NZ202522A - Pour on ectoparasiticidal and endoparasiticidal composition containing cyhalothrin and tetramisole - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £02522 2025 2 2 No.: Date: ~ Q"7 - it-81 Prionrty Date(s)- ■ Class: WUV..../ r /qo 3./ ?s... ■ ■ • 7 ; i'3 SEP. publication Date. ■ ■ ^ P.O. Journal, Wo-.

NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION A POUR-ON COMPOSITION FOR CONTROLLING OR ERADICATING ECTOPARASITE AND ENDOPARASITE INFESTATIONS IN ANIMALS xklWe, ICI AUSTRALIA LIMITED, a Company incorporated under the laws of the State of Victoria^ Australia, of 1 Nicholson Street, Victoria 3000, Australia hereby declare the invention for which ]^f we pray that a patent may be granted to rR&/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 (followed by page la) 2025 - lCL- 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 5 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 10 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 15 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.

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 25 for pour-on application of ectoparasiticides or endo- 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 5 caused by the solvent systems vised 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. 10 This is a particular problem with sheep in Australia where the major sheep breed is the Merino or Merino-cross, 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. 15 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 20 provide an effective and safe solvent system that can be used for concurrent application of an ecto-parasiticide and an endoparasiticide thus providing a single treatment as an alternative to the conventional separate treatments.

In the case of pour-on application to sheep, immediately 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 30 significant barrier to the topically applied com^ positions 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 35 of the medication. This layer of wool grease can reach 2015 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 5 and tissue reactions.

Degreasing solvents such as for example, paraffins, isoparaffins, cycloparaffins and aromatics such as the xylene, are well known. However,these solvents, which effectively penetrate the wool grease 10 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 15 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 20 the group of ectoparasi tic ides coinmonly 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 25 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 levamisole 30 or tetramisole in its free base form and cyhalothrin *in a carrier comprising a first solvent selected from the group consisting of C3 to alcohols alkoxylated with from one to three moles of ethylene oxide per mole of alcohol, and to alcohols alkoxylated with from 35 one to three moles of propylene oxide per mole of 202522 alcohol and mixtures thereof; and a co-solvent selected from di(C^ to Cg alkyl) esters of C2 to Cg dicarboxylic acids, di(C2 to Cg alkanoyl) esters of C2 to Cg dihydric alcohols, and C2 to Cg carboxylate esters of alcohol alkoxylates prepared by reacting one mole of a C0 to C, J o 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 10 adipic acid and sebacic acid, and the preferred esters of these acids are dimethyl adipate, diethyladipate, dimethyl sebacate, and diethyl sebacate. The preferred C2 to Cg dihydric alcohols are ethylene glycol, propylene glycol, diethylene glycol, and triethylene 15 glycol.

Tetramisole is the common name for the hydrochloride salt of the anthelmintic dl-2,3,5,6-tetra-hydroimidazo^2,3-b/thiazole. Levamisole is the common name for the laevo-rotatory optical isomer of 20 tetramisole. For the compositions of the present in-yention 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 25 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 pyrethroid (+)-a-cyano-3-phenoxybenzyl(+)-30 cis,trans-3-(2-chloro-3,3,3-trifluoroprop-l-en-l-yl)-2,2-dimethylcyclopropane carboxylate. Reference to cyhalothrin includes reference to geometric and optical isomers thereof, and mixtures thereof.

Other synthetic pyrethroids may optionally be 35 included in the compositions, in particular the compounds / pounds 3-phenoxybenzyl (+)-cis,trans-3-(2,2-dichlorovinyl)-2, 2-dimethyl-cyclopropane carboxylate commonly known as permethrin, o-cyano-3-phenoxybenzyl (+)-cis,trans-3-(2,2-dichlorovinyl) -2, 2-dimethylcyclopropane carboxylate commonly known as cypermethrin, and a-cyano-3-phenoxybenzyl (+) -cis, trans-3- (2,2-dibromo-vinyl)-2,2-dimethylcyclopropane carboxylate commonly 10 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 blood-15 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 20 animals.

The preferred first solvents are 2-propoxy-ethanol, 2-butoxyethanol, l-methoxy-2-propanol and 1-ethoxy-2-propanol, and mixtures thereof. The preferred co-solvents are ethylene glycol diacetate, 2-propoxy-25 ethyl acetate, 2-butoxyethyl acetate and 1-methoxy- propyl-2 acetate, and mixtures thereof. The most preferred carrier comprises 2-butoxyethanol and ethylene glycol diacetate.

These particular carriers provide rapid wetting 30 of the wool or hair of -the animal permitting movement to the skin level with 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 35 solvent to the co-solvent is in the range from 9:1 to 2025 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 5 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 endo-parasiticide and ectoparasiticide are applied topically 10 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 15 spp., Ostertagio spp., Trichostronglio spp., Nematodirus spp., Oesophagostomum spp., Chabestia spp., and Dictyocaulus spp. a typical effective amount of levamisole free base is approximately 10 mg/kg of animal body weight by topical application. With the 20 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 25 example is used at a rate of approximately 2 mg/kg of animal bodyweight for good control of body lice, Damalinia ovis.

The preferred compositions comprises )from 5 to 20% of levamisole free base in a preferred carrier such 30 that the. levamisole free base is close to the saturation point iin 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 parti-35 cular feature of our compositions that the levamisole 2 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 in-5 jection in the case of levamisole and spraying, dusting or dipping in the case of the synthetic pyrethroid.

Thus, for example, a composition containing 5% w/v of levamisole and 1% w/v of cyhalothrin applied at the rate of 0.2 ml/kg of animal bodyweight gives 10 effective control of both helminths and body lice.

While the compositions 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. 15 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-butyl-2,5-dimethyl-phenol. Other antioxidants known to those skilled in 20 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% w/v, in the final composition.

In a further embodiment of our invention we 25 provide compositions which additionally comprise a non-fast dye so that animals treated with the pour-on compositions may be readily recognized and thus unnecessary and undesirable duplicate treatment may be aboided. Suitable non-fast dyes soluble in the com-30 positions will be readily selected by those skilled in the art so that the dyed area of skin or wool will fade in sunlight within a suitable period of exposure and without deleterious effect on the skin or wool. A particularly useful dye is rhodamine which is typically used 35 in an amount to give a concentration range of from 0.01 to 0.05% w/v in the final composition.

In a further embodiment of our invention we provide a process of treating animals which process comprises applying to the surface of the animals the com-5 position 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 of our invention are applied 10 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 15 poured on to the back of the animal.

In a further preferred embodiment of our invention the compositions additionally contain one or more carboxylic acids selected from the group consisting of to Cg alkanoic acids. The molar ratio of alkanoic 20 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 25 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 C^ to C^ acids, in 30 particular acetic and propionic acid. Higher molecular weight acids, for example stearic acid, can be used tout provide less blood level enhancement than the C^ to Cg alkanoic acids. 2 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 A formulation is prepared with the following composition: Rhodamine 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: Rhodamine 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-raethoxy-2-propanol is replaced with l-Ethoxy-2-propanol.

Example 4 A formulation is prepared with the following composition: Rhodamine 0.1% w/v Cyhalothrin 1% w/v Levamisole free base 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 15 is 1.8% w/v.

Example 8 Cattle were treated with the fomrulation of Example 1 by pour-on application along the spine. The applied dose was 1 ml/kg bodyweight to provide an 20 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 body-weight.

Blood samples were drawn from the animals at 25 regular time intervals and heparinized. The plasma obtained by centrifugation was then analyzed for levamisole by a procedure involving clean-up on "Sep-Pak" C18 cartridges ("Sep-Pak" is a registered trade mark of Waters Associates) followed toy a final determination by 30 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 20f 5 ? C.y.3 by those skilled in the art to give effective control of helminth parasites.

TABLE 1 Treatment Animal number Levamisole conc (ppm) in plasma after treatment Hours: 1 2 3 7, Injectable formulation 1 1.1 0.6 in • o 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 Example 9 Lice-infested sheep were 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 were inspected periodically and within 14 days were completely 10 free of lice.

Comparative Example 1 A formulation was prepared with the composition of Example 1 except that the ethylene glycol diacetate was omitted when this formulation was applied to three 15 sheep by the procedure of Example 9 at an application

Claims (14)

202322 - 12 - dose of 4 ml tissue hardening on the animal was noted after six days. Comparative Example 2 A formulation was prepared with the composition 5 of Example 4 except that the ethylene glycol diacetate was 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. 10 Comparative Example 3 A formulation was 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 15 dose of 4 ml. After six days the tissue at the site of application was dry and cracking hard occurred. 202522 - 13 -

1. A pour-on composition for controlling or eradicating ectoparasite and endoparasite infestations in animals comprising an ectoparasiticidal amount of cyhalothrin and an endoparasiticidal amount of tetramisole free base or an optical isomer thereof in a carrier comprising a first solvent selected from the group consisting of to alcohols alkoxylated with from one to three moles of ethylene oxide per mole of alcohol, and C^ to alcohols 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^ to Cg alkyl)esters of C2 to Cg dicarboxylic acids, di(C2 to Cg alkanoyl) esters of to Cg dihydric alcohols,' and C2 to Cg carboxylate esters of alcohol alkoxylates prepared by reacting one mole of a C^ to Cg alcohol with from one to three moles of an alkylene oxide selected from ethylene oxide and propylene oxide, mixtures thereof.

2. A pour-on composition according to claim 1 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 C2 to Cg dicarboxylic acids are adipic acid and sebacic acid and the C2 to Cg dihydric alcohols are ethylene glycol, propylene glycol, diethylene glycol arid triethylene glycol.

5. A pour-on composition according to claim 4 wherein the concentration of levamisole free base is in the range of from 1.0 to 25% w/v and the concentration of the cyhalothrin is in the range of from 0.2 to 5% w/v.

6. A pour-on composition according to claim 5 wherein the carrier forms 70 to 98% w/v of the composition i, - 14 - J202 $2,0L -ȣ-3 and the weight/weight ratio of the first solvent to the co-solvent is in the range from 9:1 to 1:1.

7. A pour-on composition according to any one of claims 4 to 6 wherein the first solvent is selected from the group consisting of 2-propoxyethanol, 2-butoxyethanol, l-methoxy-2-propanol and l-ethoxy-2-propanol, and mixtures thereof.

8. A pour-on composition according to any one of claims 4 to 6 wherein the co-solvent is selected from the group consisting of ethylene glycol diacetate, 2-propoxyethyl acetate, 2-butoxyethyl acetate and 1-methoxypropyl-2-acetate, and mixtures thereof.

9. A pour-on composition according to claim 5 or claim 6 wherein the carrier comprises 2-butoxyethanol and ethylene glycol diacetate.

10. A pour-on composition according to any one of claims 2 to 9 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.

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

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

13. A method of controlling or eradicating ectoparasite and endoparasite infestations from animals which method comprises applying to a portion of said 202522 - 15 - animal a composition as claimed in any one of claims 1 to 12.

14. Pour-on composition according to any one of claims 1 tc 12 substantially as herein described with reference to the examples. mimics £4/^ sr.- es J A. J. x per agsnts for the applicants.