 10 23.0 41.4 65.3 11 18.9 55.2 61.5 12 1.7 37.3 32.2 13 8.4 48.5 46.4 It is thus observed that noteworthy efficacy, which may last for two months or more, is obtained.
Claims (91)
1. Use of a composition comprising 0.05 to 25%
weight/volume of a compound of formula (I):
wherein:
R1 is CN or methyl;
R2 is S(O)n R3;
R3 is alkyl or haloalkyl;
R4 represents NH2;
R11 represents a halogen atom;
X is C-R12;
R12 represents a halogen atom;
R13 represents a haloalkyl;
n represents an integer equal to 0, 1 or 2;
for controlling ticks of the genus Boophilus in cattle or sheep, wherein the composition is adapted as a pour-on skin solution for application to the back of the cattle or sheep according to a schedule having no less than a once-monthly application interval.
weight/volume of a compound of formula (I):
wherein:
R1 is CN or methyl;
R2 is S(O)n R3;
R3 is alkyl or haloalkyl;
R4 represents NH2;
R11 represents a halogen atom;
X is C-R12;
R12 represents a halogen atom;
R13 represents a haloalkyl;
n represents an integer equal to 0, 1 or 2;
for controlling ticks of the genus Boophilus in cattle or sheep, wherein the composition is adapted as a pour-on skin solution for application to the back of the cattle or sheep according to a schedule having no less than a once-monthly application interval.
2. The use of claim 1, wherein n=0 and R3=CF3.
3. The use of claim 1, wherein n=1 and R3=ethyl.
4. The use of claim 1, wherein the compound is 1-[2,6-Cl2 4-CF3 phenyl]3-CN 4-[SO-CF3]5-NH2 pyrazole, whose common name is fipronil.
5. The use of any one of claims 1 to 4, wherein the composition comprises from 0.05 to 10% weight/volume of the compound of formula (I).
6. The use of any one of claims 1 to 4, wherein the composition comprises from 0.1 to 2% weight/volume of the compound of formula (I).
7. The use of any one of claims 1 to 4, wherein the composition comprises from 0.25 to 1.5% weight/volume of the compound of formula (I).
8. The use of any one of claims 1 to 4, wherein the composition comprises about 1% weight/volume of the compound of formula (I).
9. The use according to any one of claims 1 to 8, wherein the composition is adapted for application as a unit dose comprising between 0.1 and 2 mg of the compound of formula (I) per kg of animal weight.
10. The use of claim 9, wherein the dose is between 0.25 and 1.5 mg/kg animal weight.
11. The use of claim 9, wherein the dose is about 1 mg/kg animal weight.
12. The use of any one of claims 1 to 11, wherein the composition is for monthly application.
13. The use of any one of claims 1 to 11, wherein the composition is for application every two months.
14. The use of any one of claims 1 to 13, wherein the cattle or sheep are pasture reared.
15. The use of claim 14, which is for application to cattle or sheep in the pasture or prior to arrival in the pasture.
16. The use of any one of claims 1 to 11, which is for application to the cattle or sheep prior to their arrival to a feed lot.
17. The use of claim 16, wherein the application prior to the arrival to the feed lot is a final application prior to slaughter.
18. The use of any one of claims 1 to 17, wherein the application ceases from between 1 to 3 months prior to slaughter.
19. The use of claim 18 wherein the application ceases from between 1.5 and 2.5 months prior to slaughter.
20. The use of claim 18 wherein the application ceases at about two months prior to slaughter.
21. The use of any one of claims 1 to 20, wherein the ticks are of the species microplus.
22. The use of any one of claims 1 to 21, wherein the solution provides for elimination of the ticks in less than 2 days.
23. The use of any one of claims 1 to 22, wherein the solution provides control for at least two months.
24. The use of any one of claims 1 to 23, wherein the solution is an oily solution.
25. The use of any one of claims 1 to 24, wherein the composition is in a form suitable for topical application to the back of the sheep or cattle, wherefrom the compound of formula (I) diffuses so as to be distributed over the body of the sheep or cattle.
26. The use of any one of claims 1 to 24, wherein the composition is in a form suitable for application to the back of the sheep or cattle at several points or along a line of the back.
27. The use of any one of claims 1 to 24, wherein the solution is for release of the compound of formula (I) onto the skin and hair for a contact action against the ticks.
28. The use of any one of claims 1 to 27, wherein the solution comprises a solvent for the compound of formula (I), and a diluent, and optionally an emollient.
29. The use of claim 28, wherein the emollient is present in a proportion of from 0.1 to 10% by volume.
30. The use of claim 28, wherein the emollient is present in a proportion of from 0.25 to 5% by volume.
31. The use according to any one of claims 28 to 30, wherein the solvent is selected from the group consisting of:
acetyl tributyl citrate, fatty acid esters, 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, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethylphthalate, or a mixture of at least two of these solvents.
acetyl tributyl citrate, fatty acid esters, 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, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethylphthalate, or a mixture of at least two of these solvents.
32. The use according to any one of claims 28 to 31, wherein the diluent is selected from the group consisting of plant oils, mineral oils, aliphatic hydrocarbons and cyclic hydrocarbons.
33. The use according to any one of claims 28 to 32, wherein the emollient is selected from the group consisting of:
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils;
nonionic sufactants;
anionic surfactants;
cationic surfactants;
amine salts of formula N+ R'R"R"'in which the radicals R'R"R"'are optionally hydroxylated hydrocarbon radicals;
amphoteric surfactants;
and a mixture of at least two of these agents.
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils;
nonionic sufactants;
anionic surfactants;
cationic surfactants;
amine salts of formula N+ R'R"R"'in which the radicals R'R"R"'are optionally hydroxylated hydrocarbon radicals;
amphoteric surfactants;
and a mixture of at least two of these agents.
34. The use according to claim 33, wherein the anionic surfactants are selected from the group consisting of sodium, potassium or ammonium stearates, calcium stearate, triethanolamine stearate, sodium abietate, alkyl sulphates, sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate, and fatty acids.
35. The use according to claim 34, wherein the alkyl sulphate is sodium lauryl sulphate or sodium cetyl sulphate.
36. The use according to claim 33, wherein the cationic surfactants are water soluble ammonium salts of N+ R'R''R'''R'''', Y- in which the radicals R are optionally hydroxylated hydrocarbon radicals, and Y- is an anion of a strong acid.
37. The use according to claim 33, wherein the cationic surfactant is octadecylamine hydrochloride.
38. The use according to claim 33, wherein the nonionic surfactants are selected from the group consisting of sorbitan esters, polyoxyethylenated alkyl ethers, polyoxypropylated fatty alcohols, polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, and copolymers of ethylene oxide and propylene oxide.
39. The use according to claim 33, wherein the amphoteric surfactants are selected from substituted lauryl compounds of betaine.
40. The use according to any one of claims 1 to 39, which is for controlling Boophilus microplus in cattle.
41. The use according to any one of claims 1 to 39, which is for controlling ticks in sheep.
42. The use according to claim 27, wherein a volume of from 10 to 150 ml per animal is used.
43. The use according to claim 27, wherein a volume of 50 ml per animal is used.
44. The use according to claim 27, wherein a volume of 5 to 20 ml per 100 kg of animal is used.
45. The use according to claim 27, wherein a volume of about 10 ml per 100 kg of animal is used.
46. The use according to claim 32, wherein the plant oils are selected from the group consisting of soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, and sunflower oil.
47. The use according to claim 32, wherein the mineral oils are selected from the group consisting of petrolatum, paraffin, and silicone.
48. A composition for controlling ticks of the genus Boophilus in cattle or sheep, the composition comprising from 0.05 to 25% weight/volume of a compound of formula (I):
wherein:
R1 is CN or methyl;
R2 i8 S (O) nR3;
R3 is alkyl or haloalkyl;
R4 represents NH2;
R11 represents a halogen atom;
X is C-R12;
R12 represents a halogen atom;
R13 represents a haloalkyl;
n represents an integer equal to 0, 1 or 2;
and wherein the composition is adapted as a pour-on skin solution for administration to the back of the cattle or sheep according to a schedule having no less than a once-monthly application interval.
wherein:
R1 is CN or methyl;
R2 i8 S (O) nR3;
R3 is alkyl or haloalkyl;
R4 represents NH2;
R11 represents a halogen atom;
X is C-R12;
R12 represents a halogen atom;
R13 represents a haloalkyl;
n represents an integer equal to 0, 1 or 2;
and wherein the composition is adapted as a pour-on skin solution for administration to the back of the cattle or sheep according to a schedule having no less than a once-monthly application interval.
49. The composition of claim 48, wherein n=0 and R3=CF3.
50. The composition of claim 48, wherein n=1 and R3=ethyl.
51. The composition of claim 48, wherein the compound is 1-[2,6-Cl2 4-CF3 phenyl] 3-CN 4-[SO-CF3] 5-NH2 pyrazole, whose common name is fipronil.
52. The composition of any one of claims 48 to 51, wherein the composition comprises from 0.05 to 10%
weight/volume of the compound of formula (I).
weight/volume of the compound of formula (I).
53. The composition of any one of claims 48 to 51, wherein the composition comprises from 0.1 to 2%
weight/volume of the compound of formula (I).
weight/volume of the compound of formula (I).
54. The composition of any one of claims 48 to 51, wherein the composition comprises from 0.25 to 1.5%
weight/volume of the compound of formula (I).
weight/volume of the compound of formula (I).
55. The composition of any one of claims 48 to 51, wherein the composition comprises about 1% weight/volume of the compound of formula (I).
56. The composition according to any one of claims 48 to 55, wherein the composition is adapted for application as a unit dose comprising between 0.1 and 2 mg of the compound of formula (I) per kg of animal weight.
57. The composition of claim 56, wherein the dose is between 0.25 and 1.5 mg/kg animal weight.
58. The composition of claim 56, wherein the dose is about 1 mg/kg animal weight.
59. The composition of any one of claims 48 to 58, wherein the composition is for monthly application.
60. The composition of any one of claims 48 to 58, wherein the composition is for application every two months.
61. The composition of any one of claims 48 to 60, wherein the cattle or sheep are pasture reared.
62. The composition of claim 61, which is for application to cattle or sheep in the pasture or prior to arrival in the pasture.
63. The composition of any one of claims 48 to 58, which is for application to the cattle or sheep prior to their arrival to a feed lot.
64. The composition of claim 63, wherein the application prior to the arrival to the feed lot is a final application prior to slaughter.
65. The composition of any one of claims 48 to 64, wherein the application ceases from between 1 to 3 months prior to slaughter.
66. The composition of claim 65 wherein the application ceases from between 1.5 and 2.5 months prior to slaughter.
67. The composition of claim 65 wherein the application ceases at about two months prior to slaughter.
68. The composition of any one of claims 48 to 67, wherein the ticks are of the species microplus.
69. The composition of any one of claims 48 to 68, wherein the solution provides for elimination of the ticks in less than 2 days.
70. The composition of any one of claims 48 to 69, wherein the solution provides control for at least two months.
71. The composition of any one of claims 48 to 70, wherein the solution is an oily solution.
72. The composition of any one of claims 48 to 71, wherein the composition is in a form suitable for topical application to the back of the sheep or cattle, wherefrom the compound of formula (I) diffuses so as to be distributed over the body of the sheep or cattle.
73. The composition of any one of claims 48 to 71, wherein the composition is in a form suitable for application to the back of the sheep or cattle at several points or along a line of the back.
74. The composition of any one of claims 48 to 71, wherein the solution is for release of the compound of formula (I) onto the skin and hair for a contact action against the ticks.
75. The composition of any one of claims 48 to 74, wherein the solution comprises a solvent for the compound of formula (I), and a diluent, and optionally an emollient.
76. The composition of claim 75, wherein the emollient is present in a proportion of from 0.1 to 10% by volume.
77. The composition of claim 75, wherein the emollient is present in a proportion of from 0.25 to 5% by volume.
78. The composition according to any one of claims 75 to 77, wherein the solvent is selected from the group consisting of:
acetyl tributyl citrate, fatty acid esters, 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, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethylphthalate, or a mixture of at least two of these solvents.
acetyl tributyl citrate, fatty acid esters, 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, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethylphthalate, or a mixture of at least two of these solvents.
79. The composition according to any one of claims 75 to 78, wherein the diluent is selected from the group consisting of plant oils, mineral oils, aliphatic hydrocarbons and cyclic hydrocarbons.
80. The composition according to any one of claims 75 to 79, wherein the emollient is selected from the group consisting of:
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters, lecithin, sodium carboxymethylcellulose, silicone oils;
nonionic sufactants;
anionic surfactants;
cationic surfactants;
amine salts of formula N+ R'R''R'''in which the radicals R'R''R'''are optionally hydroxylated hydrocarbon radicals;
amphoteric surfactants;
and a mixture of at least two of these agents.
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters, lecithin, sodium carboxymethylcellulose, silicone oils;
nonionic sufactants;
anionic surfactants;
cationic surfactants;
amine salts of formula N+ R'R''R'''in which the radicals R'R''R'''are optionally hydroxylated hydrocarbon radicals;
amphoteric surfactants;
and a mixture of at least two of these agents.
81. The use according to claim 80, wherein the anionic surfactants are selected from the group consisting of sodium, potassium or ammonium stearates, calcium stearate, triethanolamine stearate, sodium abietate, alkyl sulphates, sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate, and fatty acids.
82. The composition according to claim 81, wherein the alkyl sulphate is sodium lauryl sulphate or sodium cetyl sulphate.
83. The composition according to claim 80, wherein the cationic surfactants are water soluble ammonium salts of N+ R'R''R'''R'''', Y- in which the radicals R are optionally hydroxylated hydrocarbon radicals, and Y- is an anion of a strong acid.
84. The composition according to claim 80, wherein the cationic surfactant is octadecylamine hydrochloride.
85. The composition according to claim 80, wherein the nonionic surfactants are selected from the group consisting of sorbitan esters, polyoxyethylenated alkyl ethers, polyoxypropylated fatty alcohols, polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, and copolymers of ethylene oxide and propylene oxide.
86. The composition according to claim 80, wherein the amphoteric surfactants are selected from substituted lauryl compounds of betaine.
87. The composition according to any one of claims 48 to 86, which is for controlling Boophilus microplus in cattle.
88. The composition according to any one of claims 48 to 86, which is for controlling ticks in sheep.
89. The composition according to claim 79, wherein the plant oils are selected from the group consisting of soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, and sunflower oil.
90. The composition according to claim 79, wherein the mineral oils are selected from the group consisting of petrolatum, paraffin, and silicone.
91. A commercial package comprising a composition as claimed in any one of claims 48 to 90 together with written matter describing instructions for the use thereof for controlling ticks of the genus Boophilus in cattle or sheep.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR96/04209 | 1996-03-29 | ||
| FR9604209A FR2746595B1 (en) | 1996-03-29 | 1996-03-29 | SKIN SOLUTION FOR DIRECT DEPOSIT FOR PEST CONTROL IN CATTLE AND SHEEP |
| US69217896A | 1996-08-05 | 1996-08-05 | |
| US08/692,178 | 1996-08-05 | ||
| PCT/FR1997/000542 WO1997036486A1 (en) | 1996-03-29 | 1997-03-26 | Solution for direct application on the skin for controlling cattle and sheep parasites |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2222675A1 CA2222675A1 (en) | 1997-10-09 |
| CA2222675C true CA2222675C (en) | 2008-12-30 |
Family
ID=26232632
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002222675A Expired - Lifetime CA2222675C (en) | 1996-03-29 | 1997-03-26 | Direct pour-on skin solution for antiparasitic use in cattle and sheep |
Country Status (20)
| Country | Link |
|---|---|
| AT (2) | AT504042A1 (en) |
| AU (1) | AU2513097A (en) |
| BE (1) | BE1010483A5 (en) |
| BR (1) | BR9702162A (en) |
| CA (1) | CA2222675C (en) |
| CH (1) | CH692894A8 (en) |
| DE (1) | DE19780396B3 (en) |
| DK (1) | DK177400B1 (en) |
| ES (1) | ES2143389B1 (en) |
| FI (1) | FI119042B (en) |
| FR (1) | FR2747015B1 (en) |
| GB (1) | GB2318512B (en) |
| GR (1) | GR1002910B (en) |
| IE (1) | IE970215A1 (en) |
| IT (1) | IT1291699B1 (en) |
| LU (1) | LU90177B1 (en) |
| NL (1) | NL1005673C2 (en) |
| NO (1) | NO324071B1 (en) |
| SE (1) | SE523761C2 (en) |
| WO (1) | WO1997036486A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW524667B (en) | 1996-12-05 | 2003-03-21 | Pfizer | Parasiticidal pyrazoles |
| AUPQ441699A0 (en) * | 1999-12-02 | 2000-01-06 | Eli Lilly And Company | Pour-on formulations |
| WO2001095723A1 (en) * | 2000-06-15 | 2001-12-20 | Ssl International Plc | Parasiticidal composition |
| DE10063865A1 (en) * | 2000-12-21 | 2002-06-27 | Bayer Ag | Use of pyrazole oximes as parasiticides |
| US7514464B2 (en) | 2003-12-18 | 2009-04-07 | Pfizer Limited | Substituted arylpyrazoles |
| GB0329314D0 (en) | 2003-12-18 | 2004-01-21 | Pfizer Ltd | Substituted arylpyrazoles |
| DE102006061537A1 (en) * | 2006-12-27 | 2008-07-03 | Bayer Healthcare Ag | Agent for controlling parasites on animals comprises an N-phenylpyrazole, an aliphatic cyclic carbonate and an aliphatic polyether |
| TW200846029A (en) * | 2007-02-09 | 2008-12-01 | Wyeth Corp | High dose, long-acting ectoparasiticide for extended control |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3029426A1 (en) * | 1980-08-02 | 1982-03-11 | Bayer Ag, 5090 Leverkusen | AGAINST EFFECTIVE POUR-ON FORMULATIONS |
| GB8531485D0 (en) * | 1985-12-20 | 1986-02-05 | May & Baker Ltd | Compositions of matter |
| GB8713768D0 (en) * | 1987-06-12 | 1987-07-15 | May & Baker Ltd | Compositions of matter |
| DE3719732A1 (en) * | 1987-06-12 | 1989-01-05 | Bayer Ag | SUBSTITUTED 5-METHYLAMINO-1-ARYLPYRAZOLE |
| YU47834B (en) * | 1989-08-10 | 1996-01-09 | Schering Agrochemical Limited | THE AZOLE PESTICIDE |
| NO179282C (en) * | 1991-01-18 | 1996-09-11 | Rhone Poulenc Agrochimie | New 1- (2-pyridyl) pyrazole compounds for control of insect pests |
| GB9120641D0 (en) * | 1991-09-27 | 1991-11-06 | Ici Plc | Heterocyclic compounds |
| GB9306184D0 (en) * | 1993-03-25 | 1993-05-19 | Zeneca Ltd | Heteroaromatic compounds |
| DE4414333A1 (en) * | 1994-04-25 | 1995-10-26 | Bayer Ag | Substituted pyridylpyrazoles |
| IL116147A (en) * | 1994-11-30 | 2002-05-23 | Aventis Cropscience Sa | Emulsifiable composition for the control of insects |
-
1997
- 1997-03-20 IE IE970215A patent/IE970215A1/en not_active IP Right Cessation
- 1997-03-26 DE DE19780396T patent/DE19780396B3/en not_active Expired - Lifetime
- 1997-03-26 AU AU25130/97A patent/AU2513097A/en not_active Abandoned
- 1997-03-26 ES ES009750029A patent/ES2143389B1/en not_active Expired - Fee Related
- 1997-03-26 AT AT0900497A patent/AT504042A1/en not_active Application Discontinuation
- 1997-03-26 GR GR970100110A patent/GR1002910B/en not_active IP Right Cessation
- 1997-03-26 WO PCT/FR1997/000542 patent/WO1997036486A1/en active IP Right Grant
- 1997-03-26 FR FR9703708A patent/FR2747015B1/en not_active Expired - Lifetime
- 1997-03-26 GB GB9725003A patent/GB2318512B/en not_active Expired - Lifetime
- 1997-03-26 CH CH02791/97A patent/CH692894A8/en not_active IP Right Cessation
- 1997-03-26 BR BR9702162A patent/BR9702162A/en active IP Right Grant
- 1997-03-26 CA CA002222675A patent/CA2222675C/en not_active Expired - Lifetime
- 1997-03-27 BE BE9700276A patent/BE1010483A5/en active
- 1997-03-27 IT IT97TO000260A patent/IT1291699B1/en active IP Right Grant
- 1997-03-27 NL NL1005673A patent/NL1005673C2/en not_active IP Right Cessation
- 1997-11-24 SE SE9704303A patent/SE523761C2/en not_active IP Right Cessation
- 1997-11-26 LU LU90177A patent/LU90177B1/en active
- 1997-11-27 NO NO19975473A patent/NO324071B1/en not_active IP Right Cessation
- 1997-11-27 FI FI974353A patent/FI119042B/en not_active IP Right Cessation
- 1997-11-27 DK DKPA199701363A patent/DK177400B1/en not_active IP Right Cessation
-
2009
- 2009-09-04 AT ATA1395/2009A patent/AT506843B1/en not_active IP Right Cessation
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