WO2007109870A1

WO2007109870A1 - Veterinary composition comprising an insect growth regulator, in particular a benzoylurea compound to control ectoparasites

Info

Publication number: WO2007109870A1
Application number: PCT/BR2007/000071
Authority: WO
Inventors: Nelson Augusto Filho; Rosália Meireles de Souza ROCHA
Original assignee: Champion Farmoquimico Ltda
Priority date: 2006-03-24
Filing date: 2007-03-20
Publication date: 2007-10-04
Also published as: BRPI0601078B1; AR060082A1; UY30230A1; BRPI0601078A

Abstract

The present invention refers to a veterinary composition, preferably in powder form, to be added in the food or in the nutritional supplements (mineralized salt, vitamins, among others) based on insect growth regulator compounds, IGR, or, more particularly, based on benzoyl substituted ureas to control ectoparasites, preferably to control ticks in bovines.

Description

VETERINARY COMPOSITION COMPRISING AN

INSECT GROWTH REGULATOR, IN PARTICULAR

A BENZOYLUREA COMPOUND TO CONTROL

ECTOPARASITES

Field of the Invention

The present invention is related to a veterinary composition, preferably in^" powder form, to be added in the food or in the nutritional supplements (mineralized salt, vitamins, among others), made of IGR (insect growth regulator) compounds, which regulate the growth of the insects, or more particularly made of benzoyl substituted ureas, to control ectoparasites, preferably to control ticks in cattle. Background of the Invention

The tick {Boophilus microplus) is the main ectoparasite of bovine cattle in tropical and sub-tropical countries. The life cycle of this arthropod can be divide in two stages: parasitary and free.

The parasitary life stage begins with the arrival of the larva (with three pairs of legs) in the host, which feeds on the lymph until it turns into a metalarva. The stay of the metalarva is metamorphic, because from its interior a new individual comes out, the nymph, now with 4 pairs of legs. The nymph also feeds on the lymph until it turns into metanymph and suffers the second metamorphosis, liberating an asexual individual: male or female. The female matures and initiates the stage of hematophagism. The female full of blood is called engorged female tick. Each engorged female tick can swallow up to 3 ml of blood during its stay on the host and transforms 60% of its body weight in eggs. Therefore, a 3 grams (gr.) group of engorged female ticks (8 to 10 individuals) produces about 1 ,8 grams of eggs. One gram of eggs produces 10,000 ^■ larvae. (Gonzales,^'1993); Each female can produce anything from 2^000 to 3,000 eggs.

The free life stage initiates with the engorged female tick that falls to the ground after separating from the body of the host, and seeks a favorable environment to lay its eggs, which shall hatch forming the infesting larva.

The free life stage of the tick lasts around 28 to 51 days, and it can be extended to more than 300 days. Besides that, the larva can subsist for more than 6 months without food. The ectoparasite causes several damages to the cattle raising industry, such as the transmission of agents that cause hemolytic parasitary diseases (anaplasmosis and babesiosis), the inoculation of toxins in the meet and anemia, besides the low quality for the usage of the skin in the leather industry, due to the wounds caused by the fixation of the parasite.

Furthermore, the irritation and the loss of blood makes the animal loose weight, reduces the animal's fertility and reduces the milk production in 10 to 15% (IBGE - Brazilian Institute of Geographical Statistics data disclosed in 2000). Horn (1983), based on information collected from the Brazilian

Agriculture State Agencies, estimated that the losses caused by the thick, considering the aspects related to mortality (1 ,2%), decrease in weight gain (6kg/animal/year), effects on the leather, expenditure on anti-thick products, decrease in milk production (1 ,5 billion of liters), would add up to US$ 968 million, due to the growth in the total number of bovine cattle from 76 million in 1983 to 180 million in 2005, this losses can be estimated in US$ 2 billion.

This data from Brazilian researched are also confirmed by several international entities. Nowadays, thick control has become a challenge to cattle raising, because the application of topical products requires that the cattle be put in confinement, which is called management.

This so called management is an extremely burdensome task, which involves a lot of labor and takes a long time. During the management, the cattle does not eat, they are submitted to stress, they hurt themselves and loose a considerable amount of weight, which results in losses to the cattle raisers.

Also, it is not technically nor economically feasible to eradicate the parasite in its free life stage, treating the fields.

Even though the oral products present advantages in relation to the management and the treatment of the fields, there is the problem of the chemical residues in the meat for human consumption, caused by the absorption of the anti-thick products by the organisms of the treated animals.

Some insect growth regulator compositions are used in oral compositions against ectoparasites, however great amounts of the active ingredients are necessary to reach the necessary efficacy.

The object of the present invention avoids such shortcomings, specially those related to cost with management and the accumulation of residues in the organism of the animal, once it refers to a powder veterinary composition, which is adequate to be added to the food or to the nutritional supplements in a very efficient way of combating the ectoparasite and with low toxicity. Description of the Graphs

Graph 1 shows the variation of the weight in grams of the engorged female ticks up to 5 days after the beginning of their fall, in a natural infestation, measured on test 1 present in the examples. Graph 2 shows the variation of the number of eggs per engorged female tick up to 5 days after the beginning of the fall, measured in the same experiment of natural infestation.

Graph 3 presents the variation of the number of eggs per engorged female tick up to 5 days after the beginning of the fall, in an artificial infestation, measured on test 2 also presented in the examples.

Description of the Invention

Different from the prior art, including commercial applications and what is disclosed in the specialized literature, the present invention refers to a veterinary composition, preferably in powder form, to be added to the food or nutritional supplements consumed by animals, particularly bovines, which is effective to combat ectoparasites.

The veterinary composition, according to the present invention, comprises a first embodiment: (a) insect growth regulator compositions, IGR, which are selected from at least one of the following: diflubenzuron, cyromazine, triflumuron, methoprene, S-methoprene, hydroprene, S-hydroprene, fluazuron, dicyclanyl, azadirachtin, lufenuron, flufenuxuron, nitenpiram, imidacloprid, teflubenzuron, noviflumuron, methoxyfenozide, pyriproxyfen, tebufenozide, fenoxycarb, buprofezin, hexaflumuron, and/or one chemical derived from them; and

(b) at least one carrier acceptable to veterinary usage.

The veterinary composition, according to the present invention, comprises a second embodiment: (a) one or more compounds selected from the benzoyl substituted ureas defined in formula I bellow:

where:

Ri and R₂ can be equal or different, selected among the halogen atoms or a methyl group, being preferably fluor atoms.

R₃ can e selected among halogen atoms or alkyl groups containing 1 to 15 carbon atoms, which could be optionally halogened, more particularly, R₃ presents a chlorine atom.

(b) at least one carrier acceptable to veterinary use. Preferably, the composition of the present invention comprises the compound 1-(4-chloridephenyl)-3-(2,6-difulorobenzoyl)urea, also called diflubenzuron.

The compositions, according to the present invention, present the advantage of eliminating the ectoparasites in an efficient way, without substantially accumulating in the organisms of the animals and consequently without leaving residues in the meat that are hazardous to human health.

The efficient combat against the ectoparasites, specifically against ticks, is reached in a particular way with a dosage of active principle in the composition of the present invention, which varies according to the selected compounds. Specifically, the present invention comprises about 1 to about 10% in weight, more particularly about 5 to 7 % in weight of at least one IGR compound or a benzoyl substitute urea of formula I.

The acceptable carriers to veterinary use, according to the present invention, include all of those known in the art, for example: surfactants such as nonylphenol ethoxylate, sodium lignosulphonate, dodecyl benzene sϋlphonate, octylphenol ethόxylate, sodium polysόrbate, potassium polysorbate, citric pectin or sodium laurel sulphate, or solid carrier in particles such as micronized silica, kaolin or talc, or mixtures of them.

The composition of the present invention may also comprise thickening agents, stabilizers, flavoring agents, anticoagulants, preservatives and/or other adjuvants known in the art.

As far as another characteristic is concerned, the present invention is related to the use of benzoyl substituted ureas, as previously described, in the preparation of veterinary compositions against ectoparasites, more specifically ticks in bovine cattle.

According to yet another characteristic, the present invention refers to a method of control of ectoparasites, which comprises the availability, via food or nutritional supplement, of an efficient daily amount of about 20 to 40mg, preferably 30 mg, of at least on IGR compound or a benzoyl substituted urea of formula I.

The food made available to the animal can be, for example, grinded or peletized. As it is well knows by those skilled in the art, nutritional supplements can be one or more, without limitation, among mineralized salt, calcium phosphate, vitamin concentrations, protein supplements, etc. The quantity of the composition applied to the food or the nutritional supplement is established based on the predicted consumption for the food or supplement, which is well known in the cattle raising industry, for example, 5g of composition for each kilogram of food or nutritional supplement. According one more characteristic, the present invention refers to a kit, characterized by the fact that it comprises a recipient containing the composition, according to the present invention, a quantity dosing device and optionally instructions for its use in veterinary treatment of ectoparasites infestations, more particularly tick infestations in bovines. Herein under, some examples are presented of particular embodiments of the invention, and the scope of the invention is only limited by the claims hereof.

Example 1 Composition According to the Present Invention

Test 1 - Efficiency Test of Tick Control in Bovines - Natural Infestation

The composition of example 1 was mixed to mineral salt in the ration of 5g/kg, and freely supplied to the animals, having an average daily consumption of 10Og of mineral salt and 500mg of the product, being 30mg daily of the active principle diflubenzuron.

Ten mixed breed bovines (Holstein and Zebu) were used, of several genders and ages, naturally infested by ticks (Boophilus microplus). The animals were randomly divided in 2 groups A and B, each with 5 animals. The animals were marked with identification earrings, the animals of group A received a mineral salt composition treated according to the present invention and the group B animals received common mineral salt.

They were then transferred to individual stalls, freed of ticks and with a lath-worked floor, wherein they remained up to the fall of the engorged females of tick. These engorged females of tick were collected daily and taken to the lab to be washed, dried, counted and weighed in an analytical scale.

The efficiency was measured by calculating the percentage of inhibition and reproduction in the treated and non-treated animals, as well as the death of larvae and adult ticks that latched on the animals. The weight of the engorged female ticks, collected and weighed, of the bovines from control group B, treated only with mineralized salt, when the fell to the ground, was around the average of 199 to 299mg, which is the normal weight of healthy engorged female ticks. The engorged female ticks of group A, treated with mineralized salt containing the composition of the present invention, was under 160mg, which is way under their normal weight. This average was verified for 5 days after the beginning of the fall of the engorged female ticks, according to what is shown on graph 1.

Graph 2 presents the result of the tick egg count from group A and B, showing that in the treated group there was a significant decrease in the number of eggs to 900 eggs in average, bellow the normal average of 2000 to 3000 eggs, according to what is described in the technical literature. The number of eggs of the engorged female ticks ^"collected from group B, was an average of 2600 eggs. A significantly greater presence of dead larvae and adult ticks was also verified in the bovines of the treated group A.

Test 2 - Efficiency Test of Tick Control in Bovines - Artificial Infestation

The larvae from the engorged female ticks of the treated group A as well of the non-treated group B, from test 1 , were used for the stable test, with artificial infestation, in order to determine whether there was a decrease in the reproductive efficiency of the treated engorged female ticks.

Another group of the mixed breed bovines (Holstein and Zebu) was used in the second test, of different gender and various ages. The animals were randomly divided in 2 groups C and D, with 5 animals each. The animals were marked with identification earrings. The animals from group C received the treated mineral salt and the animal from group D received regular mineral salt. On the zero day, the animals were placed in the stalls, previously pulverized against parasites, with a residual period of 20 days, and the animals were brushed to remove eventual live and dead larvae. Each animal received 3 artificial infestations of 2,500 larvae, at 3-day intervals, totalizing 7,500 larvae per animal. These larvae hatched in the lab and were from the test of example 1, being all with^' 20 days of age (infestation stage).

The number of ticks that latched on was around 800. From this number, only a small part, about 80 engorged female ticks unlatched, reaching their adult stage. The collection of the engorged female ticks was made after the 19th day of infestation (egg laying stage). in order to calculate the results, scientific literature data was used, which demonstrates that only 12.4% of the tick larvae that climb on the animal latch on to it, reaching their adult stage. When the engorged female ticks started to fall on the floor, they were collected and weighed. As presented on Graph 3, the weight of the engorged female ticks from the treated group in the first test, remained well bellow the normal average and the weight of the engorged female ticks from the control group of the first test, remained within the normal average. The number of eggs of the treated group, remained around 700 eggs in average.

It was also verified, by means of collection by brushing the fur of the animals, that a large number of females, males and larvae ticks were dead, latched to the fur of the animals. Discussion of the Results

In the natural infestation, group A, treated with the composition of the present invention, had a significant decrease in the weight of the engorged female ticks once they fell and also a decrease in egg laying.

In the artificial infestation, with larvae from the egg laying of the engorged female ticks collected from the natural infestation test, there was a great decrease in the latching of the larvae from the treated group A and only a small part of them reached the adult stage. The number of eggs and the size of the engorged female ticks from the treated group C also significantly decreased. Based on the obtained results, one can verify that the composition of the present invention, as well as the method of treatment, are highly effective against ticks in bovines, besides presenting several technical and economical advantages.

From the data and information presented herein, a person skilled in the art could use this invention in several ways, in a non-identical manner to what was described hereby, but with the functionality and result described herein, being, therefore, within the scope of the attached claims.

Claims

1- VETERINARY COMPOSITION TO CONTROL ECTOPARASITES IN ANIMALS, characterized for comprising at least one IGR compound and at least on carrier that is acceptable for veterinary use.

2- VETERINARY COMPOSITION TO CONTROL ECTOPARASITES IN ANIMALS, characterized for comprising one or more benzoyl substituted ureas, according to formula I bellow:

where:

R₁ and R₂ can be equal or different, selected among the halogen atoms or a methyl group;

R₃ can e selected among halogen atoms or alkyl groups containing 1 to 15 carbon atoms, optionally halogened and at least one carrier acceptable to veterinary use.

3- COMPOSITION, according to claim 2, characterized by the fact that R₁ and R₂ are fluor atoms and R₃ is a chloride atom.

4- COMPOSITION, according to claims 1 to 3, characterized by the fact that the compound is 1-(4-chloridephenyl)-3-(2,6- difulorobenzoyl)urea.

5- COMPOSITION, according to claim 1 , characterized by the fact that the IGR compound is selected among diflubenzuron, cyromazine, triflumuron, methoprene, S-methoprene, hydroprene, S-hydroprene, fluazuron, dicyclanyl, azadirachtin, lufenuron, flufenuxuron, nitenpiram, imidacloprid, teflubenzuron, noviflumuron, methoxyfenozide, pyriproxyfen, tebϋfendzide, fenbxycarb, buprofezin; ^"hexaflύmϋrbn, and/όr a chemical derived from them.

6- COMPOSITION, according to claims 1 to 5, characterized for comprising about 1 to about 10% in weight of the IGR compound or of a benzoyl substituted urea of formula I.

7- COMPOSITION, according to claim 6, characterized for comprising about 5 to 7% in weight of the IGR compound or of a benzoyl substituted urea of formula I.

8- COMPOSITION, according to claims 1 to 7, characterized by the fact that the carrier is one or more among nonylphenol ethoxylate, sodium lignosulphonate, dodecyl benzene sulphonate, octylphenol ethoxylate, sodium polysorbate, potassium polysorbate, citric pectin, sodium laurel sulphate, micronized silica, kaolin and talc.

9- COMPOSITION, according to claims 1 to 8, characterized fro comprising thickening agents, stabilizers, flavoring agents, anticoagulants and/or preservatives.

10- COMPOSITION, according to claim 1 or 2, characterized by the fact that the ectoparasite is the thick and the animal is a bovine.

11 - USE OF THE COMPOSITION, defined in any of the claims 1 to 10, characterized by the fact that it is used in the preparation of a veterinary medicine against ectoparasites.

12- USE OF IGR COMPOUNDS, characterized by the fact that they are used in the preparation of a veterinary composition against ectoparasites. 13- USE OF IGR COMPOUNDS, according to claim 12, characterized by the fact that said compounds are at least one among diflubenzuron, cyromazine, triflumuron, methoprene, S-methoprene, ^ hydroprene, S-hydroprene, fluazuron, dicyclanyl, azadirachtin, lufenuron, flufenuxuron, nitenpiram, imidacloprid, teflubenzuron, noviflumuron, nϊethoxyτenoziαe, pyπproxyren, tebufeήozide, fenoxycarb, Duproteziή, hexaflumuron, and/or a chemical derived from them.

14- USE OF BENZOYL SUBSTITUTED UREAS OF FORMULA I:

where: Ri and R₂ can be equal or different, selected among the halogen atoms or a methyl group;

R₃ can e selected among halogen atoms or alkyl groups containing 1 to 15 carbon atoms, optionally halogened, characterized by the fact that such use is in the preparation of a veterinary composition against ectoparasites.

15- USE OF BENZOYL SUBSTITUTED UREAS, according to claim 14, characterized by the fact that R₁ and R₂ are fluor atoms and R₃ is a chloride atom.

16- USE as defined in one of the claims 11 , 12 or 14, characterized by the fact that the ectoparasite is the tick and the animal is a bovine.

17- CONTROL METHOD OF ECTOPARASITES IN ANIMALS, characterized by the fact that it supplies to the animal at least one IGR compound selected among diflubenzuron, cyromazine, triflumuron, methoprene, S-methoprene, hydroprene, S-hydroprene, fluazuron, dicyclanyl, azadirachtin, lufenuron, flufenuxuron, nitenpiram, imidacloprid, teflubenzuron, noviflumuron, methoxyfenozide, pyriproxyfen, tebufenozide, fenoxycarb, buprofezin, hexaflumuron, and/or a chemical derived from them. 18- CONTROL METHOD OF ECTOPARASITES IN TkNIMALS, characterized by the fact that it supplied to the animal at least one benzoyl substituted urea of formula I:

R₃ can e selected among halogen atoms or alkyl groups containing 1 to 15 carbon atoms, optionally halogened.

19- CONTROL METHOD OF ECTOPARASITES IN ANIMALS, according to claim 18, characterized by the fact that R₁ and R₂ are fluor atoms and R₃ is a chloride atom.

20- CONTROL METHOD OF ECTOPARASITES IN ANIMALS, according to claims 17 to 19, characterized by the fact that it supplies a daily opal amount of about 20 to 40mg per animal. 21- CONTROL METHOD OF ECTOPARASITES IN ANIMALS, according to claims 17 to 20, characterized by the fact that the animals are bovines and the ectoparasite is the tick.

22- METHOD FOR THE TERMINATION OF ECTOPARASITES, characterized by the fact that it supplies blood containing at least on IGR compound or a benzoyl substituted urea of formula I to the ectoparasite.

23- AUXILIARY KIT FOR THE CONTROL METHOD OF ECTOPARASITES, characterized for comprising a recipient containing at least the composition of one of the claims 1 to 10, a quantity dosing device and optionally instructions for its use.