IE832793L - Synergistic anthelmintic composition. - Google Patents

Description

■» tj *s* a $ z 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 5 and nedatodes, 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 substances forming the 10 combination. The active-substance combinations according to the invention comprise the following individual active substances: a comoound of the formula I \ (1) r wherein n is zero or 1, and the compound of the formula II 3 C£Hs \_/~V (ID, 6 5-_A.s- including che isomers thereof as well as the addition salts thereof embraced by the formula II.

The compounds described in the foregoing as active-5 substance components of the compositions according to the invention are known individually as being compounds having anthelmintic activity. Compounds of the formula I are described for example in the German Offenlegungsschrift No. 2,815,621, and the compound of the formula II in 10 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. 3,2, 545 (1971).

The combination of different chemical compounds to 15 produce a synergistic intensification of activity for controlling pests is gaining to an increasing extent in importance because of the possibility the combination offers for effectively counteracting the ever more frequent appearance of resistance of parasites to individual 20 compounds. Consequently, the normally necessitated increase in the amounts of active substance used to overcome this build-up of resistance of the parasites can largely be avoided. The"resulting saving in the amounts of active substance applied has both economic and, by virtue of a 25 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 be tolerated or even a reduction in the dose applied, with which is simultaneously associated a lowering of ehi- level of intoxication of the treated animals, with the result that their effective output during the treatment is not impaired.

Helminthic diseases among domestic animals and 5 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 10 flukes (for example Fasciola hepatica and Fasciola gigantlca), 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 15 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 of the numerous known preparations in the field covering the control of 20 helminths, it has hitherto not been possible to develop active substances which, in addition to having good general anthelmintic properties, exhibit a satisfactory-action against adult and juvenile Fasciola genera in sheep and cattle, while simultaneously 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 comprise a compound of the formula I and the compound of the formula II, display a high level of anthelminthic activity, having not 30 only a wide spectrum of activity against nematodes and trematodes, but also a very strongly marked action against Fasciola hepatica in sheep. To be e=phasised as being particularly advantageous is the fact that the active- substance combinations on which the compositions according to the invention ere based have, even in very small doses, a total action against liver flukes in sheep, so that side-effects, which could result in an impairment 5 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 greater than 10 the additive action of the individual compounds forming the combinations. Furthermore, the broad spectrum of activity induced by the composition specific to the invention is of particular advantage. The animals affected by helminthiasis can thus be treated by a single 15 administration of an active-substance combination according to the invention simultanepusly both for nematodes and for trematodes of all development stages. -Included also are in particular those nematode strains which show resistance to thiabendazole (2-14-thiazolyl]-20 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-methylthio-25 benzimidazole with B) L-(-)-2,3,5,6-tetrahydro-6-phenylimidazo{2,l-bJthiazale ("Levamisol") .

The applicable weight ratios of compounds of the formula 1 to the compound of the formula II for the active-substance combinations according to the present 30 invention are within the range of 1:5 to 5:1. The combination ratio of 1:5 to 1:1 is particularly favourable for bringing into effect the synergistic action. The 6 amount to be used of the compound of the formula I is preferably below 6 ng of active substance (AS) /kg of body, weight.

The anthelmintic action of the inventive active-5 substance combinations of compounds of the formula I with the compound of the formula 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. For this purpose, the metacercaria are injected, in a 0.4% aqueous suspension of carboxy-methyl cellulose, directly into the rumen of the test animals. The sheep are simultaneously orally infested 15 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, 20 in which the proportion of active substance of the . formula I is 2-5 mg/kg and the proportion of active substance of the formula 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. 25 In order to test the action of che individual active- substance combinations, a count is made, using a standard technique, at specific intervals of time after infestation and medication, of the helminth eggs excreted with the faeces. The test animals are subsequently killed and the 30 number of adult helminths present is determined.

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

Results: The active-substaacs combinations on which the compositions according to the invention are based are 95-lOOZ effective against Fasciola hepatica. The action 5 of these combinations in comparable or even lower doses is therefore significantly above the additive action of the individual compounds forming the combinations.

After administration of the therapeutically effective doses of the active-substance combinations, clinical 10 tests reveal no toxicity symptoms in the test animals; and these animals have moreover a healthy appearance. 8 Example: Comparative test results Indication: Fasciola hepatica Hvnnber of test animals (sheep): 19 Sheep No.

Substance or mixture of substances (dose mg/kg) EPG (Adult helminths 12th week* 13th weefr number mean value tfonC" in % 1 2 3 4 I (2,5) 210 160 120 20 130 160 180 15 sa 65 51 20 48,5 32.7 . 6 7 S II (6,75) 990 160 226 225 1140 250 250 810 108 71 89 103 92.8 9.6 9 11 12 I + II (2.5 + 6,75) 0 170 0 0 0 210 50 30 3 43 19 27 23,0 77,6 13 14 [6 : 7 18 19 untreated control animals 710 400 1290 580 860 570 600 680 670 1270 660 850 410 1450 99 60 113 130 99 110 , 116 102,5 X Substance I: 5-chloro-6-(2',3'-dichlorophensy.y)-2-methyI- thiobenzimidazole, Substance II: L-(-)-2,3,5,6-tetrahydro-6-phenylimidazo-12,1-bl-thiazole ("Levamisol").

EPG: number of eggs per gram of faeces * after infestation 9 The active-substance combinations according co 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 1 5 either in single doses to the animals, or in repeated dosesi, the single doses being, depending on the species I 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 10 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 contains the active-substance combinations preferably at a concentration of 0.005 to 0.1 X by weight. The compositions can be 15 administered to the animals perorally in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boluses or capsules. These preparations are prepared by the use for example of customary solid carriers, such as kaolin, talcum, bentonite, sodium chloride, calcium 20 phosphate or cottonseed meal, or by the use of liquids that do not react with the active substances, such as oils and other solvents and diluents harmless to the animal organism. Provided that the physical and toxicological properties of solutions or emulsions permit it, the active-substance 25 combinations can be also injected ir.co the animals for example subcutaneously, or can be applied by means of the pour-on-method. Furthermore, administration of the 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. The feed can contain, in addition to the active substances, also additives, vitamins, antibiotics, chemotherapeutical agents, or other pesticides, chiefly bacteriostatics, fungistatics, coccidiostatics, and also hormone preparations, substances having anabolic » activity, or other substances promoting growth, affecting the quality of the meat of slaughter cattle, or being in ' some other way beneficial for the organism. They can also be combined with insecticides and acaricides, by virtue of which the action of the compositions is broadened and 10 adapted to suit the given circumstances.

The anthelmintic compositions according to the invention are produced in a manner known per se by the intimate mixing and grinding of the active-substance combinations, comprising compounds of the formula 1 15 and the compound of the formula II, with suitable carriers, optionally 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 concentrates of active substance (wettable powder).

Liquid preparations: solutions, pastes, emulsions, particularly ready-for-use suspensions (drenches). f The particle size of the 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 combinations in the solid preparations is 0.5 to 80%, and 0.5 to 50% 11 in che liquid preparations■ To these mixtures can also be added additives stabilising the active-substance combinations, and/oc nonionlc, anionic and cationic substances, which ensure for example better wettability (wetting agents) and dispersibility (dispersing agents).

Example Waterrdisperslble powder mixture. parts by weight o£ an active-substance combination, of compounds of the formula I with the compound of the formula II are thoroughly mixed, in a mixer, with 7.5 parts by weight of an absorbent carrier, for example silicic acid, 59.4 parts by weight of a carrier, for example bolus alba or kaolin, 0.5 part by weight of oleic acid, .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 ^un. The wettable powder thus obtained gives a good suspension in water. 13

Claims (7)

CLAIMS:

1. A synergistic composition for controlling parasitic helminths, which composition contains as active component ' an active-substance combination comprising ac lease one 5 compound of the formula Z i wherein n is zero or 1, and the compound of the formula II °<\AA ("J. Li—i 10 including the isomers thereof, as well as the addition salts thereof, embraced by the formula IIf cogether with suitable carriers and/or dispersing and dilucing agencs.

2. A composition according to Claim 1 for controlling parasitic helminths, which contains as active component 15 an active-substance combination comprising 5-chloro-6-(2*,31-dichlorophenoxy)-2-methylthiobenzimidazole and;L-(-)-3,3,5,6.-tetrahydro-6-phenylimidazo[2, l-b]-thiazole,;y* cogecher with suitable carriers and/or dispersing and 20 diluting agents. ^

3. A composition according to Claim 1 or 2, wherein che weight racio of compounds of che formula I to che compound of the formula 11 in the active-substance combination is 1:5 co 5:1

4. A composition according to Claim 1 or 2, wherein the weight ratio of compounds of che formula I co che compound of the formula II in the active-substance conbination is 1:5 to 1:1.

5. A composition according to any one of Claims 1-4 for controlling trematodes.

6. A composition according to any one Qf Claims 1-4 for controlling liver flukes (Fasciola hftpatica).

7. A synergistic composition according to Claim 1 substantially as hereinbefore described with reference to the foregoing Example. F.R. KELLY & CO., AGENTS FOR THE APPLICANTS.