NZ202998A - Controlling ectoparasites by applying bis-(2,4-xyl-minomethyl)-amines and pyrethroids - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £02998 2 0299 PrioriLy Date(s): Complete Spocification Filed: !S.r Jr.^53. Class: Publication Date: P.O. Journal, No: . jS'SQ NEW ZEALAND PATENTS ACT 19 5 3 COMPLETE SPECIFICATION CONTROL OF ECTOPARASITES BY LOCALIZED APPLICATION WE, WELLCOME AUSTRALIA LIMITED, a company duly registered under the laws of the State of New South Wales, of 53 Phillips Street, Cabarita 2137, New South Wales, Australia, do hereby declare the invention to be described in the following statement:- 20Z998 The present invention relates to the control of ectoparasites on mammals by a localised application of a mixture of a diamidide and a pyrethroid, and to novel formulations thereof. It relates particularly to the control of lice (Damalinia ovis) and itchmite (Psorergates ovis) on sheep.

United Kingdom patent specification No. 1,564,636 describes pesticidal compositions comprising amitraz (a diamidide of chemical name N-methyl bis (2,4-xylyliminomethyl) amine) in admixture with pyrethroid. The disclosure is concerned primarily with the use of such compositions to combat plant pests and the only example relates to the use of combinations of amitraz and the pyrethroid permethrin against cotton leaf worm. The specification mentions in passing that the compositions may be used to treat animals such as cattle, pigs and sheep, for the control of ectoparasites such as ticks, mites, keds, lice and flies, by an application method such as dipping, spraying or pour-on.

Traditionally, animals have been treated for the control of ectoparasites by dipping orspraying the whole animal. However, this is an inconvenient and time-consuming operation. The application of paraciticides by the localised pour-on method (for example, pouring a low volume of a concentrated liquid formulation along the back of the animal) has acknowledged advantages in terms of convenience and savings in time and labour. However, it has been found that paraciticides which are effective when applied as dips and sprays may or may not be effective when applied as 0 202998 pour-ons. It has not proved possible to predict with certainty whether or not a paraciticide will prove effective when applied as a pour-on, and specific experimentation is required.

The present invention provides a method of controlling ectoparasites on a mammal which comprises the application onto a localised region of the external surface of the mammal of a mixture of (a) a diamidide of formula (I) x n = ch - n — ch = n in 1 5 wherein R is hydrogen or Ci-Cg alkyl, and each X is independently selected from hydrogen, Ci-Ce alkyl and halo; and (b) a pyrethroid of formula (ii) ch - 0 - m wherein Mis- co - ch - ch - ch = c \ / c / \ ch3 ch3 / \ xi - co - ch - ch - ch - c \ / c / \ ch3 ch3 / \ xi X., (II) or '|jb4 202998 co - ch - r 2 CH / \ ch3 ch3 and wherein X1 to X4 are independently selected from halo, C^ - C^alkyl, halogen-substituted - C4 alkyl, and halogen-substituted phenyl; X5 is -H or halo; Rj is -H or Cyano; and R2 is halogen-substituted phenyl.

The present invention, and its preferred embodiment wherein the mixture is used for the contro] of sheep ectoparasites such as lice (Damalinia ovis), itchmite (Psorer-gates ovis), keds (Melophagus ovinus) and blowflies, thus constitute a selection within the terms of the above-described United Kingdom specification No. 1,574,636. The selection advantages relate to the synergistic interaction between the diamidide and the pyrethroid; and to the great convenience and savings in time and labour inherent in the use of a pour-on as opposed to conventional application procedures.

By "localised application" is meant that the active agent is only applied to a minor portion of the external surface of the mammal, generally as a line or spot on the mammal's back.

The present invention is particularly concerned with the protection of sheep including merino sheep, cattle, pigs and goats.

The ectoparasite which may be controlled incluede lice 4 202998 flies including blowflies, keds, mites and ticks.

The mixture is generally applied as a liquid formulation, paste, or as a solid powder, particularly a wettable powder. The liquid formulation may comprise a non-aqueous carrier. The mixture may be dissolved, suspended or dispersed in the liquid carrier.

The localised application is preferably carried out as a pour-on treatment by pouring a liquid formulation comprising the mixture along the back of the mammal (i.e. a so-called "backline" application}. Alternatively, the application may be carried out by means of a "localised spray or aerosol, usually along the sheep's back as it passes through a sheep race. The aerosol might comprise the mixture dissolved in a liquid carbon dioxide propellant, or dissolved in a suitable solvent and pressurised with nitrogen.

It is a particular advantage of the present method that only small volumes of a formulation containing the mixture need be applied. Depending on the size of the mammal, the volume applied will generally lie in the range 2 to 30 ml, usually 2 to 15 ml.

Depending on the efficacy of the particular active compounds employed, the formulation generally contains from 0.1 to 500 mg/ml of each compound. Moreover, each compound is preferable applied in an application of from 1 to 500 mg/kg body weight, preferably 1 to 100 mg/kg.

A liquid pour-on formulation may comprise one or more organic solvents, such as xylene, toluene, cyclohexanone or 202998 a glycol.

One preferred solvent system comprises 0 to 100, preferably 30 to 70 wt % xylene; 0 to 100, preferably 20 to 4 0 wt I cyclohexanone; and 5 to 25 wt % vegetable oil.

Suitable glycols include ethylene glycol and propylene 5 glycol, polyethylene glycols and polypropylene glycols, ethylene glycol-propylene glycol copolymers, and alkyl ethers and alkyl ether esters of the general formula: n = 1-40 and m = 0 or 1.

Diethylene glycol mono-n-butyl either has been found to be particularly useful. It has been found to have minimal adverse effect on the skin in terms of a mild epidermal shedding seen with other solvents in some animals . 2q Pour-on formulations comprising the mixture in a glycol either or glycol ether ester as defined above are novel, and a further aspect of the invention embraces these. Alternatively, the carrier may comprise an ester of a fatty acid. The weight ratio of pyrethroid to diamidide is preferably from 1:1 to 1:100 depending on the particular compounds used, especially 1:10 to 1:25.

I R20 - (CH„-CHO) - (CO) - R3 2 n m ^ where R^" = methyl or hydrogen, 2 3 R = Cl~^5 al^yl, hydrogen or -CO-R , R3 = C1-C-L2 alkyl, Generally, a biodegradable dye or pigment will be 6 202998 included to enable treated mammals to be easily distinguished from untreated ones.

Paraffin oils and vegetable oils, e.g. corn oil, peanut oil, castor oil and olive oil, can be added as viscosity 5 modi fiers.

Alkylamides and esters of fatty acids are useful formulations adjuncts, e.g. n-butyl oleate, N,N-dimethyl oleamide and isopropyl myristate (IPM). Preferably, a minor proportion (i.e. less than 50% (by weight) of the liquid carrier) 10 of IPM is used. During prolonged storage, it is possible for chemical interaction to occur between the diamidide and the pyrethroid when they are dissolved together in a liquid solvent system. To avoid this, it is preferred that either or both of the active compounds be present in a 15 carrier-immiscible wax beadlet. The beadlets are then dispersed in the liquid carrier. The active compound may be provided in the wax matrix by dissolving in the melted wax and then pouring the melt into water.

Suitable waxes include fatty acid alcohols, e.g.cetyl, 20 stearyl or beheryl alcohol; halogenated castor oil; polyethylene glycol waxes; and paraffin wax. The wax will form a bio-erodible beadlet which degrades in the mammal in response to skin conditions and releases the active compound. A variety of such waxes will be well known to the skilled man. 25 The preferred diamidide is formed when R and X are each methyl. This compound is called amitraz.

Preferably, the pyrethroid is selected from those 2 02998 pyret-hroids given in Tables I-1II.

TABLE I /Xl m = - co - ch - ch - ch = c ' \ / x2 c / \ ch3 ch3 No. xi x 2 x3 x, x5 ri trivial name 1 ci ci h h permethrin 2 ch3 ch3 — — h h phenothrin 3 Br Br — — h cn deltamethrin A ci Cl — — h cn cypermethrin ci cf3 — — h cn cyhalothrin 6 CI ~{o)~CI — — f cn flumethrin 7 ci Cl — — f cn cyfluthrin 8 ch3 ch3 — H CN cyphenothrin 202998 TABLE II m = - co - ch - ch - ch \ / I c X) / \ ch3 ch3 No.

X i x2 x3 x. x5 Hi trivial name 9 Br Br Br Br H CN tralomethrin Cl Cl Br Br H CN tralocythrin - c \ X«, table iii m = - co - ch i - r2 ch / \ ch3 ch3 no. rz x5 rI trivial name 11 -(&ci h . cn fenvalerate 2 02998 Embodiments of the present invention and the performance thereof will now be described by way of example only. (1} PERFORMANCE DATA (1) Control of Lice on Sheep Merino sheep were divided into four groups. Groups 1 to 3 were treated with a backline pour-on application of an active agent in a formulation comprising 55 wt % xylene, 30 wt % cyclohexanone, and 15 wt i corn oil. Initially, the merino sheep were infested with lice. Groups 1 and 3 are for comparison and Group 2 illustrate-s the present invention.

The results are given in Table A. Lice assessments on days 0, 7, 9 and 15 were estimated scores based on a general examination involving a limited number of wool partings in each body area {i.e. not detailed counts). Lice assessments on days 35 and 42 were detailed counts which represented the total number of lice detected in 20 partings of the wool of the sheep. For comparison, the figures in brackets give the estimated corresponding score values for the control group.

The results show that the level of control of lice in Group 1 by the application of an amitraz pour-on was incomplete at the concentrations used. Group 2 according to the present invention shows the application of a combination of deltamethrin and amitraz, which results in early and complete control. For comparison, Group 3 shows the level of control found by the use of deltamethrin alone. Thus, it may be seen that the deltamethrin and amitraz form a 2 02998 synergistic combination since the level of control found in Group 2 is enhanced with respect to the level of control to be expected from a combination of the results of Groups 1 and 3.

TABLE A CONTROL OF LICE ON MERINO SHEEP Sheep No.

Lice Score Counts Group Treatment 0 day 7 9 42 Amitraz 50 mg/kg 772 . 23 died | 1 742 750 20 19 - 13 13 48 34 26 12 Deltamethrin 2 mg/kg 731 9 2 0 0 0 2 + 773 8 4 1 (I) 0 0 Amitraz 757 1 0 0 0 0 50 mg/kg 3 Deltamethrin 2 mg/kg 74 7 759 718 20 20 4 12 14 - 13 9 2(1) 10(1)2 (A) 10(1) 0 1 (A) 2(1) 741 - _ 14 — 64(18) 737 - - - 52(18) 4 Controls 764 754 20 — : 16 10 83(19) 53(15) 758 121 (19) 723 — — — 55(13) I = immature lice A = adult lice 2 02998 (2) Control of Itchniite on Sheep Merino sheep were divided into three groups. Groups 1 and 2 were treated with a backline pour-on application of active agents (amitraz and deltamethrin) in a formulation comprising 55 weight ¥. xylene, 30 weight % cyclohexanone and 15 weight % corn oil. Initially, all the sheep were infested with the sheep itchmite (Psorergates ovis).

The results are given in Table B. Itchmite assessments were made 13 weeks post-treatment. Itchmite assessments were made as follows.

An area of approximately 10 square centimetres on the flank and an area of similar size on the rib-shoulder area are clipped to remove as much wool as possible. Preference is given to areas exhibiting signs of infestation such as yellow scurf, skin thickening, bluish tinge, etc.

The bared area is lightly moistened with a light mineral oil and vigorously scraped with a blunt scalpel, four passes being made at right angles to each other. Generally slight bleeding occurs before scraping is completed. This whole process is referred to as "a scraping of one site" .

The oil, containing the scraped material, is transferred to standard microscope slides covered with 22 x 50 mm cover-slips and examined using a compound microscope at a magnification of 40 to 100 times.

The results of the examinations are expressed as the number of adults, nymphs, shells etc. per site. 2 02998 The results show that the combination of amitraz and deltamethrin is effective in the control of itchmite.

TABLE B Group Treatment Sheep No.

Weight (kg) Dose Volume (ml) Total Live Itchmite Count (Week 13) Differential Counts (Week 13) adult immature De]tamethrin 352 38 8 1 1 0 2 mg/kg 355 8 dead - - 1 + 358 38 8 0 0 0 Amitraz 370 36 8 0 0 0 mg/kg 373 45 8 0 0 0 Deltamethrin 351 40 8 0 0 0 2 mg/kg 359 38 8 0 0 0 2 + 369 38 8 0 0 0 Ami traz 372 39 8 0 0 0 50 mg/kg 375 37 8 0 0 0 357 8 3 3 Untreated Control 360 363 367 368 4 33 2 14 2 21 0 B 2 12 2 6 202998 (3]) formulations for use in the present invention Suitable formulations are presented in the following examples.

Example 1 grams of deltamethrin and 250 grams of amitraz were dissolved in one litre of a solvent blend containing: Xylene 55 wt % Cyclohexanone 30 wt % Corn Oil 15 wt % Sudan Red IV (dye) 50 ppm Example 2 grams of deltamethrin and 250 grams of amitraz were dis-15 solved in one litre of the solvent described in Example 1.

Example 3 grams of deltamethrin and 100 grams of amitraz were dissolved in one litre of a solvent consisting of diethylene 20 glycol mono-n-butyl ether containing 50 ppm Sudan Red IV.

Example 4 A pour-on formulation containing 10 grams of deltamethrin and 100 grams of amitraz was made up as follows. The 25 amitraz was contained in wax beadlets to avoid any interaction with the deltamethrin during storage. The beadlets were prepared by dissolving amitraz in a melted polyethylene 2 0 2 9 9 8 glycol way. and dropping t.he melt into water. The wax bead-lets were suspended in a solution of deltamethrin in a silicone oil containing a colouring agent.

Example 5 The procedure of Example 4 was repeated but the deltamethrin was held in the wax matrix instead of the amitraz.

Example 6 The procedure of Example 4 was repeated but both the amitraz and deltamethrin were separately held-in wax beadlets and the beadlets suspended together in the silicone oil. 202998

Claims (24)

WHAT WE CLAIM IS:
1. l.A method of controlling ectoparasites on a mammal, excluding humans, which comprises the application onto a localised region of the external surface of the mammal of a mixture of (a) a diamidide of formula (I) X. _ ^ ^X N = ch - n - ch = n r wherein r is hydrogen or Ci-C£ alkyl, and each x is independently selected from hydrogen, Ci-C6 alkyl and halo; and (b) a pyrethroid of formula (II) wherein Mis - co - ch - ch - ch = c \ / c / \ ch3 ch3 - co - ch - ch - ch - c \ / I I c x3 x / \ ch3 ch3 / \ Xi Xi x. or - co - ch - r2 I ch / \ ch3 ch3 and wherein Xi to Xi* are independently selected from halo, C1-C4 alkyl, halogen-substituted - 16 - 2 0299 Ci-Ci, alkyl, and halogen-substituted phenyl; is -H or halo; Ri is -H or cyano; and R? is halogen-substituted phenyl.
2. 2. A method according to claim 1 wherein the pyre- % throid is selected from permethrin, phenothrin, deltamethrin, cypermethrin, cyhalothrin, flumethrin, cyfluthrin, cyphenothrin, tralomethrin, tralocythrin, and fenvalerate (all as herein defined).
3. 3. A method according to claim 1 or 2 wherein the diamidide is amitraz (as herein defined).
4. 4. A method according to any preceding claim wherein the mammal is selected from sheep, cattle, pigs and goats.
5. 5. A method according to claim 4 wherein the mammal is a merino sheep.
6. 6. A method according to claim 4 or 5 wherein the mixture is applied to a shorn sheep.
7. 7. A method according to any preceding claim wherein each of the active ingredients is applied at a rate of from 1 to 500 mg per kilogram body weight.
8. 8. A method according to any preceding claim wherein an application of from 2 to 15 ml of a liquid formulation comprising the mixture is made. - 17 - 2 02998
9. 9. A method according to any preceding c]aiir. wherein a liquid formulation is applied which comprises the mixture dissolved in a solvent system comprising 30-70 wt % xylene, 20-40 wt % cyclohexanone and 5-25 wt % vegetable oil.
10. 10. A method according to any one of claims 1 to 6 wherein a liquid formulation is applied which comprises a carrier selected from ethylene glycol, propylene glycol, polyethylene glycols, polypropylene glycols, and ethylene glycol-propylene glycol copolymers.
11. 11. A method according to any one of claims 1 to 8 wherein a liquid formulation is applied which comprises a carrier selected from glycol ethers and glycol ether esters of the formula R20 - (CH2 - CHO) n - (C0)„ - R3 I R1 where R1 = methyl or hydrogen, R2 = C1-C5 alkyl, hydrogen or -CO-R3, R3 = C1-C12 alkyl, n = 1-40, and m = 0 or 1 .
12. 12. A method according to any one of claims 1 to 8 wherein a liquid formulation is applied which comprises diethylene glycol mono-n-butyl ether as carrier.
13. 13. A method according to claim 11 wherein in is 1. - 18 - 202998
14. 34. A method according to any one of claims 10 to 13 wherein the formulation further comprises a minor proportion of isopropyl myristate.
15. 15. A method according -to any one of claims 1 to 8 wherein a liquid formulation is applied which comprises an -ester of a fatty acid.
16. 16. A method according to any one of claims 1 to 8 wherein the^localised application is made by means of a localised spray or aerosol.
17. 17. A method according to claim 16 wherein the localised application is made by means of an aerosol comprising the mixture in a liquid carbon dioxide propellant..
18. 18. A method of controlling ectoparasites on a mammal, excluding humans, which comprises the localised application of a formulation substantially as disclosed in any Example.
19. 19. A pour-on formulation for the control of ectoparasites on a mammal, which comprises a mixture of a diamidide of formula (I) and a pyrethroid of formula (II) both as defined in claim 1, in a liquid carrier comprising a glycol ether or glycol ether ester of the formula RaO - (CH2 - CHO) n - (C0)m - R3 I R1 where R1 = methyl or hydrogen, R2 = Cj—C5 alkyl, hydrogen or -CO-R3/ 19 i 1 2 02998 R3 = Ci-Ci? alkyl, n = 1-40, and m = 0 or 1 .
20. 20. A pour-on formulation according to claim 19 wherein m is 1.
21. 21. A pour-on formulation according to claim 19 wherein the carrier comprises diethylene glycol mono-n-butyl ether.
22. 22. A pour-on formulation according to any one of-claims 19 to 21 which further comprises a biodegradable dye or pigment.
23. 23. A pour-on formulation according to any one of claims 19 to 22 wherein either or both of the diamidide and the pyrethroid is held in a wax beadlet matrix, the wax beadlets being dispersed in the liquid carrier.
24. 24. A pour-on formulation substantially as disclosed in Example 3. WELLCOME AUSTRALIA LIMITED By Their Attorneys,