NO324071B1 - Solution for direct application on the skin to control cattle and sheep parasites and their use. - Google Patents

Description

The present invention relates to a solution for direct application to the skin which contains an anti-parasitic product and is intended to be applied topically to cattle and sheep.

The invention also relates to the use of anti-parasitic compounds for the preparation of this solution for skin.

Cattle and sheep are affected by a large number of parasites.

The most important are mites of the genus Boophilus, and among these the species microplus (cattle mite), decoloratus and anulatus can be mentioned.

The other important parasites of cattle and sheep are indicated in order of decreasing importance: - myiasis such as Dermatobia hominis (known as Berne in Brazil) and Cochlyomia hominivorax (gold fly), ovine myiasis such as Lucilia sericata, Lucilia cuprina (known as brown flycatcher i

Australia, New Zealand and South Africa). These are flies whose larvae form the animal parasite. peculiar flies, namely those where adult individuals constitute the parasite, such as Haematobia

irritans (small stinging fly).

lice such as Linognathus vitulorum, etc.

gall wasps such as Sarcoptes scabiei and Psoroptes ovis.

Mites, in particular Boophilus microplus, are very closely linked to the grazing area in which they live and are particularly difficult to control.

There is currently no truly effective method of controlling mites, much less an effective way to control the parasites listed above.

WO-A-87/3781, EP-A-295,117 and EP-A-500,209 describe a class of insecticides which are N-phenylpyrazole derivatives. These compounds have been reported to have activity against a very large number of parasites, including Boophilus microplus, in areas as diverse as agriculture, public health and veterinary medicine. The general teachings of these publications indicate that these insecticidal compounds can be administered by various routes such as oral, parenteral, percutaneous and topical routes. Topical administration includes in particular oral formulations, baits, dietary supplements, skin solutions (for application), solutions for spraying (sprays), baths, showers, syringes, powders, greasers, shampoos, creams, etc. Solutions of the type to be poured onto the skin is designed for percutaneous administration. Example 9 in EP-A-295,117 and Example 29I in EP-A-500,209 describe a solution of the type that is poured onto the skin containing 15% insecticide and 85% dimethylsulfoxide, for percutaneous administration of the insecticide.

EP-A-296,381 also describes pyrazole compounds with insecticidal activity in the fields of agriculture, public health and veterinary medicine. Boophilus microplus is one of the many targets mentioned. There are many forms of administration here too, and these include e.g. solutions, emulsions, suspensions, powders, pastes, granules and aerosols.

The problem presented is to find an effective agent which is fully suitable for controlling the parasites in cattle and sheep, especially mites, most especially Boophilus microplus in cattle and especially lice and blowflies in sheep, under the conditions under which these animals are reared.

In the context of the invention, it has been found that it is possible to effectively control Boophilus microplus in cattle by using a specific topical formulation. In the context of the invention, it has also been found that this formulation is effective against sheep lice and sheep flies known as "spit flies".

The purpose of the present invention is thus to provide a new preparation which is fully effective against Boophilus microplus and also against all the other parasites described in the foregoing, particularly such as sheep lice and "spitflies", as this preparation is fully suitable to control 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 action, preferably longer than or equal to 2 months.

Another aim of the invention is to provide such a formulation which is quick and easy to use and fully compatible with use on livestock or herds containing a large number of animals.

Another aim of the invention is to provide such a formulation which is particularly suitable for extensive rearing on pasture and for use intended to protect animals during the period of compaction and finishing (Feed Lot in the USA), namely the last period of rearing in which a large numbers of animals are run together in a small enclosure over an average period of 2 months before slaughter.

The purpose of the present invention is thus a solution for direct application to the skin, intended to remove parasites from cattle and sheep, most especially mites, especially Boophilus microplus in cattle and lice and blowflies in sheep, comprising from 0.1 to 2% by weight /volume, relative to the total solution, of a compound (A): 1-[2,6-CI2-4-CF3-phenyl]-3-CN-4-[SO-CF3]-5-NH2-pyrazole in a low volume formulation designed to release compound (A) on the skin and hairs for a contact action against the parasites.

Low concentrations of from 0.1 to 2% are preferred. Optimally, the value is between 0.25 and 1.5%, especially in the range of 1%.

The term solution for application to the skin is understood to refer to a ready-to-use solution intended to be applied topically and locally to the animal, preferably on the animal's back and at several points or along the dorsal line, and applied in a small volume, preferably 5 to 20 ml per . 100 kg, preferably approximately 10 ml per 100 kg, with a total volume of from 10 to 150 ml per animals, preferably limited to 50 ml.

The compound works by simple contact, as the parasite becomes impregnated with the compound on contact with the hair and skin.

This therefore offers in a remarkable way both a perfect compatibility with the limitations of use in extensive grazing, particularly with regard to ease of use, and a spectrum of activity and effectiveness, as well as a period of effectiveness, which is suitable for this type of farming.

By exploiting the concentration of compound A, solutions with remarkable activities are obtained with particularly two months of effectiveness against Boophilus microplus, such a result having never been achieved before. The solution according to the invention also allows Boophilus microplus to be completely removed from an infected animal in less than 2 days.

As indicated above, the solution according to the invention is applied topically, in a small volume, to the animal's back. The compound (A) is then spread out in a remarkable way, which is expressed by a distribution of the compound over the whole body of the animal. It has also been observed that the animals remain protected in case they move through water or are exposed to rain.

The dose of compound (A) is preferably between 0.1 and 2 mg/kg (weight of animal), preferably between 0.25 and 1.5 mg/kg, and especially about 1 mg/kg.

The compound A will in particular be used in a ratio of from 0.1 to 2% by weight, more particularly about 1% by weight, in relation to the total solution.

The compound (A) may be prepared in accordance with any 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 is within the knowledge of a specialist in the field of chemical synthesis. For the chemical production of the products in accordance with the invention, an expert in the field is considered to have at his disposal, among other things the entire contents of "Chemical Abstracts" and the publications listed therein.

It does not deviate from the scope of the present invention to incorporate other insecticides into the solution in accordance with the present invention.

The solutions according to the invention, which are advantageously oily, generally comprise a diluent or carrier and also a solvent (organic solvent) for the compound

(A) if the latter is not soluble in the diluent.

As an organic solvent that can be used in the invention, the following can be mentioned in particular: 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, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, especially N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.

As a carrier or diluent, the following can be mentioned in particular:

vegetable oils such as soya oil, peanut oil, castor oil, corn oil, cotton seed oil, olive oil, grape seed oil, sunflower oil etc, mineral oils such as petrolatum, paraffin, silicone etc, aliphatic or cyclic hydrocarbons or alternatively e.g. medium chain triglycerides (especially C8 to C12).

A softening agent and/or spraying agent and/or film-forming agent will preferably be added, this agent being particularly selected from: - polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylene sorbitan esters, lecithin, sodium carboxymethyl cellulose, silicone oils , polydiorganosiloxane oils, especially polydimethylsiloxane (PDMS) oils, e.g. those containing silanol functionalities, or a 45V2 oil, - anionic surfactants such as alkaline stearates, especially sodium, potassium or ammonium stearates, calcium stearate, triethanolamine stearate, sodium abietate, alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate, sodium dodecylbenzenesulfonate,

sodium dioctyl sulfosuccinate, fatty acids, especially those derived from coconut oil,

- cationic surfactants such as water-soluble quaternary ammonium salts with the formula N+R'R"R'"R""1 Y" in which the radicals R are possibly hydroxylated hydrocarbon radicals and Y" is an anion of a strong acid such as halide, sulfate and sulfonate anions, ie

cetyltrimethylammonium bromide is among the cationic surfactants that can be used,

- amine salts with the formula N<+>R'R"R'" in which the radicals R are optionally hydroxylated hydrocarbon radicals, octadecylamine hydrochloride being among the cationic surfactants that can be used, - non-ionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated, in particular Polysorbate 80, polyoxyethylenated alkyl ethers, polyoxypropylated fatty alcohols such as polyoxypropylene styrene ethers, 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 substituted lauryl compounds of betaine,

or a mixture of at least two of these agents.

The solvent will be used in relation to the concentration of the compound (A) and its solubility in this solvent.

For example, compound A has a solubility of 4.3% mA/ in acetyltributyl citrate. An attempt will be made to have the lowest possible volume.

The carrier makes up the difference to 100%.

The softening agent is preferably used in a ratio of from 0.1 to 10% by volume, in particular from 0.25 to 5% by volume.

The present invention can be used in a method for removing parasites, in particular Boophilus microplus, from cattle and sheep using a solution for direct application to the skin in accordance with the present invention, in order to achieve long-term and broad-spectrum effectiveness, the solution being supplied to the animal's back, preferably along the back line at one or more points.

The method consists in adding the solution to the animals on pasture and/or before they come to pasture, the addition being preferably repeated every month, preferably every 2 months.

The solution is preferably added to the animals before they arrive at the "Feed Lot", as it is possible that this addition is the last before the animals are slaughtered.

The method can obviously also consist of a combination of these two embodiments, namely the first followed by the second.

In any case, the effectiveness advantageously allows any supply to be stopped 1 to 3 months before slaughter, particularly between 1.5 and 2.5 months, more particularly about 2 months before slaughter.

The solutions in accordance with the invention can be supplied using any means known per se, preferably using an applicator pressure syringe or a measuring flask.

The aim of the method is particularly to clean the skin and hair of the animals by removing the parasites present thereon, as well as their remains and faeces. The result of this is that the animals are no longer stressed by the parasites and their bites, which has positive consequences, e.g. for their growth and on the application of their nutrition.

The object of the present invention is also the use of compound A for the preparation of a solution for direct application to the skin in a small volume and which is designed to release the compound (A) on the skin and hairs for a contact effect against the parasites in cattle and sheep, especially mites in cattle, such as Boophilus microplus, and blowflies and lice in sheep.

The application in accordance with the invention is aimed at the production of skin solutions as described above.

The present invention will now be described in more detail by means of non-limiting examples of embodiments which demonstrate the activity of the solutions in accordance with the present invention, with reference to the attached drawings in which: Fig. 1 is a diagram showing the effectiveness, against Boophilus microplus, of skin solutions in accordance with the invention with a content of 0.25%, 0.5% and 1%, in relation to a control, this graph including on the x-axis the time in days after administration of the skin solutions and, on the y-axis on the left, the number of mites counted on the animals to which the skin solutions according to the invention are applied and, on the y-axis on the right, the number of mites counted in the controls, Fig. 2 is a diagram showing the population of mites in animals who have received placebo according to example 2, with time in days on the x-axis and the number of mites on the y-axis, and Fig. 3 compares the effectiveness of a skin solution according to the invention containing 1% compound A (filled say rkler) with a skin solution containing 1% flumethrin (rings), with time in days on the x-axis and the number of mites on the y-axis.

Example 1: Preparation of the solutions in accordance with the invention.

Compound A is diluted in the solvent before mixing with the other ingredients.

Example 2:

Examination of the effectiveness of skin solutions according to the invention containing respectively 0.25, 0.50 and 1% compound A to combat Boophilus microplus.

The investigation was carried out on 16 young castrated Hereford bulls (weight in the range between 114 and 172 kg).

Three skin solutions in accordance with 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 investigations, 1 ml of skin solution or placebo was used per 10 kg weight of animal.

The dose volume was administered along the animal's dorsal line, from the head to the root of the tail.

Between days -24 and -1, the animals were artificially infected 11 times with 2500 Boophilus microplus larvae. The aim of the 24-day infection is to ensure that all stages of Boophilus microplus are present on the animal (eggs, larvae, adults).

On day 0, the animals received one of the skin solutions or placebo.

Before the skin solutions or placebo are administered, the number of mites present on the different animals in the different groups is counted.

The following table indicates the recorded values, the weight of the animals and the dose of skin solution or of placebo that will be administered to each of these animals.

The blood-filled female mites that were detached are included in the count. The results are indicated in fig. 1.

A dose-dependent effect is achieved with 100% effectiveness for the skin solution according to the invention containing 1% compound A. The less concentrated solutions nevertheless give remarkable results.

The very rapid action of the solutions according to the invention is also noted, as the 1% solution allows Boophilus microplus to be completely removed in less than 2 days.

Example 3:

Comparison of effectiveness between a skin solution in accordance with 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 administered.

From day 2 to day 32, the animals received 5,000 Boophilus microplus larvae three times per week. From day 18 to 64, the blood-filled female mites that are released are collected and counted.

The results are indicated in fig. 2 and 3, which demonstrate the overall effectiveness of the skin solution in accordance with the invention.

Example 4:

Examination of effectiveness over time.

Skin solutions according to the invention containing 0.25, 0.5 or 1% compound A were used in this example.

The composition of these solutions is the same as for the preceding examples.

The cattle were pre-infected to have all stages of Boophilus microplus present (infection 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 infected with the larvae for 13 weeks, in order to determine the effectiveness of the three concentrations.

The results are set out in Table 3 below:

It is thus observed that remarkable effectiveness is achieved, which can last for two months or more.

Claims (15)

1. Solution for direct application to skin, and which is intended to eliminate parasites from cattle and sheep, most especially mites, especially Boophilus microplus in cattle and lice and blowflies in sheep, characterized in that it comprises from 0.1 to 2% by weight /volume, relative to the total solution, of 1-[2,6-Cl2-4-CF3-phenyl]-3-CN-4-[SO-CF3]-5-NH2-pyrazole in a low volume formulation, designed to deliver 1-[2,6-Cl2-4-CF3-phenyl]-3-CN-4-[SO-CF3]-5-NH2-pyrazole to the skin and hair for a contact effect against the parasites. 2. Solution as stated in claim 1, characterized in that it comprises from 0.25 to 1.5% weight/volume, in relation to the total solution, of 1-[2,6-CI2-4-CF3-phenyl] -3-CN-4-[SO-CF3]-5-NH2-pyrazole. 3. Solution as stated in claim 2, characterized in that it comprises 1% weight/volume, in relation to the total solution, of 1-[2,6-CI2-4-CF3-phenyl]-3-CN-4- [SO-CF3]-5-NH2-pyrazole. 4. Resolution as specified in one or more of claims 1 to 3, characterized in that the solution is designed to be able to be added in a volume of 5 to 20 ml, preferably, approximately 10 ml, per 100 kg animal, with a total volume of from 10 to 150 ml per animals, preferably limited to 50 ml. 5. Resolution as specified in one or more of claims 1 to 4, characterized in that it comprises a solvent for 1-[2,6-CI2-4-CF3-phenyl]-3-CN-4-[SO-CF3]-5-NH2-pyrazole and a diluent, possibly a softening agent. 6. Resolution as stated in claim 5, characterized in that the solvent is selected from the group consisting of: acetyltributyl 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, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, especially N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents. 7. Resolution as stated in claim 5 or 6, characterized in that the diluent is selected from the group consisting of: vegetable oils such as soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grape seed oil, sunflower oil etc, mineral oils such as petrolatum, paraffin, silicone etc, aliphatic or cyclic hydrocarbons or alternatively triglycerides with medium chain length (especially C8 to C,2). 8. Resolution as specified in one or more of claims 5 to 7, characterized in that the softening agent 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 carboxymethyl cellulose, silicone oils, - anionic surfactants such as alkaline stearates, especially sodium, potassium or ammonium stearates, calcium stearate, triethanolamine stearate, sodium abietate, alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate, sodium dodecylbenzene sulfonate, sodium dioctyl sulfosuccinate, fatty acids, especially those derived from coconut oil, - cationic surfactants such as water-soluble quaternary ammonium salts of the formula 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 such as halide, sulfate and sulfonate anions, ie cetyltrimethylammonium bromide is among the cationic surfactants that can be used, - amine salts with the formula isTR^R'" in which the radicals R are possibly hydroxylated hydrocarbon radicals, octadecylamine hydrochloride being among the cationic surfactants that can be used, - non-ionic surfactants such as sorbitan esters, which optionally are polyoxyethylenated, especially Polysorbate 80, polyoxyethylenated alkyl ethers, polyoxypropylated fatty alcohols such as polyoxypropylene-15-stearyl 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 substituted lauryl compounds of betaine, or a mixture of at least two of these agents. 9. Resolution as specified in one or more of claims 1 to 8, characterized in that it is an oily solution. 10. Use of a compound of formula 1-[2,6-Cl2-4-CF3-phenyl]-3-CN-4-[SO-CF3]-5-NH2-pyrazole for the preparation of a solution for direct application to the skin in a small volume, which solution comprises 0.1 to 2% w/v, relative to the total solution, of 1-[2,6-CI2-4-CF3-phenyl ]-3-CN-4-[SO-CF3]-5-NH2-pyrazole and is designed to release 1-[2,6-CI2-4-CF3-phenyl]-3-CN-4-[SO- CF3]-5-NH2-pyrazole on the skin and hair for a contact effect against the parasites in cattle and sheep, especially mites in cattle, such as Boophilus microplus, and blowflies and lice in sheep. 11. Use as stated in claim 10, characterized in that it comprises from 0.25 to 1.5% weight/volume, in relation to the total solution, of 1-[2,6-Cl2-4-CF3-phenyl] -3-CN-4-[SO-CF3]-5-NH2-pyrazole. 12. Use as stated in claim 10, characterized in that it comprises 1% weight/volume, in relation to the total solution, of 1-[2,6-Cl2-4-CF3-phenyl]-3-CN-4- [SO-CF3]-5-NH2-pyrazole. 13. Use as stated in one or more of claims 10 to 12, characterized in that the solution is designed to be able to be added in a volume of 5 to 20 ml, preferably approximately 10 ml, per 100 kg animal, with a total volume of from 10 to 150 ml per animals, preferably limited to 50 ml. 14. Use as stated in one or more of claims 10 to 13, characterized in that 1-[2,6-CI2-4-CF3-phenyl]-3-CN-4-[SO-CF3]-5-NH2- pyrazole is added in an amount of 0.1 to 2 mg/kg, preferably 0.25 to 1.5 mg/kg, especially about 0.1 mg/kg. 15. Use as stated in one or more of claims 10 to 14, for the production of such a skin solution which is intended to be administered every month, preferably every other month, to the animal, the administration preferably being stopped 1 to 3 months before slaughter.