Combination product for controlling parasites on animals

Abstract

The invention relates to novel compositions for controlling parasites on animals, comprising an N-arylpyrazole and also a pyrethroid in a formulation comprising aliphatic cyclic carbonates and aliphatic cyclic or acyclic polyethers.

Claims

1. A composition for controlling parasites on animals, comprising: a. fipronil; b. phenothrin; c. an aliphatic cyclic carbonate; and d. an aliphatic cyclic or acyclic polyether.

2. The composition of claim 1, further comprising an ester of a dihydric or trihydric alcohol having up to three carbon atoms with organic fatty acids having 6 to 18 carbon atoms.

3. The composition of claim 1, wherein the fipronil is present in an amount of from 1 to 27.5% by weight of the composition.

4. The composition of claim 1, wherein the aliphatic cyclic carbonate is present in an amount of from 10 to 70% by weight of the composition.

5. The composition of claim 1, wherein the aliphatic cyclic or acyclic polyether is present in an amount of from 20 to 77.5% by weight of the composition.

6. The composition of claim 1, wherein the fipronil is present in an amount of from 7.5 to 15% by weight of the composition.

7. The composition of claim 1, wherein the cyclic carbonate is selected from the group consisting of ethylene carbonate, propylene carbonate, and mixtures thereof.

8. The composition of claim 1, wherein the aliphatic cyclic carbonate is present in an amount of from 15 to 40% by weight of the composition.

9. The composition of claim 1, wherein the aliphatic cyclic or acyclic polyether is selected from the group consisting of diethylene glycolmonoethyl ether, diethylene glycol monopropyl ether, dipropylene glycol monopropyl ether, and tetrahydrofurfuryl alcohol.

10. A composition for controlling ticks on dogs, comprising: a. fipronil; b. phenothrin; c. propylene carbonate; and d. dipropylene glycol monomethyl ether.

11. A method of controlling ticks on an animal, which comprises applying to said animal an effective amount of the composition of claim 10.

12. The composition of claim 1, wherein the phenothrin is present in an amount of from 20 to 70% by weight of the composition.

13. The composition of claim 10, wherein the phenothrin is present in an amount of from 20 to 70% by weight of the composition.

Description

EXAMPLES

Example 1

(1) 100 ml of liquid formulation consisting of 10.0 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 57.30 g of diethylene glycol monoethyl ether 0.10 g of BHT 0.20 g of BHA 30.02 g of propylene carbonate 5.00 g of propylene glycol octanoate decanoate 0.24 g of flumethrin 10.36 g of MGK 264 0.02 g of citric acid

Example 2

(2) 100 ml of liquid formulation consisting of 10.00 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 0.24 g of flumethrin 0.02 g of citric acid 0.20 g of BHT 68.00 g of dipropylene glycol monomethyl ether 13.40 g of propylene carbonate 5.00 g of demineralized water 5.00 g of propylene glycol octanoate decanoate 5.00 g of MGK 264

Example 3

(3) 100 ml of liquid formulation consisting of 10.00 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 0.50 g of PPF (pyriproxyfen) 0.24 g of flumethrin 0.02 g of citric acid 0.20 g of BHT 67.50 g of dipropylene glycol monomethyl ether 13.40 g of propylene carbonate 5.00 g of demineralized water 5.00 g of propylene glycol octanoate decanoate 5.00 g of MGK 264

Example 4

(4) 100 ml of liquid formulation consisting of 10.00 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 0.50 g of PPF (pyriproxyfen) 0.24 g of flumethrin 0.02 g of citric acid 0.20 g of BHT 60.90 g of diethylene glycol monoethyl ether 20.00 g of propylene carbonate 5.00 g of demineralized water 5.00 g of propylene glycol octanoate decanoate 5.00 g of MGK 264

Example 5

(5) 100 ml of liquid formulation consisting of 10.00 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 45.00 g of permethrin 37.90 g of diethylene glycol monoethyl ether 0.10 g of BHT 0.20 g of BHA 25.00 g of propylene carbonate 5.00 g of propylene glycol octanoate decanoate 0.02 g of citric acid

Example 6

(6) 100 ml of liquid formulation consisting of 10.00 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 45.00 g of permethrin 1.00 g of PPF 36.90 g of diethylene glycol monoethyl ether 0.10 g of BHT 0.20 g of BHA 25.00 g of propylene carbonate 5.00 g of propylene glycol octanoate decanoate 0.02 g of citric acid

Example 7

(7) 100 ml of liquid formulation consisting of 10.00 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 45.00 g of permethrin 1.00 g of PPF 0.25 g of Silvet L 77 from GE Siliconocs GmbH D-51368 Leverkusen 36.65 g of diethylene glycol monoethyl ether 0.10 g of BHT 0.20 g of BHA 25.00 g of propylene carbonate 5.00 g of propylene glycol octanoate decanoate 0.02 g of citric acid

Example 8

(8) 10.00 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 45.00 g of permethrin 1.00 g of PPF 0.25 g of Silvet L 77 (from Bayer-GE Silicones GmbH, D-51368 Leverkusen) 36.65 g of diethylene glycol monoethyl ether 0.10 g of BHT 0.20 g of BHA 25.00 g of ethylene carbonate 5.00 g of propylene glycol octanoate decanoate 0.02 g of citric acid

Comparative Example 1

(9) A commercially available 10% fipronil spot-on formulation from Merial Ltd., 3239 Satellite Blvd., Duluth, Ga. 30096-4640, USA.

Comparative Example 2

(10) A formulation comprising 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-thiocarbamoylpyrazole, but without added flumethrin or MGK264: 100 ml of liquid formulation consisting of 10.00 g of 5-amino-4-trifluoromethylsulphinyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-thiocarbamoylpyrazole 57.7 g of diethylene glycol monoethyl ether 40.0 g of propylene carbonate 5.0 g of propylene glycol octanoate decanoate 0.1 g of butylated hydroxytoluene 0.2 g of butylated hydroxyanisole

Comparative Example 3

(11) A formulation comprising flumethrin and MGK264 and PPF, but, instead of the 3-thiocarbamoylpyrazole mentioned in the application, the known insecticide imidacloprid. 100 ml of liquid formulation consisting of 10.00 g of imidacloprid 0.50 g of PPF 56.80 g of benzyl alcohol 0.10 g of BHT 0.20 g of BHA 30.02 g of propylene carbonate 5.00 g of propylene glycol octanoate decanoate 0.24 g of flumethrin 10.36 g of MGK 264 0.02 g of citric acid

Biological Examples

(12) All compounds were metered out exactly by weight to ensure better comparability. To this end, 20 pipettes of the fipronil-containing commercial preparation were emptied into a glass bottle and likewise blinded using a code.

(13) All samples were applied as a single spot to the neck (cats and smaller dogs) using Eppendorf pipettes (volume up to 0.95 ml). For application volumes of more than 1 ml, the volume was halved and applied to the neck as two spots at a distance of about 10 cm.

(14) Further laboratory tests for the activity against fleas and ticks according to Example 2 show that the preparations in the abovementioned formulations according to the invention have very good and long-lasting action against ticks and fleas which, in the tests, is consistently superior to the prior art (CE1-CE3). Furthermore, the preparations in the abovementioned formulations according to the invention are distinguished in that they are tolerated by target animal and user, and they are thus highly suitable for controlling fleas and ticks on small animals.

(15) A. Activity Against Fleas (Ctenocephalides felis) on Dogs

(16) Between days 4 and 1, dogs are infested 1-2 times with about 100 adult unfed Ctenocephalides felis per dog. The fleas are placed on the neck of the animal. On day 0, the success of the infestation on the dog is examined by checking the awake animal for fleas. The number of live fleas is noted.

(17) After the fleas have been counted, the animals are treated. The dogs of the control group are not treated. The medicaments to be examined are administered to the animals dermally as a spot-on in an application rate of 0.1-0.15 ml/kg of bodyweight or as a spray in an application rate of 1-1.5 ml/kg of bodyweight. The application is carried out once on day 0. Only animals that are clinically healthy are used.

(18) On days 1 and 2, all dogs are examined for live fleas. The results are noted with the crude data.

(19) On days 7, 14, 21, 28 and 35 and, if appropriate, also on days 42 and 49, all dogs are reinfested with about 100 adult unfed Ctenocephalides felis per dog. In each case one day after the reinfestation, all dogs are checked for live fleas. The results are noted with the crude data.

(20) A formulation is considered to be highly effective if, between 24 and 48 hours after reinfestation, an efficacy of >95% is found, and this action persists for at least 3-4 weeks.

(21) The efficacy is calculated using a modified formula according to Abbott:

(22) $\mathrm{Efficacy}\%=\frac{\mathrm{number}\mathrm{of}\mathrm{fleas}\mathrm{CG}-\mathrm{number}\mathrm{of}\mathrm{fleas}\mathrm{TG}}{\mathrm{number}\mathrm{of}\mathrm{fleas}\mathrm{CG}}100$
CG: control group; TG: treatment group

(23) The medicaments of Formulation Example 2, applied as a spot-on at a dosage of 0.15 ml/kg, were found to be highly effective against Ctenocephalides felis.

(24) B. Activity Against Ticks (Rhipicephalus sanguineus, Dermacentor variabilis) on Dogs

(25) Between days 4 and 1, dogs are sedated using 2% Rompun (Bayer AG, active compound: xylazine hydrochloride) (0.1 ml/kg of bodyweight). Once all dogs have been sedated (after about 10-15 minutes), they are transferred to transport boxes, and 50 Rhipicephalus sanguineus or Dermacentor variabilis (25, 25) per dog are applied to the neck of the animal. After about 1 hours, the animals are retransferred from the transport box into the cage.

(26) On day 0, the success of the infestation on the dog is examined by checking the awake animal for ticks. An intensive search is carried out in the region of the head and the ears, including the folds of the ears, in the region of the neck, on the lower abdomen, on the lower breast, on the flank and in between the toes and on the limbs. The number of sucking live ticks is noted. Dead ticks are removed.

(27) After the ticks have been counted, the animals are treated. The dogs of the control group are not treated. The medicaments to be examined are administered to the animals dermally as a spot-on at 0.1-0.15 ml/kg of bodyweight or as a spray at 1-1.5 ml/kg of bodyweight. The application is carried out once on day 0. Only animals which are clinically healthy are used.

(28) On day 1 and day 2, all dogs are checked for living and dead sucking ticks. The results are noted with the crude data. On day 2, all living and dead ticks are removed from the dog.

(29) On days 7, 14, 21, 28, 35 and, if appropriate, also on days 42 and 49, all dogs are reinfested with in each case 50 Rhipicephalus sanguineus or Dermacentor variabilis (25, 25) per dog. In each case two days after the reinfestation, all dogs are checked for living and dead sucking ticks. The results are noted with the crude data. On the second day after the reinfestation, all living and dead ticks are removed from the dog.

(30) A formulation is considered to be highly effective if, on day 2 and in each case on the second day after reinfestation, an efficacy of >90% is found, and this action persists for at least 3 weeks.

(31) For calculating the efficacy, a modified formula according to Abbott is used:

(32) $\mathrm{Efficacy}\%=\frac{\mathrm{number}\mathrm{of}\mathrm{ticks}\mathrm{CG}-\mathrm{number}\mathrm{of}\mathrm{ticks}\mathrm{TG}}{\mathrm{number}\mathrm{of}\mathrm{ticks}\mathrm{CG}}100$
CG: control group; TG: treatment group

(33) The medicaments according to Formulation Example 2, applied as a spot-on at a dosage of 0.15 ml/kg, were found to be highly effective against Rhipicephalus sanguineus.

(34) C. Activity Against Fleas (Ctenocephalides felis) on Cats

(35) On day 1, cats are infested with about 100 adult unfed Ctenocephalides felis per cat. The fleas are placed on the neck of the animal.

(36) On day 0, the success of the infestation on the cat is examined by checking the awake animal for fleas. The number of live fleas is noted.

(37) After the fleas have been counted, the animals are treated. The cats of the control group are not treated. The medicaments to be examined are administered to the animals dermally as a spot-on in an application rate of 0.1-0.15 ml/kg of bodyweight. The application is carried out once on day 0. Only animals that are clinically healthy are used.

(38) On day 2, all cats are examined for live fleas. The results are noted with the crude data.

(39) On days 7, 14, 21, 28 and 35 and, if appropriate, also on days 42 and 49, all cats are reinfested with about 100 adult unfed Ctenocephalides felis per cat. In each case two days after reinfestation, all cats are checked for live fleas. The results are noted with the crude data.

(40) A formulation is considered to be highly effective if, on day 2 and in each case on the second day after reinfestation, an efficacy of >95% is found, and this action persists for at least 3-4 weeks.

(41) The efficacy is calculated using a modified formula according to Abbott:

(42) $\mathrm{Efficacy}\%=\frac{\mathrm{number}\mathrm{of}\mathrm{fleas}\mathrm{CG}-\mathrm{number}\mathrm{of}\mathrm{fleas}\mathrm{TG}}{\mathrm{number}\mathrm{of}\mathrm{fleas}\mathrm{CG}}100$
CG: control group; TG: treatment group

(43) The medicaments of Formulation Example 2, applied as a spot-on at a dosage of 0.15 ml/kg, were found to be highly effective against Ctenocephalides felis.

(44) D. Activity Against Ticks (Ixodes ricinus) on Cats

(45) In each case on day 2, cats are sedated using a mild sedative (acepromazine maleate). Once all cats have been sedated (after about 10-15 minutes), 30-50 Ixodes ricinus (15-25, 15-25) per cat are applied to the neck of the animal.

(46) On day 1, the success of the infestation on the cats is examined by checking the awake animal for ticks. An intensive search is carried out in the region of the head and the ears, in the region of the neck, on the lower abdomen, on the lower breast, on the flank and on the limbs. The number of sucking live ticks is noted. Dead ticks are removed.

(47) After the ticks have been counted, the animals are divided into groups. Treatment is carried out on day 0. The cats of the control group are not treated. The medicaments to be examined are administered to the animals dermally, as a spot-on at 0.1-0.15 ml/kg of bodyweight. Application is carried out once on day 0. Only animals which are clinically healthy are used.

(48) On day 2, all cats are checked for living and dead sucking ticks. The results are noted with the crude data. All living and dead ticks are removed from the cat. On days 7, 14, 21, 28 and 35 and, if appropriate, also on days 42 and 49, all cats are reinfested with in each case 30-50 Ixodes ricinus (15-25, 15-25) per cat. In each case two days after the reinfestation, all cats are checked for living and dead sucking ticks. The results are noted with the crude data. On the second day after the reinfestation, all living and dead ticks are removed from the cat.

(49) A formulation is considered to be highly effective if, on day 2 and in each case on the second day after reinfestation, an efficacy of >90% is found, and this action persists for at least 3 weeks.

(50) For calculating the efficacy, a modified formula according to Abbott is used:

(51) $\mathrm{Efficacy}\%=\frac{\mathrm{number}\mathrm{of}\mathrm{ticks}\mathrm{CG}-\mathrm{number}\mathrm{of}\mathrm{ticks}\mathrm{TG}}{\mathrm{number}\mathrm{of}\mathrm{ticks}\mathrm{CG}}100$
CG: control group; TG: treatment group

(52) The medicaments according to Formulation Example 2, applied as a spot-on at a dosage of 0.15 ml/kg, were found to be highly effective against Ixodes ricinus.

(53) E. Efficacy Against Fleas and Ticks Over 4 to 7 Weeks

(54) The efficacy of the compositions according to the invention against fleas and ticks was tested over a period of four to seven weeks. The test was carried out according to the description under items A to D.

(55) TABLE-US-00001 TABLE la Efficacy of the composition according to Example 2 against fleas on cats 10 Appl. Treat- Vol W0 WD W2 W3 W4 W5 ment ml/kg Parasite D2 D9 D16 D23 D30 D37 1. infes- CE 1 0.1 Ctenocephalides 97 2. infes- 100 3. infes- 100 4. infes- 100 5. infes- 99 6. Infes- 100 tation felis tation tation tation tation tation day- CE 2 0.15 Ctenocephalides 99 day 100 day 100 day 100 day 100 day 99 4 felis 7 14 21 28 35 Example 0.15 Ctenocephalides 99 100 100 100 100 100 2 felis CE 3 0.1 Ctenocephalides 100 100 100 99 94 74 felis

(56) TABLE-US-00002 TABLE 1b Efficacy of the composition according to Example 2 against ticks on cats 10 Appl. Treat- Vol W0 WD W2 W3 W4 W5 ment ml/kg Parasite D2 D9 D16 D23 D30 D37 1. infes- CE 1 0.1 Ixodes 74 2. infes- 99 3. infes- 96 4. infes- 72 5. infes- 82 6. Infes- 89 tation ricinus tation tation tation tation tation day- CE 2 0.15 Ixodes 84 day 99 day 92 day 84 day 73 day 68 4 ricinus 7 14 21 28 35 Example 0.15 Ixodes 70 100 100 97 100 95 2 ricinus CE 3 0.1 Ixodes 71 100 100 96 93 76 ricinus Appl. Vol = volume applied in ml/kg of bodyweight value % = efficacy in %, calculated via determination of the geometrical mean compared to an untreated control group

(57) TABLE-US-00003 TABLE 2a Efficacy of the composition according to Example 2 against fleas on dogs D0 Appl. Treat- Vol W0 W1 W2 W3 W4 W5 W6 W7 ment ml/kg Parasite D2 D9 D16 D23 D30 D37 D44 D51 1. CE 1 0.1 Ctenocepha- 100 3. 100 4. 100 5. 99 6. 99 7. 100 8. 62 9. 33 infes- lides felis infes- infes- infes- infes- Infes- infes- infes- tation CE 2 0.15 Ctenocepha- 100 tation 100 tation 100 tation 100 tation 100 tation 99 tation 99 tation 76 day-4 lides felis day day day day day day day 2. Exam- 0.15 Ctenocepha- 100 7 99 14 100 21 100 28 100 35 100 42 100 49 77 infes- ple 2 lides felis tation CE 3 0.1 Ctenocepha- 100 100 100 100 98 74 nd nd day-1 lides felis

(58) TABLE-US-00004 TABLE 2b Efficacy of the composition according to Example 2 against ticks on dogs D0 Appl. Treat- Vol W0 W1 W2 W3 W4 W5 W6 W7 ment ml/kg Parasite D2 D9 D16 D23 D30 D37 D44 D51 1. CE 1 0.1 Rhipicephalus 97 3. 100 4. 100 5. 100 6. 99 7. 94 8. 93 9. 65 infes- sanguineus infes- infes- infes- infes- Infes- infes- infes- tation CE 2 0.15 Rhipicephalus 96 tation 100 tation 100 tation 100 tation 100 tation 99 tation 98 tation 74 day-4 sanguineus day day day day day day day 2. Exam- 0.15 Rhipicephalus 92 7 100 14 100 21 100 28 100 35 99 42 99 49 88 infes- ple 2 sanguineus tation CE 3 0.1 Rhipicephalus 60 94 99 98 98 91 nd nd day-1 sanguineus Appl. Vol = volume applied in ml/kg of bodyweight value % = efficacy in %, calculated via determination of the arithmetic mean compared to an untreated control group

(59) TABLE-US-00005 TABLE 3 Efficacy of the composition according to Example 2 against ticks on dogs D0 Appl. Treat- Vol W0 W1 W2 W3 W4 ment ml/kg Parasite D2 D9 D16 D23 D30 1. infes- CE 1 0.15 Dermacentor 25 2. infes- 98 3. infes- 99 4. infes- 100 5. infes- 98 tation variabilis tation tation tation tation day- Example 0.15 Dermacentor 55 day 100 day 99 day 100 day 100 4 2 variabilis 7 14 21 28 CE 3 0.1 Dermacentor 34 89 80 66 87 variabilis Appl. Vol = volume applied in ml/kg of bodyweight value % = efficacy in %, calculated via determination of the geometrical mean compared to an untreated control group