BRPI0406788B1 - USE OF A PIRETROID OR PIRETRINE COMPOSITE WITH A NICOTINIC AGONIST AS REPELLENT - Google Patents

Description

(54) Title: USE OF A PIRETROID OR PIRETRIN COMPOUND IN COMBINATION WITH A NICOTINIC AGONIST AS A REPELLENT (73) Holder: BAYER INTELECTUAL PROPERTY GMBH. Address: Alfred-Nobel-Strasse 10, 40789 Monheim, GERMANY (DE) (72) Inventor: NORBERT MENCKE; DOROTHEE STANNECK; ANDREAS TURBERG; HANS DAUTEL

Validity Term: 10 (ten) years from 10/02/2018, subject to legal conditions

Issued on: 10/02/2018

Digitally signed by:

Liane Elizabeth Caldeira Lage

Director of Patents, Computer Programs and Topographies of Integrated Circuits

1/75

Invention Patent Descriptive Report for: USE OF A PIRETROID OR PIRETRIN COMPOUND IN COMBINATION WITH A NICOTINIC AGONIST AS A REPELLENT.

The present invention relates to the use of a component of the pyrethroid / pyrethrin class, which has a repellent action against arthropods, in combination with an arthropod nicotinic cholinergic receptor agonist, which is designed to perform repellency efficiently and long-term. duration of arthropods, preferably in animals.

The use of topical formulations that contain in their composition permethrin, (3-phenoxyphenyl) methyl 3- (2,2dichloroethyl) -2,2-dimethylcyclopropanecarboxylate, (CAS N ° [52645-53-1]), intended to combat insects parasites in animals are already known (for example, in WO 95/17 090, JP 07 247 203, EP-A-567 368, EP-A461 962, US-5 236 954 and US-5,074,252).

The agonists of nicotinic insect cholinergic receptors are already known, for example, from European patent application publications

No. 464 830, 428 941, 425 978, 386 565, 383 091, 375 907, 364 844, 315 826, 259 738, 254 859, 235 725, 212 600, 192 060, 163 855, 154 178, 136 636, 303 570, 302 833, 306 696, 189 972, 455 000, 135 956, 471 372, 302 389; of publication

Petition 870180025816, of March 29, 2018, p. 12/13 q

• · • 9 • 9 9 9 9 99 9 9 • · • 9 9 9 9 9 9 · • · • * · • · · « • • · 9 9 • 9 9 9 9 9 9 • · • • • • • 9 • · • · 9 • • · • · 9

German patent application No. 3,639,877, 3,712,307; Japanese Patent Application Publication No. 03 220

176, 02 207 083, 63 307 857, 63 287 764, 03 246 283, 04

9371, 03 279 359, 03 255 072; American Patent Application No. 5,034,524, 4,948,798, 4,918,086,

039 686, 5,034,404; PCT records No. WO 91/17 659,

92/4965; the French registry No. 2 611 114; the Brazilian registry N ° 88 03 621. The use of spot on formulations that contain agonists or antagonists of the nicotinic cholinergic receptors of insects, which are intended to combat parasitic insects in animals, in a similar way, is also knowledge (see, for example, WO 98/27 817, EP-A-682

869 and EP 0 976 328).

According to the state of the art, combinations of permethrin with agonists or antagonists of the insect nicotinic cholinergic receptors have also been described, which are intended to fight parasites (for example, CN-1 245 637, WO 00/54 591, US-6 080 796, EP-A-981

955, US-6 033 731, JP-07 089 803). The repellent action of type I pyrethroids against arthropods was first described in US-4 178 3 84 (Pyrethroid insect repellent. Ensing, Kenneth J., 1979, US 417 8384, ro

• · • · «· • · subject: repellent agents against cockroaches); Matthewson et al. (1981, Screening techniques for the evaluation of

Chemicals with activity as tick repellents. Matthewson,

Michael D; Hughes, Graham; Macpherson, Ian S; Bernard,

Colette P, Pesticide Science, 12 (4), 455-62) and Shemanchuk (1981, Repellent action of permethrin, cypermethrin and resmethrin against black flies (Simulium spp.) Attacking cattle. Shemanchuk, Joseph A, Pesticide Science, 12 (4 ),

412-16) described the repellent action of type I and II pyrethroid substances against ticks, as well as against flies.

The disadvantage of permethrin-based spot on formulations, for example, lies in the fact that they have reduced activity against fleas, mosquitoes and flies.

Spot on formulations based on nicotinic cholinergic receptor agonists or antagonists (see, for example, WO 96/175 20) have, as a rule, very good activity against insects. However, these formulations have the disadvantage that they are practically inactive against ticks, in addition to not showing a repellent activity.

li • · ····· · · • ·· * ····· ······ · · · ··· ······ · · · ······ · · · · · · • · · · · ·

For this reason, it was necessary, until now, to use a combined treatment of animals with different formulations, so that it could verify an effective combat of ticks and fleas, as well as for the defense against mosquitoes and flies. Due to ecological and economic reasons, it is desirable to replace these formulations with those that are compatible with the skin, as well as not having the inconvenience of being toxic. In addition, these formulations must be distinguished by the fact that they have a long duration of effect of at least three to four weeks, especially against ticks, fleas, mosquitoes and flies, when applied in a small volume (for example,

0.1 mL / l, 0kg [body weight of the animal to be subjected to treatment]). In addition, such a formulation should have sufficient storage stability in all climatic zones, generally at least three years, for example, in traditional spot on tubes.

WO 02/08 7338 describes the preparation of a formulation compatible with the skin and not harmful to the environment, advantageous for the user, which has action against parasitic insects, especially against ticks and fleas, intended for dermal application, which contains in his / 3

permethrin composition and insect nicotinic cholinergic receptor agonists or antagonists.

Surprisingly, it has recently been described that preparations containing substances belonging to the group of pyrethroid compounds / pyrethrin, in combination with substances that have an agonist action on arthropod nicotinic cholinergic receptors, have very good repellent properties against arthropods, such as for example, ticks, mosquitoes and flies, which have the characteristic of overcoming the repellent effects of formulations that contain only pyrethroid / pyrethrin compounds in their composition. This concerns, in particular, both the relative contact times of the ectoparasites with the treated animal, as well as the contact time necessary to achieve 100% mortality after contact. In this case, as can be seen from comparative in vitro tests, this effect has no reason to be in the formulation.

Therefore, these combined formulations of the types of compounds described in more detail below are not only able to control parasites that have already infested the animal, but also to prevent,

very efficiently, surprisingly, the acute infestation of parasites and, consequently, the potential transmission of disease-causing pathogens through arthropods, in particular ticks, mosquitoes and sucking flies.

The present invention concerns:

1. The use of a pyrethroid or pyrethrin compound in combination with a nicotinic cholinergic receptor agonist to promote arthropod repellency.

2. Use, according to item 1, in which the pyrethroid compound is selected from the group consisting of:

I. Type I pyrethroid compounds

II. Type II pyrethroid compounds

III. Pyrethroid compounds not belonging to the ester class

IV. Naturally occurring pyrethroid compounds

3. Use, according to item I, in which the nicotinic cholinergic receptor agonist is selected from the group consisting of:

V. Neonicotinoids

SAW. Nithiazine

VII. Spinosyns

4. Use, according to item 1, intended to promote the repellency of ticks, fleas, mosquitoes and / or flies in warm-blooded animals.

5. Procedure designed to promote the repellency of 5 arthropods of warm-blooded animals, according to which a pyrethroid compound or pyrethrin is applied topically in combination with a nicotinic cholinergic receptor agonist on blood animals hot.

6. Procedure designed to keep arthropods away from sites and materials, in which they are considered undesirable, according to which a pyrethroid compound or pyrethrin is applied in combination with a nicotinic cholinergic receptor agonist, on the site or on the material, from which arthropods should be removed.

Preferably, the described preparations according to the present invention are liquid, in addition to being suitable for dermal application, especially in

0 pour on or spot on formulations. Other forms of application are also possible (see below).

These formulations present the pyrethroid compound or pyrethrin in its composition, in general, in the following amounts:

I. Type I pyrethroid compounds, such as permethrin: from 15 to 75% w / w, preferably from 33 to 55% w / w ·

II. Type II pyrethroid compounds, such as cypermethrin: from 1 to 20% w / w, preferably from 5 to 15% w / w;

III. Pyrethroid compounds not belonging to the ester class, such as etofenprox and silafluofen: from 15 to 75% w / w, preferably from 40 to 60% w / w.

IV. Naturally occurring pyrethroid compounds, such as pyrethrin I, jasmine I, cinerin I, pyrethrin

II, Jasmine II, Cinerin II: 25 to 75% w / w, preferably 30 to 50% w / w.

The preparations that can be used, according to the present invention, present in their composition an active ingredient of class V-VII of nicotinic cholinergic receptor agonists, in the following amounts:

V. Neonicotinoids with 1 to 25% w / w, preferably 5 to 15% w / w. For example, the following can be cited:

imidacloprid, thiaclopride, clothianidin, nitenpyram, dinotefuran, thiamethoxam.

SAW. Nithiazine with 20 to 40% w / w, preferably 25 to 35% w / w.

VII. Spinosyns with 1 to 25% w / w, preferably 5 to 15% w / w. For example, in this case, spinosad and butyl-spinosad can be mentioned.

In addition, the preparations that can be used, according to the present invention, usually present in their composition, solvents and emollient agents, as well as usual auxiliary agents, if necessary.

The specifications in percentage weight on weight (% w / w) refer to the total weight.

The classification of pyrethroid / pyrethrin compounds into type I pyrethroid compounds, type II pyrethroid compounds, non-ester pyrethroid compounds and naturally occurring pyrethroid compounds is explained in more detail in Encyclopedic

Reference of Parasitology 2nd Ed., Disease, Treatment, Therapy, (H. Mehlhorn Ed.), 2001, pp. 91-96, which formally refers to this.

Type I pyrethroid compounds are, for example, alethrin, bioalethrin, permethrin, phenothrin, resmethrin, and tetramethrin.

Type II pyrethroid compounds are, for example, α-cypermethrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucitrinate, flumethrin and τ-fluvalinate.

Pyrethroid compounds not belonging to the ester class are, for example, etofenprox and silafluofen.

Naturally occurring pyrethroid compounds are, for example, pyrethrin I, pyrethrin II, cinerin I, cinerin II, jasmine I and jasmine II.

As agonists of the insect nicotinic cholinergic receptors, preferably the compounds of the neonicotinoid group can be mentioned.

The concept of neonicotinoids must include, in particular, the compounds of formula (I):

(Z)

X AND

Formula I in which,

R represents a hydrogen atom or, in some cases, substituted radicals of the groups acyl, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl;

A represents a monofunctional group of the sequence hydrogen, acyl, alkyl, aryl or represents a bifunctional group, which is linked with the radical Z;

And it represents a radical electron acceptor;

X radical -CH = ou = N, it being possible that the radical -CH =, instead of being attached to a hydrogen atom, may be linked with the radical Z;

Z represents a monofunctional group of the sequence z

alkyl, -O-R, -S-R, where:

R represents the same or different radicals and has the aforementioned meaning;

or Z represents a bifunctional group, which is linked to the radical A or the radical X.

Especially preferred are the compounds of the formula (I), in which the radicals have the following meaning:

R represents a hydrogen atom, as well as, in some cases, substituted radicals of the acyl sequence,

-N.

faith

alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl.

As acyl radicals, in this case, the formyl radicals, (Ci- ₈ -alkyl) -carbonyl, (C ₆ -i ₀ -aryl) 5 carbonyl, (Ci- ₈ -alkyl) -sulfonyl, ( C ₆ -io-aryl) sulfonyl, (C ₈ alkyl) - (C -i _{0 6} aryl) phosphoryl, which for its part may undergo substitution.

As alkyl radicals may be cited, in which case the radicals ₍₀ Ci_i -alkyl), especially Cl - ₄ alkyl, in their details, methyl, ethyl, isopropyl, sec- or tbutila which, in turn, can be replaced.

aryl group is characterized, in particular, by C ₆ -ioaryl, and the phenyl, naphthyl groups, in particular, phenyl can be mentioned as examples.

The aralkyl group is characterized, in particular, by (C ₆ -io-aryl) - (Ci-4-alkyl), being examples such as the phenyl, methyl and phenethyl groups in this case.

As heteroaryl groups, in this case, heteroaryl groups with up to 10 atoms per ring and, N, O,

S, especially N, as heteroatoms. In more detail, the groups thienyl, furyl, thiazolyl, imidazoyl, pyridyl and benzotriazolyl can be mentioned in this case.

âO • · · ······. ····· * characterized, in such a way that the

The heteroarilalquila particular group is, for heteroaryl- (CI - ₄ alkyl) heteroaryl group is as defined above. As examples, in this case, the heteroarylmethyl, heteroarylethyl groups with up to 6 atoms per ring and N, O, S, especially N, as hetero atoms can be mentioned.

The heterocyclyl group is characterized, in particular, by an unsaturated but not aromatic or saturated heterocycle, with up to 6 atoms per ring, which contains up to 3 heteroatoms selected from N, O, S, for example, tetrahydrofuril.

The heterocyclylalkyl group is characterized, in particular, by heterocyclyl- (Cx-2-alkyl), such as, for example, tetrahydrofuranylmethyl and tetrahydrofuranylethyl.

As substituents can be mentioned, for example, and, preferably, the following groups:

Alkyl groups preferably 1 to 4, in particular 1 to 2 carbon atoms, such as methyl, ethyl, n- and i-propyl and η-, i- and t-butyl; alkoxy groups

0 with preferably 1 to 4, in particular 1 to 2 carbon atoms, such as methoxy, ethoxy, n- and i-propyloxy and η-, i- and t-butyloxy; thioalkyl groups with preferably a to 4, in particular 1 or 2 carbon atoms, such as

»· • · <· • · ♦ · · · ··· * • · thiomethyl, thioethyl, n- and i-thiopropyl and n-, i- and ttiobutyl; halogenalkyl groups having preferably 1 to 4, in particular 1 or 2 carbon atoms and, preferably, 1 to 5, in particular 1 to 3 atoms of 5 halogen, such that the halogen atoms can be equal to or different from each other, and may be represented by halogen atoms, preferably the fluorine, chlorine or bromine atoms, in particular fluorine, such as trifluoromethyl; hydroxyl groups; halogen atoms, preferably fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine; cyan group; nitro group; amino group; monoalkyl- and dialkylamino groups with preferably 1 to 4, in particular 1 or 2 carbon atoms for each alkyl group, such as methylamino, methyl-ethyl-amino, n- and i-propylamino and methyl-n-butylamino; carboxy group; carbalcoxi group with preferably 2 to

4, in particular 2 or 3 carbon atoms, such as carbomethoxy and carboethoxy; sulfo group (-SO ₃ H); alkylsulfonyl group with preferably from 1 to 4, in particular

1 or 2 carbon atoms, such as methylsulfonyl and ethylsulfonyl; arylsulfonyl group with preferably 6 or aryl-carbon atoms, such as phenylsulfonyl, as well as

Μ • · · • · ·· • ·

such as the heteroarylamino and heteroarylalkylamino groups, such as chloropyridylamino and chloropyridylmethylamino.

A represents, in a particularly preferential way, the hydrogen atom, as well as, in some cases, it represents substituted radicals of the acyl, alkyl, aryl series, which have the meanings mentioned for R. A represents, in addition, a bifunctional group. In some cases, alkyl groups substituted with 1 to 4, in particular from 1 to 2 carbon atoms, may be mentioned, such that the substituents listed above can be mentioned as substituents, and such that the alkyl groups can be intercalated through heteroatoms selected from the sequence N, O, S.

A and Z can form a saturated or unsaturated heterocyclic ring, together with the atoms, to which they are attached. The heterocyclic ring can also contain 1 or 2 more hetero atoms and / or heterogroups, which are the same or different. As heteroatoms, oxygen, sulfur or nitrogen may be mentioned, preferably, and as heterogroups, the N-alkyl group may be mentioned, such that the alkyl portion of the N-alkyl group, preferably containing 1 to 4, in particular 1 or 2 carbon atoms.

As alkyl radicals can be mentioned the groups

methyl, ethyl, n- and i-propyl and n-, i- and t-butyl. The heterocyclic ring contains from 5 to 7, preferably 5 or 6 ring members.

As examples for the heterocyclic ring, the pyrrolidine, piperidine, piperazine, hexamethylenimine, hexahydro-1,3,5-triazine, morpholine and oxadiazine rings can be mentioned, which, in some cases, can preferably be replaced by methyl groups.

And it represents an electron accepting group, so that NO ₂ , CN, haloalkylcarbonyl groups, such as halo-C _1-4 alkylcarbonyl with 1 to 9 halogen atoms, especially COCF ₃ , can be mentioned in this case. and CI_ -alquilsulfonil ₄ and halo-CI - ₄ alkylsulfonyl 15 with 1 to 9 halogen atoms, in particular

SO2CF3.

X represents -CH = or -N =

Z represents, in some cases, the substituted alkyl radicals, -OR, -SR, -NRR, such that R 20 and the substituents have, especially preferably, the meaning mentioned above.

Z can form, in addition to the ring mentioned above, together with the atom to which it is attached and the radical = c- at the position of X, a saturated or unsaturated heterocyclic ring. The heterocyclic ring may contain, in addition, 1 or 2 more heteroatoms and / or heterogeneous groups. As heteroatoms, oxygen, sulfur or nitrogen atoms are preferably mentioned and, as heterogroups, the N-alkyl group, such that the alkyl or N-alkyl group preferably contains from 1 to

4, in particular 1 or 2 carbon atoms. As alkyl groups, methyl, ethyl, n- and i-propyl and n-, i- and t-butyl groups can be mentioned. The heterocyclic ring contains 5 to 7, in particular 5 or 6 ring members.

Examples of the heterocyclic ring include pyrrolidine, piperidine, piperazine, hexamethylenimine, morpholine and N15 methylpiperazine rings.

Particularly preferably, the compounds mentioned below with the general formulas (II), (III) and (IV) can be used, according to the present invention:

Compound II,

Compound III, (A) (Subst) _n (CH ₂ ) nN.

- (Z)

Compound IV in which, n can be represented by 1 or 2, m can be represented by 0, 1 or 2

Subst. may be represented by one of the substituents listed above, in particular halogens and, especially preferably, chlorine,

A, Ζ, X and E have the meanings mentioned above.

In detail, the following compounds can be mentioned:

Imidacloprid

AKD 1022

Ν-ΝΟ ₂

ONLY

In detail, the following compounds can be mentioned, especially preferably:

Cl

AKD 1022

Cl

Cl

Imidacloprid

Acetamipride

-ch ₃

Clothianidin

Cl

Nintenpyram

Thiamethoxam (diacloden)

Dinotefuran

In addition to nicotinic agonists selected from the group of neonicotinoids, other nicotinic agonists can also be used according to the present invention.

For example, compounds in the group of spinosyns, in particular spinosyn A and D, can be mentioned, as described in Boeck et al. In EP 3 75 316 Al and Deamicis et al. In WO 97/00 265 Al , which are referred to in detail in the documents listed.

Spinosyn A:

Laugh

Spinosyn D:

«· ·

Similarly, spinosyns are understood, in this case, the synthetic and semisynthetic derivatives of natural spinosyns, as well as those derived from strains of Saccharopolyspora spp, for example, modified by means of gene manipulation techniques, such as is described in the document

W002 / 77004 and W002 / 77005, which are referred to in detail in the mentioned documents.

For example, they can be mentioned as compounds of formulas I and II, where R ³ is characterized by a glycoside (R ³ = R ¹ ), R ⁴ is an H, OH or alkoxy (in general with 1 to 8, in particular 1 to 4 carbon atoms); R ⁵ is H or methyl; R ⁶ and R ⁷ are H or else combined by a double bond or an alkoxy group; R ⁸ in formula I is represented by trans-l-butenyl, 1,3-butadienyl, butyl, 3-hydroxybutenyl, propyl, 1-propenyl, 1,2-epoxy-l-butyl, 3-oxol-butenyl, CH ₃ CH (OCH ₃ ) CH = CH-, CH ₃ CH = CHCH (CH ₂ CO ₂ CH ₃ ) - or CH ₃ CH = CHCH [CH ₂ CON (CH ₃ ) ₂ ] R ⁹ is H or glycoside (R ⁹ = R ² ).

R, =

Ό '

ιι:

r ₂ w- ······ ·········· • • ·

CK, ·· * ··· • · · · h ₃ c ^v 'ίτ'' ^{Z /} /

Other compounds that act as nicotinic cholinergic receptor agonists, which, similarly, can be successfully combined with group I compounds are, for example, nicotine or nitiazine.

Nitíazina

The repellent effect, as well as the short contact mortality of the combination used, according to the present invention, of active substances from the group of nicotinic agonists in combination with active substances from the group of pyrethroid compounds / pyrethrin is, surprisingly, better than expected from the actions

individual components. Therefore, by using this preparation, the application rates of the individual substances can be reduced, as well as an increased long-term effect can be obtained. As a result, its use has economic and ecological advantages.

The combinations used in accordance with the present invention are shown to be excellently suitable for use in combating parasites and, in addition, they are capable of promoting a reduction in the transmission of disease-causing pathogens, which are transmitted by these parasites. Parasites can be combated directly in humans or animals or in the environment. In addition, the aforementioned combination of active ingredients can also be used to protect materials and, in fact, to remove arthropods from places and materials where they are not desirable.

As parasites can be mentioned:

of the order of anoplures, such as, for example,

Haematopinus spp., Linognathus spp., Solenopotes spp.,

Pediculus spp., Pthirus spp .;

3.5

from the order of malophages, such as, for example, Trimenopon spp., Menopon spp., Eomenacanthus ^S PP · / Menacanthus spp., Trichodectes spp., Felicola spp., Damalinea spp., Bovicola spp .;

of the order of diptera, such as, for example, Aedes spp., Culex spp., Simuliuim spp., Phlebotomus spp., Lutzomyia spp., Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp. , Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp., Aipmeromyia spp., Cordylobia ssp., Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohl spp., Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypoderma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp .;

of the order of siphonapters, such as, for example,

Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., Pulex spp .;

of the order of metastigmata, such as, for example, Hyalomma spp., Rhipicephalus spp.,

Ambolyomma spp., Haemaphysalis spp.,

Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp .;

of the order of mesostigmata, such as, for example,

Dermanyssus spp., Ornithonyssus spp., Pneumonyssus spp .;

Boophilus spp.,

Dermacentor spp.,

from the order of the prostigmata, such as, for example, Cheyletiella spp., Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp .; and from the order of astigmata, such as, for example, Acarus spp., Myocoptes spp., Psoroptes spp., Chorioptes spp.,

Otodectes spp., Sarcoptes spp., Notoedres spp.,

Knemidocoptes spp., Neoknemidocoptes spp., Cytodites spp.,

Laminosioptes spp ..

In accordance with the present invention, the preparations are used to promote the repellency of arthropods, preferably ticks, fleas, mosquitoes and flies from animals, especially from warm-blooded animals. Thus, use in humans is also possible.

Animals are represented, for example, by breeding animals or livestock: mammals, such as cattle, horses, sheep, pigs, goats, camelids, buffalo, donkeys, rabbits, fallow deer, reindeer; tannery animals, such as American minks, chinchillas, laundry coatis; birds, such as, for example, chickens, geese, turkeys, ducks and ostriches.

In addition, these animals are represented by laboratory animals and experimental animals, such as

• · ·

such as mice, rats, guinea pigs, hamsters, dogs and cats.

Especially preferably, it is used by pets, such as, for example, dogs and cats.

Since the treated animals, as a rule, also release a certain amount of the preparation used in the environment, for example, through friction or with accumulations, the effect of the preparation described according to the present invention, in some cases, it is carried out not only directly on the animal, but also in corresponding proportions, in its environment.

It is evident that the preparations used in accordance with the present invention may, in addition to containing the active ingredients mentioned above, still present in their composition appropriate additional active substances.

As examples, mention may be made of active substances and synergistic compounds with inhibitory action on growth, such as, for example, pyriproxyphene, {2- [1methyl-2- (4-phenoxyphenoxy) -ethoxy] -pyridine CAS NO: 95737 -68l}, methoprene [(Ε, E) -1-methylethyl ll-methoxy-3,7,11-trimethyl2,4-dodecadienoate CAS No: 40596-69-8] and triflumuron {231

chloro-N- [[[4- (trifluoromethoxy) phenyl] amino] carbonyl] benzamide CAS No.: 64628-44-0}.

It is also possible to imagine the addition of other substances with repellent action, such as DEET (diettyltoluamide), Bayrepel® (CAS name: 1piperidinecarboxylic acid, 2- (2-hydroxyethyl) -, 1-methylpropylester, 2- (thiooctyl) -ethanol or 3- (N-acetyl-N-butylamino) ethylpropionic acid.

The use in animals is carried out directly or in the form of pharmaceutical preparations appropriate, as a rule, for dermal application.

Since the repellent mechanism of the pyrethroid / pyrethrin compounds requires a possibility of contact with the active ingredient, it is suggested that the active ingredients be distributed over the entire extension of the surface that must be protected from parasite infestation, such as, for example , on all regions of the animal's body to be treated. With regard to the repellent effect, there is, therefore, that the occurrence of a penetration of the active ingredients through the cutaneous route is, in fact, disadvantageous, since the active ingredients that penetrated the skin are no longer found available to exert its repellent effect.

Dermal use is carried out, for example, in the form of mechanized spraying (sprays) or immersion baths (pour on and spot on).

The appropriate preparations are as follows:

concentrated solutions or products intended for administration after dilution for use on the skin or in body cavities, immersion formulations and gels;

emulsions and suspensions, semi-solid preparations; formulations in which the active ingredient is handled in an ointment base or in an oil-in-water or water-in-oil emulsion base;

solid preparations such as powders, base mixes or concentrated, granulated, pellet, aerosol and solid products containing active ingredients.

The solvents that can be mentioned in this case are physiologically compatible solvents, such as, for example, water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, N-methyl-pyrrolidone, 2-pyrrolidone , as well as mixtures thereof.

The active ingredients, in some cases, can also be dissolved in physiologically compatible vegetable oils or synthetic oils.

In this case, excipients that mediate dissolution can be mentioned the solvents that favor the solubilization of the active principle in the main solvent or prevent its precipitation. Examples include polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene castor oil and polyoxyethylene sorbitan ester.

In this case, the following preservative agents may be mentioned: benzyl alcohol, trichlorobutanol, hydroxybenzoic acid ester, n-butanol.

The solutions can be used directly. The concentrated products are used, after the previous dilution, in the use concentration.

The solutions can be dripped on the skin, spread on the skin, rubbed, squirted or sprayed on the skin.

Thus, it may be advantageous to carry out the addition of thickening agents at the time of production. The thickening agents that can be mentioned in this case are: thickening agents of an inorganic nature, such as, for example, bentonite, colloidal silicic acid, aluminum monostearate; thickeners of an organic nature, such as, for example, cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

The gels are applied or spread on the skin or inserted into body cavities. The gels are produced in such a way that the solutions that have been produced as described with regard to the solutions for injections are mixed with such an amount of thickening agent that this results in a clear mass with an ointment consistency. The thickening agents mentioned above are used as thickening agents.

The immersion formulations are applied or sprayed 10 over a restricted region of the skin, in such a way that the active ingredient can penetrate the skin and act in a systemic manner.

Immersion formulations are produced in such a way that the active ingredient is dissolved, suspended or emulsified in appropriate solvents or solvent mixes compatible with the skin. In some cases, it is also possible for other auxiliary substances to be added, such as coloring agents, resorption promoting agents, antioxidant substances, protective agents against light degradation and adhesion agents.

As solvents, water, alkanols, glycols, polyethylene glycols, polypropylene may be mentioned in this case • · · · · * • · # · · · · · · ····· · • · · · · ··· benzyl, phenylethanol, phenoxyethanol; esters such as acetic ester, butyl acetate, benzyl benzoate;

ethers, such as alkylene glycol alkyl ethers, 5 such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether; ketones, such as acetone, methyl ethyl ketone; cyclic carbonates, such as propylene carbonate, ethylene carbonate, aromatic or aliphatic hydrocarbons, oils of vegetable origin or synthetic oils, DMF, dimethylacetamide, n-alkylated pyrrolidones, such as n-methylpyrrolidone, n-butyl or N-octylpyrrolidone, N-methylpyrrolidone, 2-pyrrolidone, 2,2-dimethyl-4-oxy-methylen-1,3-dioxolane and glycerinformal.

Coloring agents are all substances with coloring action approved for use in animals, which can be subjected to solubilization or suspension.

The resorption-promoting agents are characterized, for example, by DMSO, dispersible oils, such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, as well as their copolymers with polyethers, fatty acid esters, triglycerides, lipid alcohols .

· • · · · «··· • · • ·

Antioxidant substances are sulfites or metabisulfites, such as potassium metabisulfite, ascorbic acid, butylhydroxytoluol, butylhydroxyanisole and tocopherol.

Protective agents against light degradation are, for example, novantisol acid.

Adhesive agents are, for example, cellulose derivatives, starch derivatives, polyacrylates, naturally occurring polymers, such as alginates and gelatin.

Emulsions can be of the water in oil type or also of the oil in water type.

These emulsions are produced by dissolving the active principle in the hydrophobic or hydrophilic phase and these are homogenized with the aid of appropriate emulsifying agents with the solvent from the other phase and, in some cases, also with other auxiliary agents, such as substances dyes, resorption promoting agents, preservative agents, antioxidant substances, protective agents against light degradation and substances capable of increasing the viscosity of the medium.

Hydrophobic phases (oils) that can be mentioned, in this case, are paraffin oils, silicone oils, vegetable oils of natural origin, such as sesame oil, almond oil, castor oil, synthetic triglycerides, such as diglyceride of caprylic / caprine acid, mixtures of triglycerides with fatty acids of vegetable origin that have a chain length of

C ₈ -i2 or other specially selected fatty acids of natural origin, mixtures of partial glycerides, saturated or unsaturated fatty acids and, in some cases, also of fatty acids containing hydroxyl and mono and diglycerides of Ce-io fatty acids esters fatty acids, such as ethyl stearate, di-n-butyryl-adipate, lauric acid hexylester, dipropylene glycol pelargonate; esters of branched fatty acids, with an intermediate chain length, with saturated fatty alcohols with a Ci6-i8z chain length isopropyl myristate, isopropyl palmitate, caprylic / caprine acid ester of fatty alcohols

0 saturated with chain length C12-18 / isopropyl stearate, oleic acid ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester;

esters of waxy fatty acids, such as secretion

oil produced by the uropigian gland of ducks, dibutyl phthalate, diisopropyl ester of adipic acid, mixtures of analogs of the latter, among others.

Fatty alcohols are, for example, isotridecyl alcohol, 2-octyldodecanol, ceto-stearyl alcohol, oleic alcohol.

Fatty acids are, for example, oleic acid and mixtures thereof.

The hydrophilic phase can be mentioned:

water, alcohols, such as, for example, propylene glycol, glycerin, sorbitol and mixtures thereof.

As emulsifying agents can be mentioned:

non-ionogenic surfactants, such as, for example, polyoxyethylene castor oil, polyoxyethylene sorbitan monooleate, sorbitan monostearate, glycerin monostearate, polyoxy ethylene stearate, polyphenol polyglycol ether;

ampholytic surfactants, such as disodium N-laurylβ-iminodiproprionate or lecithin.

anionic surfactants, such as, for example, sodium lauryl sulfate, fatty alcohol ether sulfate, mono / dialkyl polyglycol ether salt - orthophosphoric acid ester - monoethanolamine; and cationic surfactants, such as, for example, cetyl trimethyl ammonium chloride.

As other auxiliary agents, in this case, substances capable of increasing the viscosity of the medium and emulsion stabilizing substances, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, arabic gum, polyvinylpyrrolidone can be mentioned , polyvinyl alcohol, methylvinyl ether copolymers and maleic acid anhydride, polyethylene glycols, waxes, colloidal silicic acid or mixtures of the substances mentioned.

The suspensions are produced by suspending the active principle in a liquid base and, in some cases, with the aid of other auxiliary agents, such as wetting agents, coloring substances, resorption promoting agents, preservative agents, antioxidant substances and protective agents against degradation by luminosity.

As liquid bases, all homogeneous solvents and solvent mixtures can be mentioned.

As wetting agents (dispersing agents), in this case, the surfactants mentioned above can be mentioned.

As other auxiliary substances can be mentioned, in this case, the agents mentioned above.

Semi-solid preparations differ from the suspensions and emulsions that were described above only in that they have a high viscosity.

For the production of solid preparations, the active ingredient is mixed with the appropriate excipient agents and, in some cases, through the addition of auxiliary substances, which are then shaped into the desired shape.

As excipient agents, in this case, all solid inert substances that are physiologically compatible can be mentioned. As such, they serve inorganic and organic substances. Inorganic substances are, for example, sodium chloride, carbonates, such as calcium carbonate, hydrogen carbonates, aluminum oxide, titanium oxide, silicic acids, clays, colloidal or precipitated silicon dioxide, phosphates.

Organic substances are, for example, sugar, cellulose, foodstuffs and animal feed, such as powdered milk, animal flours, cereal flours and crushed cereals, starches.

Auxiliary substances are, for example, preservatives, antioxidants, coloring substances, which have already been mentioned above.

The other suitable auxiliary substances are, for example, lubricating agents and anti-friction agents, such as, for example, magnesium stearate, stearic acid, talc, bentonite, substances that promote disintegration, such as starch or polyvinylpyrrolidone cross-linked; binding agents, such as, for example, starch, gelatin or linear polyvinylpyrrolidone, as well as dry binding agents, such as microcrystalline cellulose.

The active ingredients can occur in preparations in the form of mixtures with synergistic substances or with other active ingredients, which have activity against pathogenic endoparasites.

In this sense, the formulations that have been described in WO 02/087338 are especially suitable, especially for preparations that contain permethrin in their composition.

These formulations contain N-methylpyrrolidone in an amount of 27.5 to 62.5% w / w, in particular 35 to 50% w / w, with a special preference of 40 to 45% w / w.

Antioxidant substances must be contained in an amount of 0 to 0.5% w / w, in particular 0.05 to 0.25% w / w, with a special preference of 0.05 to 0.15% w / w P. Thus, all useful antioxidant substances may be of interest, although phenolic antioxidant substances are preferred, such as, for example, butyl hydroxytoluene, butylhydroxyanisole and tocopherol.

Organic acids in an amount of 0 to 0.5% w / w, preferably from 0.05 to 0.25% w / w, especially preferably from 0.05 to 0.15% w / w. For use, all organic acids which are pharmaceutically compatible, in particular carboxylic acids, such as, for example, citric acid, tartaric acid, lactic acid, succinic acid and malic acid, are suitable. Of particular preference are organic acids - citric acid and malic acid. Of particular preference is citric acid. Their quantity can be varied, in particular, in the range of 0.05 to 0.25% w / w. On the other hand, quantities are especially preferred in the range of 0.075 to 0.15% w / w.

The quantities of co-solvents must be in the range of

2.5 to 10% w / w, in particular 2.5 to 7.5% w / w, with a special preference of 3.5 to 6.0% w / w.

5 (9

As co-solvents, organic solvents with a boiling point> 80 ° C and a flash point> 75 ° C can be considered. Preferably, co-solvents have a broad action. In this context, aliphatic alcohols with a high boiling point should be mentioned, as well as aromatic alcohols, aliphatic polyethers, aliphatic and / or aromatic esters, cyclic and / or acyclic carbonates.

The co-solvents used are preferably aliphatic acyclic or cyclic ethers, as well as polyesters and also esters of fatty acids, in particular triglycerides.

For example, ethers are known, as well as polyethers, for example, of the sequence composed of diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, tetrahydrofurfuryl alcohol and tetrahydrofurfuryl ethoxylate, so that the last two compounds mentioned are especially preferred; fatty acid esters, as well as triglycerides, such as isopropyl myristate, Miglyol 810,

Miglyol 812, Miglyol 818, Miglyol 829, Miglyol 840 and

Miglyol 8810 (for the definition of Miglyois see, for example,

Encyclopedia

H.P

Substance fiedler

5À

excipients for pharmacy, cosmetics and related areas, pages 1008-1009, 2. Ed., Editora Edito Cantor, Aulendorf (1996)).

The preparations modified with the aforementioned co-solvents are distinguished, in particular, by the fact that they present a very good compatibility with the skin and eyes, an excellent biological activity, as well as through their stable behavior advantageous in cold temperatures inside of the single dose application tubes that are commonly used.

In addition to the components mentioned above, the preparations according to the present invention may have other useful auxiliary substances, pharmaceutically plausible, in their composition. As such, for example, emollient agents and surfactants can be mentioned.

Emollient agents are, for example, diffusible oils, such as, for example, adipic acid 2-ethyl hexyl diester, isopropyl myristate, dipropylene glycol perlagonate, cyclic and acyclic silicone oils, such as dimethicone and, in addition, its copolymers and terpolymers with ethylene oxide, propylene oxide and

formalin, fatty acid ester, triglycerides and fatty alcohols.

As surfactants can be mentioned, in this case:

non-ionogenic surfactants, such as, for example, polyoxyethylene castor oil, polyoxy ethylene sorbitan monooleate, sorbitan monostearate, glycerin monostearate, polyoxyethylene stearate, polyphenyl polyglycol ether;

ampholytic surfactants can be for example disodium N-lauryl-β-iminodiproprionate or lecithin; and anionic surfactants can be, for example, sodium lauryl sulfate, fatty alcohol sulfate ether, mono / dialkyl polyglycol ether salt - orthophosphoric acid ester - monoethanolamine;

cationic surfactants, such as, for example, cetyl trimethyl ammonium chloride.

The preparations used, according to the present invention, can be produced, according to the usual procedures, through which, for example, the active ingredients are mixed, under agitation, with the other components, producing a solution . This solution can, in some cases, be filtered. To the

carrying out the filling are suitable, for example, plastic tubes.

Preferred application volumes for the formulations described in document W002 / 0873 38 are in the range of 0.0075 to 0.25mL / l, 0kg [body weight of the animal to be treated], preferably 0.1 at 0.15mL / l, 0kg [body weight of the animal to be subjected to treatment].

These preparations are excellently suitable for filling and marketing in critical storage containers, such as, for example, single-dose polypropylene plastic tubes with a wall thickness of 300 to 500gm and a volume from 1.0 to 4.0mL.

The preparations are, in addition, excellently compatible with the skin, have low toxicity and are not harmful to the environment due to their biological degradability.

Examples:

0 Example 1:

A homogeneous solution of the spot on type that consists of:

45g lOg

44.8 g

0.1 g

0.1 g

Permethrin with a 40% ratio of cis isomers and 60% trans isomers

Imidacloprid (1— [6] -chloro-3-pyridinyl) methyl] -Nnitro-2-imidazolidinimine) by Bayer AG

N-methylpyrrolidone citric acid

BHT (butyl hydroxytoluene)

Example 2:

A homogeneous solution of the spot on type that consists of:

45g

Permethrin with a 40% ratio of cis isomers and 60% trans isomers

Imidacloprid

N-methylpyrrolidone water citric acid

BHT lOg

40.8g

4.0g

0, lg

0, lg

Example 3:

A homogeneous solution of the spot on type that is composed

45g Permethrin with a 40% ratio of cis isomers and 60% trans isomers

10g Ti 435, Clothianidin from Takeda AG

44.8g N-methylpyrrolidone

0.1 g citric acid

0.1 g BHT

Example 4:

A homogeneous solution of the spot on type that consists of:

5g Permethrin with a proportion of 40% cis isomers and 60% trans isomers

Diacloden (Tiametoxam) by Sygenta AG

N-methylpyrrolidone citric acid

BHT lOg

44.8g

0, lg

0, lg

Example 5:

A homogeneous solution of the spot on type that consists of:

45g lOg

44.8g o, lg o, lg

Example 6:

Permethrin with a 40% ratio of cis isomers and 60% trans isomers

Spinosad (8.5g Spinosyn A; 1.5g Spinosyn D) from Dow Agrosciences

N-methylpyrrolidone citric acid

B HT

• · ·· · ······ · • · ··· · · · · · · · · · ··· · ···· * · · · · · ··· · · · · · ··· · · ·

A homogeneous solution of the spot on type that is composed

45g

Permethrin with a proportion of 40% cis isomers and 60% trans isomers

Nitiazine by Shell AG

N-methylpyrrolidone citric acid

B HT

0g

34.8g

0, lg

0, ig

Example 7:

A homogeneous solution of the spot on type that consists of:

45g Permethrin with a proportion of 40% cis isomers and 60% trans isomers 10g Ti 435, Clothianidin from Takeda AG

39.8g N-methylpyrrolidone

0, lg citric acid

0, lg BHT

5.0g Tetrahydrofurfuryl alcohol

Example 8:

A homogeneous solution of the spot on type that consists of:

cis and 60% trans isomers

45g

Permethrin with a proportion of 40% isomers

Ò ^ ··· ········ • · ··· · · · · ········ • · · · · ·

10g Diacloden (Tiametoxam) from the firm Sygenta AG 39.8g N-methylpyrrolidone 0, ig Citric acid 0, lg B HT 5, Og Tetrahydrofurfuryl ethoxylate Example 9: An homogeneous spot type solution on that is composed in: 45g Permethrin with a proportion of 40% isomers cis and 60% trans isomers 10g Spinosad (8.5g Spinosyn A; 1 , 5g Spinosyn D) from Dow Agrosciences 39.8g N-methylpyrrolidone 0, lg Citric acid 0, lg B HT 5.0g Tetrahydrofurfuryl ethoxylate Example 10: An homogeneous spot type solution on that is composed in: 45g Permethrin with a proportion of 40% isomers cis and 60% trans isomers 20g Nitiazine by Shell AG 29.8g N-methylpyrrolidone

Hi G Citric acid 0, lg B HT 5.0g Tetrahydrofurfuryl ethoxylate Example 11: An homogeneous spot-on solution that in: lOg a-cypermethrin 10g Imidacloprid 79.8g N-methylpyrrolidone Hi G Citric acid 0, lg BHT (butyl hydroxytoluene) Example 12: An homogeneous spot-on solution that in: lOg a-cypermethrin lOg Imidacloprid 75.8g N-met ilpyrrolidone 4.0g Water Hi G Citric acid 0, lg BHT (butyl hydroxytoluene) Example 13: An homogeneous spot-on solution that

is composed is composed is composed of:

5th \

• · · · · ·· · ····· • ····· «· • · · · · · • · ······ • · · · · · · · 10g a-cypermethrin 10g Ti 435, Clothianidin from Takeda AG 79.8g N-methylpyrrolidone 0, ig Citric acid 5 Hi G BHT (butyl hydroxytoluene) Example 14: An homogeneous spot-on solution that is composed in: lOg a-cypermethrin 10 lOg Diacloden (Tiametoxam) by Sygenta AG 79.8g N-methylpyrrolidone 0, lg Citric acid 0, lg BHT (butyl hydroxytoluene) Example 15: 15 An homogeneous spot-on solution that is composed in: lOg a-cypermethrin 10g Spinosad (8.5 g Spinosyn A; 1.5 g Spinosyn D) from Dow Agrosciences 20 79.8g N-methylpyrrolidone Hi G Citric acid Hi G BHT (butyl hydroxytoluene) Example 16:

Q> O

A homogeneous solution of the spot on type that is composed of 10g a-cypermethrin

20g Nitiazine from Shell AG

69.8g N-methylpyrrolidone

0, lg citric acid

0. lg BHT (butyl hydroxytoluene)

Example 17:

A homogeneous solution of the spot on type that consists of:

10g a-cypermethrin 10g Ti 435, Clothianidin from Takeda AG

74.8g N-methylpyrrolidone

0, lg citric acid

0. lg BHT (butyl hydroxytoluene)

5.0g Tetrahydrofurfuryl alcohol

Example 18:

A homogeneous solution of the spot on type that consists of:

lOg lOg

74.8g

0. lg a-cypermethrin

Diacloden (Tiametoxam) by Sygenta AG

N-methylpyrrolidone citric acid <5f

0. lg BHT (butyl hydroxytoluene)

5.0g Tetrahydrofurfuryl ethoxylate Example 19: An homogeneous spot type solution on what is composed in: 10g a-cypermethrin 10g Spinosad (8.5 g Spinosyn A; 1.5 g Spinosyn D) from Dow Agrosciences 74.8g N-methylpyrrolidone 0, lg Citric acid o, lg BHT (butyl hydroxytoluene) 5.0g Tetrahydrofurfuryl ethoxylate Example 20: An homogeneous spot type solution on what is composed in: lOg a-cypermethrin 20g Nitiazine by Shell AG 64.8g N-methylpyrrolidone o, lg Citric acid Hi G BHT (butyl hydroxytoluene) 5, Og Tetrahydrofurfuryl ethoxylate Example 21:

An homogeneous solution of type spot on what in: 45g Etofenprox 10g Imidacloprid 44.8g N-methylpyrrolidone Hi G Citric acid 0, ig BHT (butyl hydroxytoluene) Example 22: An homogeneous solution of type spot on what in: 45g Etofenprox lOg Imidacloprid 40.8g N-methylpyrrolidone 4.0g Water 0, lg Citric acid 0, lg BHT (butyl hydroxytoluene) Example 23: An homogeneous solution of type spot on what in: 45g Etofenprox lOg Ti 435, Clothianidin from Takeda AG 44.8g N-methylpyrrolidone Hi G Citric acid

• · · • · · • · · · · · · · · · · • · · · • · · • · · • · ········ ········· • · • · · o, lg BHT (butyl hydroxytoluene) Example 24: An homogeneous spot type solution on what if compose in: 5 45g Etofenprox lOg Diacloden (Tiametoxam) from the firm Sygenta AG 44.8g N-methylpyrrolidone Hi G Citric acid 0, Ig BHT (butyl hydroxytoluene) 10 Example 25: An homogeneous spot type solution on what if compose in: 45g Etofenprox 10g Spinosad (8.5 g Spinosyn A; 1.5 g Spinosyn 15 D) from Dow Agrosciences 44.8g N-methylpyrrolidone 0, ig Citric acid 0, lg BHT (butyl hydroxytoluene) Example 26: 20 An homogeneous spot type solution on what if compose

in :

5g Etofenprox

20g

Nitiazine by Shell AG

34.8g N-methylpyrrolidone Hi G Citric acid 0, lg BHT (butyl hydroxytoluene) Example 27: 5 An homogeneous spot-on solution that in: 45g Etofenprox lOg Ti 435, Clothianidin from Takeda AG 39.8g N-methylpyrrolidone 10 0, lg Citric acid 0, lg BHT (butyl hydroxytoluene) 5.0g Tetrahydrofurfuryl alcohol Example 28: An homogeneous spot-on solution that 15 in: 4 5g Etofenprox 10g Diacloden (Tiametoxam) by Sygenta 39.8g N-methylpyrrolidone o, lg Citric acid 20 o, lg BHT (butyl hydroxytoluene) 5, Og Tetrahydrofurfuryl ethoxylate Example 29:

compose compoe ¢ 3 ·· · · · * ····· · ·· · · · · · · · · · ·· · ········ · · • • ······· ··· · · • · ·· ······ · · • · · ···· ·

A homogeneous solution of the spot on type that is composed

in : 45g Etofenprox lOg Spinosad (8.5 g Spinosyn A; 1.5 g Spinosyn 5 D) from Dow Agrosciences 39.8g N-methylpyrrolidone Hi G Citric acid Hi G BHT (butyl hydroxytoluene) 5.0g Tetrahydrofurfuryl ethoxylate

Example 3 0:

An homogeneous solution of the spot on type that is composed in:

45g Etofenprox 20g Nitiazine by Shell AG 15 29.8g N-methylpyrrolidone Hi G Citric acid 0, lg BHT (butyl hydroxytoluene) 5.0g Tetrahydrofurfuryl ethoxylate

Example 31:

2 0 One homogeneous solution of the spot on type that is composed in:

45g Pyrethrum extract lOg Imidacloprid

44.8g N-methylpyrrolidone 0, lg Citric acid 0, lg BHT (butyl hydroxytoluene) Example 32:

A homogeneous solution of the spot on type that is composed

in : 45g Pyrethrum extract 10g Imidacloprid 40.8g N-methylpyrrolidone 4, Og Water o, lg Citric acid o, lg BHT (butyl hydroxytoluene) Example 33:

A homogeneous solution of the spot on type that consists of:

45g Pyrethrum extract 10g Ti 435, Clothianidin from Takeda AG

44.8g N-methylpyrrolidone

4, Og Water

0, lg citric acid

0. lg BHT (butyl hydroxytoluene)

Example 34:

60 • · · • · · • · • · · • · · · · • · · · · 9 • 9 9 99 9 9 9 • · · · · • · · • · · · · An homogeneous spot type solution on what if compose in: 45g Pyrethrum extract 10g Diacloden (Tiametoxam) from the firm Sygenta AG 44.8g N-methylpyrrolidone 0, lg Citric acid 0, lg BHT (butyl hydroxytoluene) Example 35: An homogeneous spot type solution on what if compose in: 45g Pyrethrum extract lOg Spinosad (8.5 g Spinosyn A; 1.5 g Spinosyn D) from Dow Agrosciences 44.8g N-methylpyrrolidone 0, lg Citric acid 0, lg BHT (butyl hydroxytoluene) Example 36: An homogeneous spot type solution on what if compose

in :

45g

20g

34.8g

0, lg

Pyrethrum extract

Nitiazine by Shell AG

N-methylpyrrolidone citric acid

0, ig BHT (butyl hydroxytoluene) Example 37: An homogeneous spot-on solution what if compose in: 5 45g Pyrethrum extract 10g Ti 435, Clothianidin from Takeda AG 39.8g N-methylpyrrolidone 0, lg Citric acid Hi G BHT (butyl hydroxytoluene) 10 5.0g Tetrahydrofurfuryl alcohol Example 38: An homogeneous spot-on solution what if compose in: 45g Pyrethrum extract 15 lOg Diacloden (Tiametoxam) by Sygenta AG 39.8g N-methylpyrrolidone 0, lg Citric acid 0, lg BHT (butyl hydroxytoluene) 5.0g Tetrahydrofurfuryl ethoxylate 20 Example 39: An homogeneous spot-on solution what if compose

in :

45g

Pyrethrum extract

10g Spinosad (8.5 g Spinosyn A; 1.5 g Spinosyn

D) from Dow Agrosciences

39.8g N-methylpyrrolidone

0, lg citric acid

0. lg BHT (butyl hydroxytoluene)

5.0g Tetrahydrofurfuryl ethoxylate

Example 40:

A homogeneous solution of the spot on type that consists of:

45g 10g Nitiazine pyrethrum extract from Shell AG

29.8g N-methylpyrrolidone

0, lg citric acid

0. lg BHT (butyl hydroxytoluene)

5.0g Tetrahydrofurfuryl ethoxylate

A. Evaluation of tick repellency in biological test of moving object.

Comparison with the state of the art.

Method

Biological test of the moving object according to

Dautel et al. (1999).

Brief description: Individual ticks approach a slowly rotating heated vertical membrane that

is on a glass stick that is in an upright position. Ticks are attracted by the heat of the membrane and change its direction at a junction site present on the rotating membrane. If a repellent agent is applied over this junction site, then the repellent effect can be assessed in the following ways: i) in a reduced number of ticks that move towards the membrane or ii) through a reduced number of ticks that change its direction at the junction site or iii) 10 by means of a high number of ticks that fall, early, once again from the junction site. As a standard, a membrane with a control not subjected to treatment is used. In this way, repellencies can be measured by both contact and distance.

Test conditions:

Each test value is performed with 30 ticks. All ticks are evaluated individually, one after the other, on the same device. For each sequence of tests, a control test was performed, with a pure solvent without repellent, in order to assess the basal activity of ticks. As a borderline activity for carrying out a test, the growth of at least 70% of ticks on the membrane is evaluated. For each product test it is> 41

• · • · • • • · ··· • • • · • · · « • · • • • • • • • t <· · · • · • • • • « • 4 · • · · • • • · • • • • • • · · • • · • · • • • • • •

A dedicated test membrane is used. After each test sequence, all materials used are carefully cleaned.

For the testing of ticks of the species Ixodes 5 ricinus and Rhipicephalus sanguineus the following conditions were used.

I. ricinus:

A standard membrane and junction region were used (Dautel et al., 1999). The junction region was located 1 to 3 mm above the membrane surface. The distance between the 2mm diameter glass rod and the junction region was between 1mm and at most

1.5mm.

The membrane rotation time was between 15 3.9 and 4.1 ls / rotation, corresponding to 7.66-8.05 cm / s relative to ticks. The surface temperature in the junction region was between 34.6 and 35.5 ° C. Room temperature and room humidity were determined between

19.1-22.3 ° C, as well as 43.4-78.1% u.r.

R. sanguineus:

Adult ticks of the species R. sanguineus have a higher movement speed than that of nymphs of the species I. ricinus. Therefore, the junction region

7S • · · · · ······ ·

• · • • • • »· • ·· · • • • • • ··· · • • · · • • · ·

it must be so extended over the membrane that a contact time of at least 10 can be guaranteed also for specimens that move quickly. In that case, the entire membrane therefore functions as a junction site. Due to the reduced adherence of the ticks to the paper filters, the membrane was covered with a Molton tissue. The distance between the Molton handkerchief and the glass rod (4mm diameter) made a value of 1 to 3mm, whereby ticks were always able to move from the glass rod to the membrane.

membrane rotation time was between 5.6 and 6. Os / rotation, corresponding to 5.23-5.61 cm / s relative to ticks. The surface temperature in the junction region was between 35 and 36 ° C. Room temperature and room humidity were determined between

19.4-23.5 ° C, as well as 59.1-79.5% u.r.

Application of test substances:

Acetone was used as a solvent and for dilutions in all tests. The application was carried out 1 to 2 hours before the beginning of the experiment, in order to have enough time for the evaporation of the solvent.

The active ingredients were applied to the paper filters with a disposable pipette. A distribution

uniform over the larger surface of the Molton scarf was achieved with the aid of a nitrogen pressure spraying apparatus. The volume that is exactly applied is determined, in this case, by weighing the tissues before and after application.

Biological test of moving object:

In the test, only those ticks that were able to actively climb on a glass canaliculum to the upper margin were used and, in an uninterrupted manner, they were switched to a badger hair brush (0 or 1), which was used for the transfer of the ticks. These ticks were placed with the head towards the membrane, on the glass rod, at a distance of 1.5 cm (I. ricinus) or 2.5-4 cm (R. sanguineus) at the end of the glass rod. The test time was started as soon as a tick had passed the 1cm mark (J. ricinus), as well as the 2cm mark (R. sanguineus) on the glass stick. Ticks that fell off the brush or fell before they passed the glass stick mark were not evaluated.

The following time periods were determined with the aid of a stopwatch:

6Ί

> the time from passing the mark until the end of the glass stick is reached> the time from reaching the end of the glass stick until it passes through the membrane> the time that the tick remains on the filter paper or on the Molton tissue, until he falls or leaves the treated surface.

For each of these time periods, a maximum of 120 seconds were foreseen. After 2 minutes, the tick was removed and the time was considered as 120 seconds.

An overall repellent action relative to the control was calculated in such a way that all ticks that did not move towards the membrane, those that did not move towards the membrane and those that suffered a drop in the junction region were considered. All of these ticks were evaluated as repelled. The repellent action was calculated as follows:

where R refers to the repellent action, pt is the percentage of ticks that have not been repelled and pc is the percentage of control ticks that have not been repelled.

Results of the repellency experiments with ticks

Rhipicephalus sanguineus - Comparison with the state of the art (Exspot ⁸ , firm Schreing-Plow).

Table la: sanguineus ·. Dwell time [s] on the treated membrane surface.

Formulation n Composition Detour 95 % (Dosage) standard Conf. Control 25 83.8 39.7 67.4 - 100.2 Example 1 (17 / 83gg / cm ² ) 18 5.5 3.9 3.6 - 7.5 (*) Exspot (83.3qg / cm ² ) 20 21.9 30.3 7.7 - 36.0

(*) the first value refers to the amount of imidacloprid, the second to the amount of permethrin.

The formulation of example 1 shows, surprisingly, a repellent action markedly stronger than that of the standard (Exspot® contains in its composition permethrin as the only active ingredient). Ticks that passed over the membrane in example 1 fall again, significantly faster than with the standard. The repellent action of the pattern is intensified, in the previous example, in the preparation, by a factor of about.

Table lb: R. sanguineus ·. Duration time [s] for the passage of the end of the glass rod to the membrane.

Formulation n Preparation Detour 95% (Dosage) standard Conf. Control 30 3.5 6.2 1.2 - 5.8 Example 1 (17/83 μg / cm ² ) 30 7.9 22.1 0.3 - 16.2 (*) vy Exspot (83.3 μg / cm ² ) 27 2.8 6.9 0.0 - 5.5

(*) the first value refers to the amount of imidacloprid, the second to the amount of permethrin.

Another sign for the improvement of the repellent activity is characterized by the delay in the passage of the glass rod to the membrane. In this case too, in the example 1, the ticks show, in comparison to the standard, a time interval in the preparation, increased by a factor of 3. The standard, in this case, is found in the region of a control.

Table 2: R. sanguineus: Evaluation of the biological test of 10 moving object - Formulation described according to the present invention and state of the art (Exspot®, firm

Schreing-Plow) against control

Dosage Control Example 1 16.6 / 83.1 μ9 / οιη ² Control Exspot ”8.3 pg / cm ² Ticks not repelled 27 0 25 3 Repelled ticks 3 30 5 27 % of no repelled 90.0 0.0 83.3 10 Repellent action [% of control] 100 88.8

In comparison with its respective control, it appears that the formulation of example 1, described in accordance with the present invention, shows a repellent action of 100% in the relevant dosage range for a uniformly distributed topical formulation, after using the spot on type . The commercial product already known, under the same test conditions, surprisingly, was not able to promote the repellency of all ticks.

Results of repellency tests with Ixodes ricinus ticks - Comparison with the state of the art (Exspot ⁸ , firm Schreing-Plow).

Table 3: I. ricinus: Evaluation of the biological object test in motion - Formulation described according to

present invention and state of the art (Exspot,

Schreing-Plow) against control.

Formulation Dosage Control Example 1 Control (according to the present invention) Parameters experiment s 1.9 / 9.3 pg / cm ² 5/25 gg / cm ² 19/93 gg / cm ² 190/930 gg / cm ² Ticks not repelled 28 20.5 17 18 15 27 Ticks repelled 2 9.5 13 12 15 3 % in ticks 93.3 6.3 56.7 60.0 50.0 90.0 not repelled Action repellent (%] - 25.3 39.3 33.3 44.4 -

Formulation Dosage Control Exspot® Control Parameters experimental 9.3 μg / cm ² 25 μg / cm ² 93 μg / cm ² 930 μg / cm ² Ticks not

repelled 26 24 22 18 15 28 Ticks repelled 4 6 8 12 15 2 % in ticks not repelled 86.7 80.0 73.3 60.0 50.0 93.3 Repellent action [%] 7.7 21.4 30.8 42.3

Also with regard to ticks of the species

Ixodes, a type of tick that is not well repelled by

Exspot, it appears that the example described in accordance with the present invention surprisingly demonstrated a markedly better repellent activity. Especially when low dosages are used, as expected at the beginning of the treatment of body surfaces that are very far from the point of application of the spot on, as well as at the end of the duration of action on the whole animal, the example described , according to the present invention, shows repellency in the same range as at higher dosages, whereas the repellent activity curve, according to the state of the art, is reduced by about 6 times.

Thus, the formulations described according to the present invention show, when applied in similar amounts, a markedly better repellent activity

against ticks, in comparison with the state of the art, in the important experimental parameters probability of passing to the surface, time of residence on the surface, as well as in the parameter effectiveness at low dosages.

B. Mortality of ticks in biological testing of moving object.

Method:

Determination of final mortality after a short contact time in a biological object test.

Brief description: After exposure, the ticks were transferred, one by one, to Eppendorf tubes with a perforated lid and stored at a humidity of 90% ur and at a temperature of 20 ° C. After 24 hours and after 7 days, ticks were evaluated using a binocular microscope. Ticks that were shown to be able to perform coordinated movements were evaluated as alive. Ticks that made only small movements with the tarsi or with the oral appliance or were shown to be unable to walk were considered dying. Ticks that remained immobile after a C0 ₂ stimulus or a strong light stimulus were considered dead.

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The tests should show whether there is a relationship between the exposure time (= residence time on the treated membrane surface during a biological test on a moving object) and mortality in different concentrations of different preparations, compared to the state of the art .

Table 1: R. sanguineus: Mortality (d 7) and contact times at different concentrations in the biological object test

Formulation O Dosage (there.) Mortality Contact time n % Preparation Detour standard 95% Conf. 16.6 / 83.1 2.2 - Example 1 pg / cm ² 21 70% 4.2 4.4 6.2 83.3 6.9 - Exspot® gg / cm ² 16 53% 24.7 33.56 42.6

Table 2: I. ricinus (d 7) and contact times at different concentrations in the biological test of the moving object.

Formulation Dosage (there.) Mortality Contact time n % Preparation Detour standard 95% Conf. 19/93 21.6 - Example 1 pg / cm ² (*) 27 90 33.7 30.6 45.9

93 29.3 - Exspot® [ig / cm ² 26 87 41.9 31.1 54.4 (*) O first value if refers to amount it's from

imidacloprid, the second to the amount of permethrin.

Both ticks of the Ixode species and those of the Rhipicephalus species are eliminated in a high percentage, after they have had contact with the membrane surface. According to the present invention, the average contact time necessary for this high mortality to occur is, with this, in terms of the formulations described, shorter than that described according to the state of the art.

Thus, the formulations described, according to the present invention, protect it, in addition, by the fact that ticks repelled also after short contact times of markedly less than 1 minute are already killed 15 and, as a consequence, it has to be said that other hosts can no longer be infested by repelled ticks.

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Claims (3)

1. Use in one compound pyroid or pyrethrin in combination with one agonist nicotinic characterized by fact of being for arthropod repellency in dogs and cats in what O compound pyroid is permethrin and O nicotinic agonist is the neonicotinoid imidacloprid. 2. Use, according to claim 1, characterized by the fact that it is intended to repel 10 ticks, fleas, mosquitoes and / or flies from dogs and cats. 3. Use according to claim 1 or 2, characterized by the fact that arthropod repellency is a contact repellency or a remote actuation repellency. 15 4. Use, according to claim 3, characterized by the fact that arthropod repellency is a remote-acting repellency in dogs. Petition 870180051991, of 06/18/2018, p. 6/8