HK1111354A - Liquid formulations for dermal application in inhibition of parasitic insects in animals - Google Patents

Description

Liquid formulation for dermal application for inhibiting parasites on animals

The present application is a divisional application of the chinese patent application (national application No.02807934.5, international application No. PCT/EP02/03619) entitled "liquid formulation applicable to the skin for inhibiting parasites on animals" filed on day 4, month 2 of 2002.

Technical Field

The present invention relates to novel, skin-friendly and skin-applicable liquid formulations comprising permethrin and agonists or antagonists of the insect nicotinic (nicotinergen) acetylcholine receptor for inhibiting parasites on animals.

Background

Topical formulations for the inhibition of parasites on animals are known which comprise permethrin, (3-phenoxy-phenyl) methyl 3- (2, 2-dichlorovinyl) -2, 2-dimethylcyclopropanecarboxylate, (CASNO [52645-53-1]) (see for example WO 95/17090, JP-07247203, EP-A-567368, EP-A-461962, US-5236954 and US-5074252).

Agonists or antagonists of nicotinic acetylcholine receptors of insects are well known, such as european publications 464830, 428941, 425978, 386565, 383091, 375907, 364844, 315826, 259738, 254859, 235725, 212600, 192060, 163855, 154178, 136636, 303570, 302833, 306696, 189972, 455000, 135956, 471372, 302389; german specification publication nos. 3639877, 3712307; japanese laid-open patent nos. 03220176, 02207083, 63307857, 63287764, 03246283, 049371, 03279359, 03255072; U.S. patent specification nos. 5034524, 4948798, 4918086, 5039686, 5034404; PCT application Nos. WO91/17659, 92/4965; french application No. 2611114; brazilian application No. 8803621 discloses agonists or antagonists of the nicotinic acetylcholine receptors of insects. The use of spot-on formulations containing agonists or antagonists of nicotinic acetylcholine receptors of insects for inhibiting parasites on animals is also known (see for example WO98/27817, EP-A-682869 and EP 0976328).

There have also been some descriptions in the prior art of combined preparations of permethrin and agonists or antagonists which inhibit the nicotinic acetylcholine receptors of parasitic insects (see, for example, CN-1245637, WO00/54591, US-6080796, EP-A-981955, US-6033731, JP-07089803).

A disadvantage of the drip formulation of the benzethonium chloride ester group is that it has very little effect on ticks and fleas.

Spot-on formulations based on agonists or antagonists of the insect nicotinic acetylcholine receptors generally have a very good efficacy against fleas. It also has the disadvantage of having no efficacy against ticks.

The combined preparations known to date which contain permethrin and agonists or antagonists of nicotinic acetylcholine receptors are not well suited for use in the inhibition of parasites on animals, especially on small animals. They require the addition of large amounts of active substances, which in many cases lead to skin irritation. Permethrin is a very potent aprotic compound, whereas agonists or antagonists of nicotinic acetylcholine receptors, particularly imidacloprid analogues, are protic. Therefore, it is difficult to find a liquid formulation which can be applied to the skin and which contains two effective substances and has the following properties:

the active substance has good solubility

Very good skin affinity

Very minor toxicity

Very little skin permeability (since the active substance should preferably be non-systemically acting)

High efficacy.

For these reasons, it has hitherto been necessary to subject animals to a secondary therapeutic treatment with the spot formulation described above in order to obtain the desired tick and flea suppression effect. For environmental and economic reasons, it is desirable to replace these preparations which are characterized by being skin-friendly and non-toxic and which, in addition, above all against ticks and fleas, have a very good long-term action at very low application doses, for example (0.1ml/1.0kg body weight of the animal to be treated), of at least three to four weeks. In addition, such a formulation has sufficient storage stability in all climatic regions, and is generally required to be stored for at least three years, for example in a conventional dropper.

It is therefore an object of the present invention to provide a dermophilic, environmentally friendly formulation for application to the skin which is effective against parasites, in particular ticks and fleas, and which contains permethrin and an agonist or antagonist of the nicotinic acetylcholine receptor of insects.

Disclosure of Invention

The solution of this task is achieved by the medicament of the present invention described below.

The invention relates to

1. Medicament comprising

a)35-60 wt% of permethrin as active substance

b)2.5-12.5 wt% imidacloprid or imidacloprid analog

c) 27.5-62.5% by weight of N-methylpyrrolidone

d) 0-5% by weight of water

e)0-0.5 wt.% of a phenolic antioxidant

f)0-0.5 wt% of an organic acid.

The weight percentages are based on the total weight.

According to a preferred embodiment, the medicament of the invention additionally comprises:

g)2.5-10 wt% of cosolvent

The medicament of the invention is generally liquid and suitable for application to the skin, in particular as a pour-on or spot-on formulation as described.

The effect of the agent of the invention containing permethrin in combination with imidacloprid or an imidacloprid-analogue on ectoparasites is surprisingly higher than the effect which can be produced by the individual components. Thus, the use of such agents can reduce the amount of active substance used and improve the long-term effect. In addition, its use brings a series of advantages both environmentally and economically.

The agents of the invention are extremely useful for the inhibition of parasites.

The so-called parasitic organisms are:

from the order of the louse, such as the genus anopheles, the genus hemibarbus, the genus tubus, the genus louse, the Pthirus spp;

mallophaga, such as the genera trichophaera, brachyporus, eomnacanthus spp, Menacanthus spp, psocolla, feliola spp, damalina spp, phylloxera;

from the order of the diptera, for example, Aedes, Culex, Arachnocampa, Chrysomyiame, Tabanus, Musca, Hydrotaea spp, Serratia, Haemato-bosca spp, Haematobia spp, Christina, Siphonostegia, Okistrodon, Calliptera, Drosophila, Oestromyelia, Sarcophaga, Oestromyelia spp.

From the order of Siphonaptera, e.g. Ctenocephalides, Cytoptera, Ceriporiopsis, Siphonaptera

Metastingmata, such as Boehmeria, Rhipicephalus, Boophilus, Orientia, Haematococcus, Dermacentor, hard tick, Rhynchophorus, Iridago, Odonorhynchus;

from the order of the Sida, for example, Dermatophagoides, and Dermatophagoides.

Predamates, such as the genus hemibarbus, the genus sheep sarcoptidae, Myobia spp, the genus lipomite, the genus tsutsugamushi;

from the phylogenetic sub-order, for example, Acarina, Myocop-tes spp, Primeria, Dermatophagoides, and Dermatophagoides.

The agents of the invention are particularly suitable for inhibiting ectoparasites, preferably ticks and/or fleas, on animal bodies, particularly on warm-blooded animal bodies. Preferably, the agents of the invention are administered to small animals. Herein, small animals are understood to mean in particular dogs, cats and other warm-blooded animals not larger than dogs; that is to say they weigh no more than 90kg, preferably no more than 50 kg. It is particularly preferred to administer the agents of the invention to dogs and cats, especially dogs.

Since the treated animal in principle also has a certain amount of the agent used dispersed in the surroundings, for example by friction or debris, the action effect of the agent according to the invention is, if appropriate, not only directly present in the animal body but also in the surroundings by corresponding measures.

To prepare the liquid formulations of the present invention, all common permethrin-active isomer mixtures can be used. The preferred isomer mixture consists of 35-45% cis and 55-65% trans permethrin. A particularly preferred isomer mixture consists of 37.5-42.5% cis and 57.5-62.5% trans permethrin.

The amount of permethrin in the medicament of the invention may vary widely from 35 to 60%. The preferred amount is in the range of 45-60%, and the particularly preferred amount of permethrin contained in the medicament of the present invention is in the range of 47.5-55%.

The amount of imidacloprid or imidacloprid-analog can vary within the same broad range of 2.5-12.5%, with amounts of 5.0-10.0% being preferred. It is particularly preferred to use imidacloprid or imidacloprid-analogues in the medicament of the invention in an amount of 7.5 to 10%.

It will be apparent that the formulation may also contain some other suitable active substance.

Examples of growth-inhibiting actives and synergists are pyriproxyfen {2- [ 1-methyl-2- (4-phenoxyphenoxy) -ethoxy ] -pyridine CAS No.: 95737-68-1}, methoprene [ (E, E) -1-methylethyl 11-methoxy-3, 7, 11-trimethyl-2, 4-dodecenoate CAS number: 40596-69-8 and chlorsulfuron { 2-chloro-N- [ [ [4- (trifluoromethoxy) phenyl ] amino ] carbonyl ] benzamide CAS number: 64628-44-0}.

Preferred as agonists or antagonists of the nicotinic acetylcholine receptors of insects are the so-called imidacloprid analogues.

The imidacloprid analogues should be compounds having the general formula (I):

and wherein

R represents hydrogen, and may be a substituent group selected from acyl, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;

a represents a monofunctional group selected from hydrogen, acyl, alkyl, aryl or represents a difunctional group to which a group Z is attached;

e represents an electron withdrawing group;

x represents a group-CH ═ or ═ N-, and the group-CH ═ can be attached to the group Z in place of the H atom;

z represents a radical selected from alkyl, -O-R, -S-R,a series of monofunctional groups, or a difunctional group attached to either group a or group X.

Particularly preferred compounds of the formula (I) are those which have the following meanings:

r represents hydrogen and, if desired, a substituent selected from the series acyl, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl.

As acyl are formyl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, (alkyl-) - (aryl-) -phosphoryl; they may also be substituted.

As alkyl there is C_1-10Alkyl of, especially C_1-4Alkyl of (a), in particular methyl, ethyl, isopropyl, sec-or tert-butyl; they may also be substituted.

As aryl there may be mentioned phenyl, naphthyl, preferably phenyl.

As the arylalkyl group, there are phenylmethyl and phenylethyl.

As heteroaryl are heteroaryl having not more than 10 ring atoms and N, O, S, preferably N, as heteroatoms. In particular thienyl, furyl, thiazolyl, imidazolyl, pyridyl and benzthiazolyl.

As heteroarylalkyl there are heteroarylmethyl, heteroarylethyl having not more than 6 ring atoms and N, O, S, preferably N, as heteroatoms.

Preferred substituents are the following:

alkyl having preferably 1 to 4 carbon atoms, particularly preferably 1 or 2 carbon atoms, such as methyl, ethyl, n-and i-propyl and n-, i-and t-butyl; alkoxy having preferably 1 to 4 carbon atoms, particularly preferably 1 or 2 carbon atoms, such as methoxy, ethoxy, n-and i-propoxy and n-, i-and t-butoxy; alkylthio having preferably 1 to 4, particularly preferably 1 or 2, carbon atoms, such as methylthio, ethylthio, n-and isopropylthio and n-, iso-and tert-butylthio; haloalkyl having preferably 1 to 4, particularly preferably 1 or 2, and preferably 1 to 5, particularly preferably 1 to 3 halogen atoms, the halogen atoms may be identical or different, while fluorine, chlorine or bromine are preferred as halogen atoms, particularly preferably fluorine, such as trifluoromethyl; a hydroxyl group; halogen, preferably fluorine, chlorine, bromine and iodine, particularly preferably fluorine, chlorine and bromine; a cyano group; a nitro group; an amino group; monoalkyl-and dialkylamino having preferably 1 to 4, particularly preferably 1 or 2, carbon atoms per alkyl group, such as methylamino, methyl-ethyl-amino, n-and isopropylamino and methyl-n-butylamino; a carboxyl group; carbalkoxy groups having preferably 2 to 4, particularly preferably 2 or 3, carbon atoms, such as carbalkoxy and carbalkoxy groups; sulfo (-SO)₃H) (ii) a Alkylsulfonyl groups having preferably 1 to 4, particularly preferably 1 or 2, carbon atoms, such as methylsulfonyl and ethylsulfonyl; arylsulfonyl having preferably 6 or 10 aryl carbon atoms, such as phenylsulfonyl and heteroarylamino and heteroarylalkylamino such as chloropyridylamino and chloropyridylmethylamino.

A particularly preferably represents hydrogen, and may be a substituent group selected from the group consisting of acyl, alkyl and aryl groups preferably defined in R. In addition, a also represents a bifunctional group. Optionally substituted alkylene having 1 to 4, particularly preferably 1 to 2, C atoms, while the substituents mentioned above are substituents which may be interrupted by heteroatoms of the N, O, S series.

A and Z may together with the atoms to which they are attached form a saturated or unsaturated heterocyclic ring. The heterocycle may additionally contain 1 or 2 identical or different heteroatoms and/or heterogroups. As heteroatoms, preference is given to oxygen, sulfur or nitrogen, and as heteroatoms there are N-alkyl groups, the alkyl groups of which contain preferably from 1 to 4, particularly preferably 1 or 2, carbon atoms. As alkyl there are mentioned methyl, ethyl, n-and i-propyl, and n-, i-and t-butyl. The heterocyclic ring contains 5 to 7, preferably 5 or 6 ring-forming atoms.

Examples of heterocycles are pyrrolidine, piperidine, piperazine, hexamethylimine, hexahydro-1, 3, 5-triazine, morpholine; they may also be substituted, if desired, preferably with methyl groups.

E represents an electron withdrawing group, and particularly preferably NO₂CN, haloalkylcarbonyl such as 1, 5-halogen-C_1-4Carbonyl, particularly preferably COCF₃。

X represents-CH or-N ═

Z represents an optionally substituted alkyl, -OR, -SR, -NRR group, and wherein R and the substituents preferably have the above-mentioned meanings.

Z may form, in addition to the rings mentioned above, together with the atoms to which it is attached and the radical in position X ═ C ≦ a saturated or unsaturated heterocyclic ring. The heterocycle may contain 1 or 2 further identical or different heteroatoms and/or heterogroups. As heteroatoms, preference is given to oxygen, sulfur or nitrogen, and as heteroatoms there are N-alkyl groups, and the alkyl or N-alkyl groups contain preferably 1 to 4, particularly preferably 1 or 2, carbon atoms. As alkyl there are mentioned methyl, ethyl, n-and i-propyl, and n-, i-and t-butyl. The heterocyclic ring contains 5 to 7, preferably 5 or 6 ring-forming atoms.

Examples of heterocycles are pyrrolidine, piperidine, piperazine, hexamethylimine, morpholine and N-methylpiperazine.

Particularly preferred compounds which can be used according to the invention are compounds of the general formulae (II) and (III):

wherein the content of the first and second substances,

n represents 1 or 2, sub.st represents one of the substituents listed above, preferably halogen, particularly preferably chlorine,

a, Z, X and E have the meanings indicated above, in particular the following particularly preferred compounds (imidacloprid and analogues):

the amount of N-methylpyrrolidone may vary from 27.5 to 62.5% by weight. Preferably in the range from 35 to 50% by weight, particularly preferably in the range from 40 to 45% by weight.

The amount of antioxidant may vary from 0 to 0.5% and a preferred amount is between 0.05 and 0.25%. For the preparation of the medicament according to the invention, the use amount of 0.05 to 0.15% is particularly preferred. All customary antioxidants, preferably phenolic antioxidants, such as butylhydroxytoluene, butylhydroxyanisole, tocopherol, come into consideration here.

The amount of organic acid may vary from 0 to 0.5%, and a preferred amount is from 0.05 to 0.25%. For the preparation of the medicament according to the invention, the use amount of 0.05 to 0.15% is particularly preferred. Suitable for use in the medicament of the present invention are all pharmaceutically compatible organic acids, in particular carboxylic acids, such as citric acid, tartaric acid, lactic acid, succinic acid and malic acid. Particularly preferred organic acids are citric acid and malic acid, more particularly citric acid. The amount thereof may particularly preferably vary within the range of 0.05 to 0.25. The amount used is in turn particularly preferably in the range from 0.075 to 0.15%.

The amount of co-solvent may vary from 2.5 to 10 wt% and is preferably in the range of 2.5 to 7.5 wt%. Particularly preferably, 3.5 to 6.0% by weight of the medicament of the invention is used.

Organic solvents having a boiling point of > 80 ℃ and a flash point of > 75 ℃ are suitable as cosolvents. The co-solvent preferably has a spreading effect. In this connection, higher-boiling aliphatic and aromatic alcohols, aliphatic polyethers, aliphatic and/or aromatic esters, cyclic and/or ring-opened carbonates may be used.

However, for the production of the agents according to the invention, preference is given to using aliphatic, ring-opening or cyclic ethers or polyethers and also fatty acid esters, particularly preferably triglycerides.

The ethers or polyethers which are suitable for use in the medicament according to the invention can be selected from the group consisting of diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, tetrahydrofurfuryl alcohol and tetrahydrofurfuryl ethoxylate, of which the latter two are particularly preferred.

As fatty acid esters and triglycerides are: isopropyl myristate, Miglyol 810, Miglyol812, Miglyol 818, Miglyol 829, Miglyol 840 and Miglyol 8810 (see, for example, the meaning of Miglyol in the dictionary of auxiliaries for pharmaceutical, cosmetic and adjacent fields, page 1008-1009, volume 2, audi lender (1996)).

From the tests carried out to date, it is known that the mixtures according to the invention modified with the said co-solvents are characterized by better skin and eye compatibility, better bioaffecting effects and more favourable low-temperature stability in the usual single-dose tubes.

In addition to the above-mentioned components, the pharmaceutical preparation of the present invention may contain other conventional pharmaceutically acceptable auxiliary agents. Such substances may be a spreading agent and a surfactant.

Examples of spreading agents are spreading oils such as di-2-ethylhexyl adipate, isopropyl myristate, dipropylene glycol pelargonate, cyclic and ring-opened silicone oils such as dimethicone and its co-and ter-polymers with ethylene oxide, propylene oxide and formaldehyde, fatty acid esters, triglycerides, fatty alcohols.

As the surfactant, there may be mentioned nonionic surfactants such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerin monostearate, polyoxyethylstearate, alkylphenol polyglycol ethers;

amphoteric surfactants such as di-Na-N-lauryl-beta-iminodipropionate or lecithin;

anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfate, mono/dialkyl polyglycol ether orthophosphate-monoethanolamine salt;

cationic surfactants such as cetyltrimethylammonium chloride.

The pharmaceutical preparations of the present invention can be prepared by conventional methods, for example, by mixing the active substance with other ingredients under stirring to prepare a solution. The solution may be filtered if necessary. Suitable for being poured into plastic tubes.

The liquid formulations of the present invention are characterized by excellent storage stability for at least three years in all climatic regions. Due to its good therapeutic effect, the application volume can be kept small. Preferred volumes to be used are in the range of 0.075-0.25ml/1.0kg [ body weight of the small animal to be treated ], preferably 0.1-0.15ml/1.0kg [ body weight of the small animal to be treated ].

They are particularly suitable for filling and for sale in containers which are subject to stringent storage conditions, such as "single-dose polypropylene plastic tubes" having a tube wall thickness of 300-.

The agents of the invention are further characterized by being skin-friendly and having only minimal toxicity.

Finally, they are environmentally friendly due to biodegradability.

Detailed Description

Example (b):

example 1

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

10g Imidacloprid (1- [ (6-chloro-3-pyridyl) methyl ] -N-nitro-2-imidazolidinium salt) manufactured by Bayer AG

44.8g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT (butylhydroxytoluene)

Example 2

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

10g Imidacloprid

40.8g N-Methylpyrrolidone

4.0g of water

0.1g citric acid

0.1g BHT

Example 3

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

10g of Ti435, Chlorhianidine Takeda AG

44.8g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT

Example 4

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

10g of Diacloden (Thiamethoxam) by Novartis AG

44.8g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT

Example 5

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

7.5g imidacloprid

43.3g N-Methylpyrrolidone

4.0g of water

0.1g citric acid

0.1g BHT

Example 6

The homogeneous drop solution consisted of

47.5g permethrin with 40% cis and 60% trans isomer composition

10.0g imidacloprid

38.3g N-Methylpyrrolidone

4.0g of water

0.1g citric acid

0.1g BHT (butylhydroxytoluene)

Example 7

The homogeneous drop solution consisted of

47.5g permethrin with 40% cis and 60% trans isomer composition

10g Imidacloprid

42.3g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT

Example 8

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

8g Imidacloprid

46.8g N-Methylpyrrolidone

0.1g lactic acid

0.1g BHT

Example 9

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

8g Imidacloprid

46.8g N-Methylpyrrolidone

0.1g lactic acid

0.1g of butylhydroxyanisole

Example 10

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

10g Imidacloprid (1- [ (6-chloro-3-pyridyl) methyl ] -N-nitro-2-imidazolidinium salt) manufactured by Bayer AG

39.8g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT (butylhydroxytoluene)

5.0g of Miglyol812 from Sasol Germany GmbH, D-58453Witten

Example 11

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

10g Imidacloprid

35.8g N-Methylpyrrolidone

4.0g of water

0.1g citric acid

0.1g BHT

5.0g of Miglyol 840 from Sasol, GmbH, D-58453Witten, Germany

Example 12

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

10g of Ti435, Chlorhianidine Takeda AG

39.8g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT

5.0g tetrahydrofurfuryl alcohol

Example 13

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

10g of Diacloden (Thiamethoxam) by Novartis AG

39.8g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT

5.0g tetrahydrofurfuryl ethoxylate

Example 14

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

7.5g imidacloprid

40.0g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT

3.3g Miglyol 812

Example 15

The homogeneous drop solution consisted of

47.5g permethrin with 40% cis and 60% trans isomer composition

10.0g imidacloprid

33.8g N-Methylpyrrolidone

4.0g of water

0.1g citric acid

0.1g BHT (butylhydroxytoluene)

5.0g Miglyol 812

Example 16

The homogeneous drop solution consisted of

47.5g permethrin with 40% cis and 60% trans isomer composition

10g Imidacloprid

34.3g N-Methylpyrrolidone

0.1g citric acid

0.1g BHT

4.0g tetrahydrofurfuryl alcohol

4.0g Miglyol 812

Example 17

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

8g Imidacloprid

40.8g N-Methylpyrrolidone

0.1g lactic acid

0.1g BHT

6.0g tetrahydrofurfuryl alcohol

Example 18

The homogeneous drop solution consisted of

45g permethrin with 40% cis and 60% trans isomer composition

8g Imidacloprid

42.8g N-Methylpyrrolidone

0.1g lactic acid

0.1g of butylhydroxyanisole

4.0g diethylene glycol monoethyl ether

A. Action on fleas on dogs

Ctenocephalides felis

Approximately 100 adult, starved Ctenocephalides felis were infected per dog on days-4 and-1. And removing fleas on the neck of the animal.

The dogs were checked for infection on day 0 by seeking fleas on conscious animals. The number of fleas alive was recorded.

The animals were treated after flea inventories. The dogs in the control group were not treated. The agents of examples 1 to 18 to be tested were applied to the skin of the dogs as drops in an amount of 0.1ml/kg body weight. Only once on day 0. And only clinically healthy animals were used.

All dogs were examined for live fleas on day 1. The results are recorded in the raw data.

Approximately 100 adult, starved Ctenocephalides felis were reinfected on days 7, 14, 21 and 28 per dog. Fleas were checked on all dogs the day after each re-infection. The results are recorded in the raw data.

The formulation can be considered as highly efficacious if the therapeutic effect determined on day 1 and the next day after re-infection in each case is > 95% and the effect lasts at least 3-4 weeks.

To calculate the effect, a revised Abbott formula can be used:

the effect is [ ([. phi. ] flea figure KG-. phi. ] flea figure BG)/. phi. ] flea figure KG ]. times 100

KG: control group

BG: treatment group

If the agents of formulation examples 1-18 were used in spot-on form at a dose of 0.1ml/kg, the data demonstrates a high effect on Ctenocephalides felis.

B. Effect on ticks on dogs

Dogs were hypnotized on days-1 and-4 each with 2% Rompun  (Bayer AG, active: selazine hydrochloride) (0.1ml/kg body weight). After all dogs had been hypnotized (approximately 10-15 minutes elapsed), they were transferred to a shipping box and 50 rhipicephalus sanguineus per dog (25 female, 25 male) were extracted on the animal neck. After about 1.5 hours the animals were again removed from the transport boxes and placed in cages.

The dogs were checked for infection on day 0 by looking for fleas on conscious animals. These ticks were found to be concentrated on the head and ears, including the folds of the ears, the nape area, the lower abdomen, under the chest, the lateral flanks, and between the toes and on the extremities. The number of caught, living ticks was recorded. Dead ticks were removed.

Dogs were treated after tick counting. The dogs in the control group were not treated. The agent to be tested is applied to the skin of the dog in the form of a spot. Only once on day 0. And only clinically healthy animals were used.

All dogs were examined for live and dead adsorbed ticks on days 1 and 2. The results are recorded in the raw data. All live and dead ticks were removed from the dogs on day 2.

The dogs were reinfected with approximately 50 rhipicephalus sanguineus ticks (25 female, 25 male) per dog on days 7, 14, 21 and 28, respectively. Live and dead adherent ticks were checked on all dogs, one and two days after re-infection, respectively. The results are recorded in the raw data. The next day after reinfection all live and dead ticks were removed from the dogs.

The formulation can be considered as highly efficacious if the therapeutic effect determined on 2 days and the respective second day after re-infection is > 90% and the effect lasts at least 3 weeks.

To calculate the effect, a revised Abbott formula can be used:

effect% (% phi tick number KG-phi tick number BG)/phi tick number KG ] × 100

KG: control group

BG: treatment group

If the agents of formulation examples 1 to 18 were used in the form of drops at a dose of 0.1ml/kg, the data demonstrate a high effect on rhipicephalus sanguineus.

Flea and tick action Effect after C.6 weeks

The effect of the agents of the invention on fleas and ticks was tested after 6 weeks. The test was carried out as described in the above two sections A and B.

TABLE 1 flea and tick Effect of the agent according to example 10

Test No	Experimental design/use bodyProduct 0.1ml/kg	Flea effect (geometric mean)/tick effect (geometric mean) after 1-2 days of treatment	Flea effect (geometric mean)/tick effect (geometric mean) after 1 week of treatment	Flea effect (geometric mean)/tick effect (geometric mean) after 2 weeks of treatment	Flea effect (geometric mean)/tick effect (geometric mean) after 3 weeks of treatment	Flea effect (geometric mean)/tick effect (geometric mean) after 4 weeks of treatment	Flea effect (geometric mean)/tick effect (geometric mean) after 5 weeks of treatment	Flea effect (geometric mean)/tick effect (geometric mean) after 6 weeks of treatment
									1	Ctenocephalides felis/Rhipicephalus sanguineus	100％/87.2％	100％/89.9％	100％/89.9％	95.3％/97.6％	95.9％/91.4％	90.6％/85.5％	92.3％/83.6％
2	Ctenocephalides felis/Oreodactylus americanus	100％/38.9％	100％/100％	100％/100％	99.7％/100％	99.0％/50.0％	96.3％/92.8％	99.0％/50.0％
									3	Ctenocephalides felis/Rhipicephalus sanguineus	100％/67.0％	100％/95.9％	99.8％/96.8％	98.9％/94.1％	94.5％/85.0％	68.1％/80.0％

Claims (7)

1. Composition of containing

a) 35-60% by weight of permethrin as active substance

b)2.5-12.5 wt% imidacloprid or imidacloprid analog

c) 27.5-62.5% by weight N-methylpyrrolidone

d)0-5 wt% water

e) 0-0.5% by weight of phenolic antioxidants and

f)0-0.5 wt% of an organic acid.

2. The composition according to claim 1, further comprising

g)2.5-10 wt% co-solvent.

3. A method for the preparation of a composition according to claim 1 or 2, characterized in that permethrin and imidacloprid or imidacloprid-analogue are mixed with stirring with the remaining ingredients listed in claim 1 or 2 and made into a solution.

4. Use of a composition according to claim 1 or 2 for inhibiting parasites on an animal.

5. Use according to claim 4 for the inhibition of ticks and/or fleas on warm-blooded animals.

6. Use according to claim 5 for inhibiting ticks and/or fleas on dogs.

7. Use according to claim 5 for inhibiting ticks and/or fleas on cats.