IE54305B1

IE54305B1 - Parasiticidal compositions

Info

Publication number: IE54305B1
Application number: IE2799/82A
Authority: IE
Original assignee: Ici Australia Ltd
Priority date: 1981-11-27
Filing date: 1982-11-24
Publication date: 1989-08-16
Also published as: FR2517207A1; ES517709A0; GB2110091A; NZ202522A; AU550754B2; ES8500712A1; IE822799L; DE3244166C2; GB2110091B; ZA828524B; FR2517207B1; AU9089482A; DE3244166A1

Abstract

A composition for topical application to animals to control endoparasites and ectoparasites comprising a mixture of cyhalothrin with levamisole or tetramisole free base in a carrier comprising particular combinations of an alcohol solvent with an ester co-solvent.

Description

This invention relates to compositions for topical application of chemicals to animals for the control of parasites. In particular it relates to compositions comprising levamisole free base and the synthetic pyrethroid, cyhalothrin, for the concurrent control of endoparasites and ectoparasites.

Topical application of parasiticides for the control of ectoparasites is well known and usually takes the form of spraying or dipping animals with suitable formulations of the parasiticides. Recently attempts have been made to develop pour-on formulations, that is, formulations that are fully effective against parasites when a suitable amount of the formulation is applied to a particular area of the animal's surface, typically along the spinal region. A pour-on approach has inherent advantages over spraying or dipping techniques in that complete coverage of the animal is not necessary and the storage and loss of expensive chemicals in dip baths is avoided. ‘20 Similarly, topical application for control of endoparasites offers advantages over parenteral administration in removing the need to restrain animals and to maintain sterile formulations. In addition trained personnel are not needed. Formulations prepared for pour-on application of ectoparasiticides or endo3 parasiticides have so far suffered from a number of disadvantages. The range of parasiticides which are effective in this technique are limited and the prior art compositions have associated tissue reactions caused by the solvent systems used for preparing these compositions. These tissue reactions lead to considerable discomfort for the treated animals and in addition lead to severe damage to the hides and skins of the animals with consequent economic loss to the grazier. This is a particular problem with sheep in Australia where the major sheep breed is the Merino or Merinocross, since this breed has been found to be very sensitive even to those solvent systems which have been tolerated to some degree by other breeds.

It is an object of the present invention to provide effective and non-toxic solvent systems that are tolerated by-animals with a wide range of type and degree of sensitivity. Since labour costs are increasing it is a -further object of the present invention to provide an effective and safe solvent system that can be used for concurrent application of an ectoparasiticide and an endoparasiticide thus providing a single treatment as an alternative to the conventional separate treatments.

Zn the case of pour-on application to sheep, ianediately after shearing is potentially a good time to treat sheep for parasite control by topical application since the sheep are already mustered and the wool is relatively short. However the wool cover is still a significant barrier to the topically applied compositions particularly in the case of Merinos because the individual fibres are fine and closely packed. In addition there is a layer of wool grease covering the skin which provides a further barrier to penetration of the medication. This layer of wool grease can reach a very high level in Merinos. It is a further object of our invention to provide compositions which are effective in penetrating these wool and wool grease barriers while maintaining the freedom from adverse skin and tissue reactions.

Degreasing solvents such as for example, paraffins, isoparaffins, cycloparaffins and aromatics such as the xylenes, are well known. However these solvents, which effectively penetrate the wool grease cover, produce severe tissue reactions such as pain, swelling, dryness and cracking of the skin. This in turn leads to wool loss and permanent hide damage.

Other solvents, such as alcohols and alcohol ethoxylates, do not produce tissue reactions but are relatively ineffective at penetrating the wool or wool grease cover.

We have now found certain compositions which are effective for the topical application to animals of the endoparasiticides, tetramisole and levamisole, and the group of ectoparaaiticides, commonly referred to as the synthetic pyrethroids, and which are free from adverse tissue reaction even when applied to sensitive breeds of animals. A further advantage of these compositions is that organo-metallic materials may be readily incorporated to counteract specific mineral deficiencies in the animals.

Accordingly we provide compositions for topical application to animals for the control of endoparasites and ectoparasites which compositions comprise tetramisole in its free base form or an optical isomer thereof and cyhalothrin in a carrier comprising a first solvent selected from the group consisting of C3 to C* alcohols alkoxylated with from one to three moles of ethylene oxide per mole of alchohol, and Οχ to C4 alcohols alkoxylated with from one to three moles of propylene oxide per mole of alcohol and mixtures thereof; and a co-solvent selected from ditC^ to Cg alkyl) esters of C2 to Cg dicarboxylic acids, ditC^ to Cg alkyl) esters of C2 to Cg dihydric alcohols, and C2 to Cg carboxylate esters of alcohol alkoxylates prepared by reacting one mole of a to Cg alcohol with from one to three moles of an alkylene oxide selected from ethylene oxide and propylene oxide, and mixtures thereof.

The preferred C2 to Cg dicarboxylic acids are adipic acid and sebacic acid, and the preferred esters of these acids are dimethyl adipate, diethyl adipate, dimethyl sebacate, and diethyl sebacate. The preferred C2 to Cg dihydric alcohols are ethylene glycol, propylene glycol, diethylene glycol, and triethylene glycol.

Tetramisole is the common name for the hydrochloride salt of the anthelmintic dl-2,3,5,6-tetrahydroimidazo/2,l-b7thiazole. Levamisole is the conmon name for the laevo-rotatory optical isomer of tetramisole. For the compositions of the present invention these hydrochloride salts are unsuitable being of low solubility in the first solvent and essentially insoluble in the co-solvent. Tetramisole and levamisole are readily converted to the respective free base forms for the compositions of the present invention by conventional methods of basifying the salts. The preferred compound is the free base of levamisole.

Cyhalothrin is the name commonly given to the •synthetic pyre thro id (+)-a-cyano-3-phenoxybenzyl(+)cis, trans-3- C 2-chloro-3,3,3-trif luoroprop-l-en-l-yl) 2,2-dimethy Icy clop ropane carboxylate. Reference to •cyhalothrin includes reference to geometric and optical isomers thereof, and mixtures thereof.

Other synthetic pyrethroids may optionally be included in the compositions, in particular the com6 4 305 pounds 3-phenoxybenzy1 (+)-cis,trans-3-{2,2-dichlorovinyl) -2, 2-dimethyl-cyclopropane carboxylate commonly known as permethrin, a-cyano-3-phenoxybenzyl (+)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcydopropane carboxylate commonly known as cypermethrin, and a-cyano-3-phenoxybenryl (+) -cis,trans-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate commonly known as deltamethrin, and geometric and optical isomers thereof, and mixtures thereof.

A particular feature of our compositions is that even when the pour-on composition is applied to a limited surface area of the host animal, both blood15 sucking parasites such as ticks, and non-blood-sucking parasites such as lice and flies, are effectively controlled at sites on the animal remote from the application area even though the pyrethroids are not generally considered to operate systemically in animals.

The preferred first solvents are 2-propoxye thanol, 2-butoxyethanol, l-methoxy-2-propanol and 1ethoxy-2-propanol, and mixtures thereof. The preferred co-solvents are ethylene glycol diacetate, 2-propoxy25 ethyl acetate, 2-butoxyethyl acetate and 1-methoxypropyl-2 acetate, and mixtures thereof. The most preferred carrier comprises 2-butoxyethanol and ethylene glycol diacetate.

These particular carriers provide rapid wetting of the wool or hair of “the animal permitting movement to the skin level vith minimal run-off and loss of formulation, and have the required solubility for the ectoparasiticide and parasiticide.

Preferably the weight/weight ratio of the first solvent to the co-solvent is in the range from 9:1 to 1:1.

The concentration of the levamisole free base In the compositions of our invention is in the range from 1.0 to 25% weight/volume. The concentration of the synthetic pyrethroid is in the range from 0.2 to 5% weight/volume. The particular concentration can be readily chosen by those skilled in the art so that when a selected quantity of the solution of the endoparasiticide and ectoparasiticide are applied topically to the animal then each parasticide will be present in an effective amount to control the particular parasitic infestations in the animal.

For animals infested with parasitic gastro intestinal and pulmonary nematodes such as Haemonchus spp., Ostertagia spp., Trichostrongylus spp., Nematodirus spp., Oesophagostomum spp., Chabertia spp., and Dictyocaulus spp. a typical effective amount of levamisole ‘free base is approximately 10 mg/kg of animal body weight by topical application. Hith the synthetic pyrethroids the effective dose range is dependent on the particular, synthetic pyrethroid as well as the prevailing ectoparasite, but such dose ranges are readily determined by those skilled in the art. The synthetic pyrethroid, cyhalothrin, for exanple is used at a rate of approximately 2 mgAs of animal bodyweight for good control of body lice, Damalinia ovis.

The preferred oonpositions comprises from 5 to 20% of levamisole free base in a preferred carrier such that the levamisole free base is close to the saturation point in that carrier.

The species of parasites controlled by levamisole and the various synthetic pyrethroids have been well-documented in the prior art. It is a parti35 cular feature of our compositions that the levamisole and synthetic pyrethroid are fully effective in topical applications in the compositions of our invention at the same dose rates that are employed by conventional methods of applications such as oral drenching and injection in the case of levamisole and spraying, -dusting or dipping in the case of the synthetic pyrethroid.

Thus, for exanple, a conposition containing 5% v/v of levamisole and lt v/v of cyhalothrin applied at the rate of 0.2 ml/kg of animal bodyweight gives effective control of both helminths and body lice.

While the oonpositions are particularly effective for control of ectoparasites and endoparasites in cattle and sheep they may also be used for pigs and domestic animals such as dogs and cats.

The compositions may additionally contain other ingredients such as, for example, preservatives and stabilizers. A particularly useful stabilizer is an antioxidant such as for example 4-buty1-2,5-dimethy1phenoli. other antioxidants known to those skilled in the art may be used and the selected antioxidant or mixture of antioxidants is typically added to provide a concentration in the range of from 0.1 to 1.0% w/v, preferably 0.5 to 1.0% v/v, in tbe final composition.

In a further embodiment of our invention ve provide oonpositions vhich additionally comprise a nonfast dye so that animals treated vith the pour-on compositions may be readily recognized and thus unnecessary and undesirable duplicate treatment may be avoided. Suitable non-fast dyes soluble is the compositions vill be readily selected by those skilled in the art so that the dyed area of skin or wool vill fade in' sunlight vithin a suitable period of exposure and without deleterious effect on the skin or wool. A particularly useful dye is rhodamine vhich is typically used in an amount to give a concentration range of from 0.01 to 0.054 w/v in the final composition.

The compositions of our invention are used in a process of treating animals which process comprises applying to the eurface of the animals the composition of our invention comprising levamisole or tetramisole in the free base form and cyhalothrin in a first solvent as hereinbefore defined and a co-solvent as hereinbefore defined.

The compositions are applied in a line along the back of the animal from the withers to the rump. The compositions spontaneously wet and penetrate the wool or hair and migrate rapidly down to the skin level. The compositions may be applied by brushing or rolling-on but more conveniently are simply poured on to the back of the animal.

Xn a further preferred embodiment of our invention the compositions additionally contain one or more carboxylic acids selected from the group consisting of C2 to Cg alkanoic acids. The molar ratio of alkanoic acid to levamisole free base should not exceed 1.1 and most preferably the alkanoic acid and levamisole free base are in substantially equimolar proportions. The addition of the alkanoic acid to the composition increases the measured blood levels of levamisole in the treated animals. Smaller proportions of alkanoic acid give a correspondingly smaller increase in the blood levels and the preferred molar ratio of alkanoic acid to levamisole free base is in the range of 0.5 to 1.0. The preferred alkanoic acids are the Cj to C4 acids, in particular acetic and propionic acid. Higher molecular weight acids, for example stearic acid, can be used but provide less blood level enhancement than the C2 to Cg alkanoic acids.

This invention is now illustrated by but not limited to the following examples in which all parts and percentages are by weight unless otherwise specified. example 1 λ formulation is prepared with the following composition: Shodamine 0.1% w/v Cyhalothrin 1% w/v Levamisole free base 10% w/v Ethylene glycol diacetate 25% v/v 2-Butoxyethanol to 100 vols Example 2 A formulation is prepared with the following composition: Ehodamine 0.1% w/v Cyhalothrin 1% w/v Levamisole free base 10% w/v Ethylene glycol diacetate 25% w/v l-Methoxy-2-propanol to 100 vols Example 3 A formulation is prepared with the composition of Example 2 except that the l-methoxy-2-propanol is replaced with 1-e thoxy-2-propanol.

Example 4 A formulation is prepared with the following composition: Ehodamine Cyhalothrin Levamisole free base 0.1% w/v 1% w/v 10% w/v Ethylene glycol diacetate 25» w/v Propionic acid 3.6» w/v 2-Butoxyethanol .to 100 vols Example 5 A formulation is prepared with the composition of Example 4 except that the 2-butoxyethanol is replaced by l-methoxy-2-propanol.

Example 6 A formulation is prepared with the composition 10 of Example 4 except that the propionic acid is replaced with an equimolar amount of octanoic acid.

Example 7 A formulation is prepared with the composition of Example 4 except that the concentration of propionic is 1.8» w/v.

Example 8 Cattle were treated with the formulation of Example 1 by pour-on application along the spine. The applied dose was 1 ml/kg bodyweight to provide an effective dose rate of 10 mg/kg of levamisole. Control animals were treated subcutaneously with a levamisole injectable formulation at a dose rate of 6 mg/kg bodyweight.

Blood samples were drawn from the animals at regular time intervals and heparinized. Tbe plasma obtained by centrifugation was then analyzed for levamisole by a procedure involving clean-up on Sep-Pak C^g cartridges (”Sep-Pak* is a registered trade mark of Waters Associates) followed by a final determination by high performance liquid chromatography. The results are given in Table 1 and indicate that blood levels of 0.3 ppm and higher are rapidly reached and then maintained over a five-hour period. This level is known by those skilled in the art to give effective control of helminth parasites.

TABLE 1 Treatment Animal number Levamisole cone (ppm) in plasma after treatment Bours: 1 2 3 5 7 Injectable formulation 1 1.1 0.6 0.5 0.3 0.2 Injectable formulation 2 1.5 1.2 0.9 0.5 0.2 Pour-on formulation 3 0.6 0.6 0.5 0.3 0.2 Pour-on formulation 4 0.4 0.5 0.4 0.3 0.3 4- Example 9 Lice-infested sheep vere sheared and the formulation of Example 1 applied as a pour-on at the rate of 1 ml/kg bodyweight to provide an effective dose rate of 1 mg/kg of cyhalothrin. The sheep vere inspected periodically and within 14 days were completely ^•0 free of lice.

Comparative Example 1 A formulation vas prepared with the composition of Example 1 except that the ethylene glycol diacetate was omitted. Whem this formulation was applied to three sheep by the procedure of Exanple 9 at an application &43ϋ5 dose of 4 ml tissue hardening on the animal was noted after six days.

Comparative Example 2 A formulation vas prepared vith the composition 5 of Example 4 except that the ethylene glycol diacetate vas omitted. When this formulation was applied to three sheep by the procedure of Example 9 at an application dose of 4 ml, the tissue at the site of application became dry and hard after six days.

Comparative Example 3 A formulation vas prepared with the composition of Example 7 except that the ethylene glycol diacetate was omitted. The formulation was applied to three sheep by the procedure of Example 9 at an application dose of 4 ml. After six days the tissue at the site of application was dry and cracking had occurred.

Claims

CLAIMS:

1. A pour-on composition for controlling or eradicating ectoparasite and endoparasite infestations in animals comprising from 0.2 to 5% w/v of cyhalothrin and 5 from 1.0 to 254 w/v of tetramisole free base or an optical isomer thereof in a carrier comprising a first solvent selected from the group consisting of Cj to C 4 alcohols alkoxylated with from one to three moles of ethylene oxide per mole of alcohol, and Cj to C 4 alcohols 10 alkoxylated with from one to three moles of propylene oxide per mole of alcohol and mixtures thereof, and a co-solvent selected from di(C 2 to Cg alkyl)esters of C 2 to Cg dicarboxylic acids, diiCj to Cg alkyl)esters of C 2 to Cg dihydric alcohols and C 2 to Cg carboxylate esters 15 of alcohol alkoxylates prepared by reacting one mole of a Cj to Cg alcohol with from one to three moles of an alkylene oxide selected from ethylene oxide and propylene oxide, and mixtures thereof.

2. A pour-on composition according to claim 1 20 wherein the isomer of tetramisole is levamisole.

3. A pour-on composition according to claim 2 wherein the animals comprise cattle or sheep.

4. A pour-on composition according to claim 3 wherein the C 2 to Cg dicarboxylic acids are adipic acid 25 and sebacic acid and the C 2 to Cg dihydric alcohols are ethylene glycol, propylene glycol, diethylene glycol and triethylene glycol.

5. A pour-on composition according to claim 1 wherein the carrier forms 70 to 984 w/v of the 30 compos ition. and the weight/weight ratio of the first solvent to the co-solvent is in the range from 9:1 to 1:1.

6. A pour-on composition according to claim 4 or 5 wherein the first solvent is selected from the group consisting of 2-propoxyethanol, 2-butoxyethanol, 1-methoxy-2-propanol and l-ethoxy-2-propanol, and mixtures thereof.

7. A pour-on composition according to claim 4 or 5 wherein the co-solvent is selected from the group consisting of ethylene glycol diacetate, 2-propoxyethyl acetate, 2-butoxyethyl acetate and l-methoxypropyl-2acetate, and mixtures thereof.

8. A pour-on composition according to claim 5 wherein the carrier comprises 2-butoxy-ethanol and ethylene glycol diacetate.

9. A pour-on composition according to any one of claims 2 to 8 wherein the carrier additionally comprises a to Cg alkanoic acid such that the molar ratio of alkanoic acid to levamisole is in the range from 0.5 to 1.1.

10. A pour-on composition according to claim 9 wherein the levamisole and Cj to Cg alkanoic acid are in substantially equimolar proportions.

11. A pour-on composition according to any one of claims 1 to 10 that comprises a synthetic pyrethroid selected from the group consisting of permethrin, cypermethrin and deltamethrin, and geometric and optical isomers thereof.

12. Pour-on compositions substantially as described herein and with reference to the Examples 1 to 9.