GB2124904A

GB2124904A - Synergistic anthelmintic compositions

Info

Publication number: GB2124904A
Application number: GB08320650A
Authority: GB
Inventors: Joseph Coleman Boray
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1982-08-13
Filing date: 1983-08-01
Publication date: 1984-02-29
Also published as: GB8320650D0; AU1792783A; ES8502610A1; DE3379497D1; JPS5948420A; ZA835956B; EP0101412A2; NL930087I1; ES524897A0; JPH0347250B2; EP0101412A3; GB2124904B; AU567299B2; NZ205238A; EP0101412B1

Description

SPECIFICATION Anthelmintics The present invention relates to novel synergistic anthelmintic compositions containing as active component an active-substance combination, and to the use of these compositions for controlling helminths, particularly trematodes and nematodes, in domestic animals and in productive animals.

The active-substance combinations on which the compositions according to the invention are based have an unexpected synergistic activity exceeding in a very advantageous manner the additive effect of the individual active substancesforming thecombina- tion. The active-substance combinations according to the invention comprise the following individual active substances: a compound oftheformula I

wherein n is zero or 1, and the compound oftheformula II

including the isomers thereof as well as the addition salts thereof embraced by the formula II.

The compounds described in the foregoing as active-substance components ofthe compositions according to the invention are known individually as being compounds having anthelmintic activity. Com poundsoftheformula I are described for example in the German Offenlegungsschrift No.2,815,621, and the compound oftheformula II in the U.S. Patent Specifications Nos. 3,274,209,3,565,907 and 3,579,530, in the French Patent Specification No.

1,544,972, in Tetrahedron Letters 1967,1467, and in Am. Journ. Vet. Res. 32,545(1971).

The combination ofdifferentchemical compounds to produce a synergistic intensification of activity for controlling pests is gaining to an increasing extent in importance because of the possibilitythe combination offersforeffectively counteracting the ever more frequent appearance of resistance of parasites to individual compounds. Consequently, the normally necessitated increase in the amounts of active substance used to overcome this build-up of resistance ofthe parasites can largely be avoided. The resulting saving in the amounts of active substance applied has both economic and, by virtue of a lessening of environmental contamination, significant ecological advantages.In the administration of anthelmintics to productive animals, this can mean a continuance of the applied dose that can betolerated or even a reduction in the dose applied, with which is simultaneously associated a lowering ofthe level of intoxication ofthetreated animals, with the result that heir effective output during the treatment is not impaired.

Helminthic diseases among domestic animals and productive animals are widespread as is well known, and these diseases lead to a reduction in the growth and in the output of the affected animals, and in many cases even result in their death. A particularly dangerous helminthic disease is Fasciolose, which is caused by parasitic liver flukes (for example Fasciola hepatica and Fasiola gigantica), and which occurs especially in ruminants, such as sheep and cattle. The losses attributable to this helminthic disease can assume considerable proportions, particularly when this disease occurs in epidemic form in herds of cattle. The control and prevention of Fasciolose are therefore considered a matter of urgency in order that such, above all economically grave, losses in animal production may be avoided.In spite ofthe numerous known preparations in the field covering the control of helminths, it has hitherto not been possible to develop active substances which, in addition to having good general anthelminthic properties, exhibit a satisfactory action against adult and juvenile Fasciola genera in sheep and cattle, while simul taneously having low toxicity.

It has now been found that the active-substance combinations which are contained in the compositions according to the invention, and which comprised a compound oftheformula I andthe compound of the formula II, display a high level of anthelminthic activity, having not only a wide spectrum of activity against nematodes and trematodes, but also a very strongly marked action against Fasciola hepatica in sheep.To be emphasised as being particularly advantageous is the fact that the active-substance combinations on which the compositions according to the invention are based have, even in very small doses, a total action against liverflukes in sheep, so that side-effects, which could result in an impairment of the development and of the effective output of the treated animals during the period of treatment, are avoided by virtue of small doses. The action of the active-substance combinations according to the invention against Fasciola hepatica is significantly greaterthan the additive action of the individual compounds forming the combinations. Furthermore, the broad spectrum of activity induced by the composition specifictothe invention is of particular advantage.The animals affected by helminthiasis can thus be treated by a single administration of an active-substance combination according to the invention simultaneously both for nematodes and for trematodes of all development stages. Included also are in particularthose nematode strains which show resistance to thiabendazole(2 - [4 - thiazolyl] - benzimidazole), and in some cases also to other benzimidazole derivatives.

The following combination is to be regarded as being preferred: A) 5-chloro-6- (2',3'-dichlorophenoxy) -2- methylthiobenzimidazole with B) L- (-) -2,3,5,6 -tetrahydro 6 - phenylimidazo[2,1 -b]thiazole("Levamisol").

The applicable weight ratios of compounds ofthe formula I to the compound oftheformula II for the active-substance combinations according to the present invention are within the range of 1:5 to 5:1. The combination ratio of 1:5 to 1:1 is particularlyfavour- able for bringing into effectthe synergistic action.

The amount to be used of the compound ofthe formula I is preferably below6 mg ofactivesubstance (AS)Ikg of body weight.

The anthelmintic action of the invention activesubstance combinations of compounds of the formu- la I with the compound oftheformula II is demonstrated by the following test.

Test on sheep infested with Fasciola hepatica and nematodes Sheep are artificially infested with metacercaria of Fasciola hepatica. Forthis purpose, the metacercaria are injected, in a 0.4% aqueous suspension of carboxymethyl cellulose, directly into the rumen of the test animals. The sheep are simultaneously orally infested each with 10,000 and 5,000 infectious larvae (L 3) of benzimidazole-resistant Trichostrongylus colubriformis and Haemonchus contortus, respectively. The animals are divided for medication into equally large groups and one control group. The active-substance combinations, in which the proportion of active substance of the formula I is 2-5 mgAcSy and the proportion of active substance of the formZa II is 3-7 mg/kg, are subsequently administered to the test animals.The sheep are kept during the test under normal conditions in paddock boxes. In order to test the action of the individual active-substance combinations, a count is made, usmg a standard technique, at specific intervals of time after infestation and medication, ofthe helminth eggs excreted with the faeces. The test animals are subsequently killed and the number of adult helminths present is determined.

The results provided by the medicated groups and the control group are compared forthe purpose of making an evaluation.

Results: The active-substance combinations on which the compositions according to the invention are based are 95-100% effective against Fasciola hepatica. The action ofthese combinations in comparable or even lower doses is therefore significantly above the additive action ofthe individual compounds forming the combinations.

After administration ofthe therapeutically effective doses of the active-substance combinations, clinical tests reveal no toxicity symptoms in the test animals; and these animals have moreover a healthy appearance.

Example: Comparative test results Indication: Fasciola hepatica Numberoftestanimals(sheep): 19

Sheep Substance or EPIC Adult helminths Mo. mLx of of substances 12th week*113th number (b l uc :dosemg/kg) 1 58 1 210 130 58 2 I (2,5) 160 1860 65 48,5 52,7 120 180 51 20 15 20 5 990 6 11 (6.75) 160 92.8 9.6 226 225 103 0 0 3 LO I+IZ(2,5+ 170 210 43 23,0 LZ 6.75) 0 50 . 19 177.6 13 710 680 99 14 400 670 60 15 untreated 1290 1270 113 16 control 580 660 130 1 102,6 animals 860 850 99 18 570 410 110 19 600 1450 116 KeV Substance I: 5-chloro-6-(2',3'-dichlorophenoxy)-2-methyl- thiobenzimidazole, Substance II: L-(-)-2,3,5, 6-tetrahydro-6-phenylimidazo- [2,1-b]-thiazole ("Levamisol") .

EPG: number of eggs per gram of faeces * after infestation The active-substance combinations according to the invention are used to control parasitic helminths in domestic animals and productive animals, such as cattle, sheep and goats. The combinations can be administered either in single doses to the animals, or in repeated doses, the single doses being, depending on the species of animal, between 0.5 and 7.5 mg per kg of body weight. A better effect can be obtained in some cases by a protracted administration, or smaller complete doses may suffice. The active substances or the mixtures containing them can also be added to the feed or be introduced into drinking troughs.The finished feed containsthe active-substancecombina- tions preferably at a concentration of 0.005 to 0.1 % by weight. The compositions can be administered to the animals perorally in theform of solutions, emulsions, suspensions (drenches), powders, tablets, boluses or capsules. These preparations are prepared bythe use for example of customary solid carriers, such as kaolin, talcum, bentonite, sodium chloride, calcium phosphate or cottonseed meal, or bythe use of liquidsthat do not react with the active substances, such as oils and other solvents and diluents harmlesstothe animal organism.Provided thatthe physical and toxicological properties of solutions or emulsions permit it, the active-substance combinations can be also injected into the animals for example subcutaneously, or can be applied by means of the pour-on-method. Furthermore, administration ofthe active substances to the animals is also possible by means of licking stones (salt) or molasses blocks.

When the anthelmintic compositions are in the form of feed concentrates, the main carriers used are feed materials, such as hay, production feed,fodder grain or protein concentrates. Thefeed can contain, in addition to the active substances, also additives, vitamins, antibiotics, chemotherapeutical agents, or other pesticides, chiefly bacteriostatics, fu ngistatics, coccidiostatics, and also hormone preparations, substances having anabolic activity, or other substances promoting growth, affecting the quality ofthe meat of slaughter cattle, or being in some otherway benefi cialfortheorganism.Theycan also be combined with insecticides and acaricides, by virtue of which the action ofthe compositions is broadened and adapted to suitthe given circumstances.

The anthelmintic compositions according to the invention areproduced in a mannerknown peruse by the intimate mixing and grinding ofthe active substance combinations, comprising compounds of theformula landthecompoundoftheformulall,with suitable carriers, optionaily with the addition of dispersing agents or solvents which are all inert to the active substances.

The anthelmintic compositions according to the invention can be used for example in the following preparations: Solid preparations: granulates (coated granules, impregnated granules and homogeneous granules); water-dispersible con centrates of active substance (wettable powder).

Liquid preparations: solutions, pastes, emulsions, particularly ready-for use suspensions (drenches).

The particlesize ofthe carriers is advantageously up to about 0.1 mm for dusts and wettable powders, and 0.01 -0.5 mm for granulates.

The concentration of the active-substance com binations in the solid preparations is 0.5 to 80%, and 0.5 to 50% in the liquid preparations.

To these mixtures can also be added additives stabilising the active-substance combinations, and/or nonionic, anionic and cationic substances, which ensure for example betterwettability (wetting agents) and dispersibility (dispersing agents).

Example Water-dispersible powder mixture 25 parts by weight of an active-substance combina tion ofcompoundsoftheformula I with the com pound oftheformula ll are thoroughly mixed, in a mixer, with 7.5 parts by weight of an absorbentcarrier,for example silicic acid, 59.4 parts by weight of a carrier, for example bolus alba or kaolin, 0.5 part byweightofoleic acid, 5.3 parts by weight of octylphenylpolyglycol ether, and 2.3 parts by weight of a stearyl-benzimidazole derivative.

This mixture is ground in a dowelled disk mill or an air-jet mill until the particle size is 5-15 um. The wettable powderthus obtained gives a good suspension in water.

Claims

1. Asynergisticcompositionforcontrolling parasitic helminths, which composition contains as active component an active-substance combination comprising at least one compound ofthe formula I

wherein niszeroorl, and the compound of the formula II

including the isomers thereof, as well as the addition salts thereof, embraced by the formula 11, together with suitable carriers and/or dispersing and diluting agents.

2. A composition accordingto Claim 1 forcontrolling parasitic helminths, which contains as active component an active-substance combination comprising 5-chloro-6-(2',3'- dichlorophenoxy)-2methylthiobenzimidazole and L- (-) - 2,3,5,6 -tetrahydro - 6 - phenylimidazo[2,1 - b] - thiazole, together with suitable carriers and/or dispersing and diluting agents.

3. A composition according to Claim 1 or2, wherein the weight ratio of compounds of the formula I to the compound ofthe formula II in the active-substance combination is 1 :5to 5:1.

4. Acomposition according to Claim 1 or2, wherein the weight ratio of compounds of the formula ltothe compound oftheformula II in the active-substance combination is 1 :5to 1:1.

5. Acomposition according to any one of Claims 1 4for controlling trematodes.

6. Acomposition according to any one of Claims 14forcontrolling liverfiukes (Fasciola hepatica).

7. A method of controlling parasitic helminths, which method comprises treating the host animal with an effective amount of an active-substance combination according to any one of Claims 14.

8. A method according to Claim 7 wherein the helminths are trematodes.

9. A method according to Claim 7 wherein the helminthsareliverflukes (Fasciola hepatica).

10. A method according to Claim 7, wherein the proportion ofthe compound ofthe formula I in the active-substance combination is less than 6 mg of ASikg of body weight.

11. Asynergisticcomposition according to Claim 1 substantially as hereinbefore described with refer encetotheforegoing Example.