NZ202526A - Endoparasiticidal(pour-on)compositions containing tetramisole - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £02526 202526 Priority Date(s): ..

Complete Specification Msd: Class: I Publication Date: ... H .1 .OCT 1985 P.O. Journal, No: ..

No.: Date: NO DRAWINGS NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION A POUR-ON COMPOSITION FOR CONTROLLING OR ERADICATING ENDOPARASITE INFESTATIONS IN ANIMALS vfitlWe, ici AUSTRALIA LIMITED, a Company Incorporated under the laws of the State of Victoria, Australia, of 1 Nicholson Street, Melbourne, Victoria 3000, Australia hereby declare the invention for which^/ we pray that a patent may be granted togggft/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 2 - lo^ 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 for the 5 control of endoparasites.

Topical application of parasiticides for the control of endoparasites is well known and usually takes the form of injecting or drenching animals with suitable formulations of the parasiticides. Recently attempts 10 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 in-15 herent advantages over the other techniques 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 endoparasiticides have so far suffered from a number of 20 disadvantages. The range mf parasiticides which are Affective 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 consider- 2025 able 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 5 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.

It is an object of the present invention to 10 provide effective and non-toxic solvent systems that are tolerated by animals with a vide range of type and degree of sensitivity./ In the case of pour-on application to sheep, .immediately after shearing is potentially a good time 15 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 utill a "y Significant barrier to fche ^topically applied coaa-'^os it ions particularly in the case of Merinos because 20 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 aedication. this layer of wool grease can reach a very high level in Merinos. Zt is a further object of 25 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, 30 ; paraffins, isoparaffins, cycloparaffins and aromatics such as the xylene, are well known. However these solvents, which effectively penetrate the wool grease cover, produce severe tissue reactions such as pain. selling, 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 10 vhich 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. 15 Accordingly we provide compositions for topical application to animals for the control of endoparasites which compositions comprise levamisole or tetramisole in its free base form in a carrier comprising a first solvent selected from the group consisting of to 20 alcohols alkoxylated with from one to three moles of ethylene oxide per mole of alcohol, and 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 25 from ditC^ to Cg alkyl) esters of C2 to Cg dicarboxylic acids, di(C2 to Cg alkanoyl) esters of C2 to Cg dihydric alcohols, and C^ 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 30 oxide selected from ethylene oxide and propylene oxide, and mixtures thereof.

TCie preferred C2 to Cg dicarboxylic acids are adipic acid and sebacic acid, and the preferred esters of these acids are dimethyl adipate, diethyladipate, 35 dimethyl sebacate, and diethyl sebacate. The preferred 202,' 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-tetra-hydroimidazo^2,3-b7thiazole. Levamisole is the cornnon name for the laevo-rotatory optical isomer of tetramisole. For the conqpositions 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.

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-&0 «thyl acetate, 2-butoxyethyl acetate and 1-methoxy- .propyl-2 acetate, and mixtures thereof. The most preferred carrier comprises 2-butoxyethanol and ethylene >glycol diacetate.

T ^ These ^particular carriers provide rapid vetting >%>f ,-fche wool «r Siair of the animal permitting movement ",:'"^to 'the skin level with minimal run-off and loss of formulation, and have the required solubility for the &ii$opar asites^ 5 Preferably the weight/weight ratio of the first 30 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 particular concen-35 tration can be readily chosen by those skilled in the 207,526 art so that when a selected quantity of the solution of the endoparasiticide is applied topically to the animal then the parasticide will be present in an effective amount to control the particular parasitic infestations 5 in the animal.

For animals infested with parasitic gastro intestinal and pulmonary nematodes such as Haemonchus spp., Ostertagio spp., Trichostronglio spp., Nematodirus spp., Oesophagostomum spp., Chabestia spp., 10 and Dictyocaulus spp. a typical effective amount of levamisole free base is approximately 10 mg/kg of animal body weight by topical application., The preferred compositions comprises from 5 to 20% of levamisole free base in a preferred carrier such 15 that the levamisole free base is close to the saturation point in that carrier.

The species of parasites controlled by levamisole have been we11-documented in the prior art. It is a particular feature of our compositions that the 20 levamisole is 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.

Thus, for example, a composition containing 5% 25 w/v of levamisole applied at the rate of 0.2 ml/kg of animal bodyweight gives effective control of helminths.

While the compositions are particularly effective for control of endoparasites in cattle and sheep ±hey may also be used for pigs and domestic animals 30 such as dogs and cats* 20252$ 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-5 phenol. 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% w/v, in the final composition. 10 in a further embodiment of our invention we 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 15 aboided. Suitable non-fast dyes soluble in the compositions will be readily selected by those skilled in the art so that the 4yed 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 parti-20 cularly useful dye is rhodamine which is typically used 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 com-25 prises applying to the surface of the animals the composition of our invention comprising levamisole or tetramisole in the free base form in a c. first solvent as hereinbefore defined and a co-solvent as hereinbefore defined.

The compositions of our invention 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 202 5 brushing or rolling-on but more conveniently are simply poured on to the back of the animal.

In a further preferred embodiment of our invention the compositions additionally contain one or 5 more carboxylic acids selected from the group consisting of 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 10 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 15 to levamisole free base is in the range of 0.5 to 1.0. ;The preferred alkanoic acids are the C^ to c4 acids, in particular noetic and propionic acid. Higher molecular weight acids, for example stearic acid, can be used but provide less blood level enhancement them the C^ to Cg 20 alkanoic acids. 2025 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 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 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-ethoxy-2-propanol.

A formulation J.8 prepared with &he following composition: Rhodamine 0.1% w/v Levamisole free base % w/v 20232 Ethylene glycol diacetate 20% 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 formulation 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 mgAg body-weight.

Blood samples were drawn from the animals at 25 ^regular time intervals and heparinized. The plasma ob- Jtained by centrifugation was then analyzed for :';:-^|ttvmi8ole ty m ^ocedure'3|jHrolving fclean-up*>n *Sop-Pak" registered trade mark of Haters Associates) followed t>y 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 ?$?,$ 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 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 - u - 2025 26 Example 9 The procedure of Example 8 was followed with the pour-on formulation of the following composition; Levamisole free base 10% w/v Ethylene glycol diacetate 20% w/v 2-Butoxyethanol to 100 vols The results for the treated animals are shown in Table 2.

Example 10 The procedure of Example 8 was followed with a pour-on formulation of the following composition: Levamisole free base 10% w/v Acetic acid 2.5% w/v Ethyleneglycol diacetate 20% w/v 2-Butoxyethanol to 100 vols The results for the treated animals are shown in Table 2.

Example 11 The procedure of a pour-on formulation of The results are shown in Example 8 was followed with the composition of Example 4. Table 2.

TABLE 2 Example Levamisole conc (ppm) in plasma after treatment Hours: 1 2 3 4 9 Animal No 1 No 2 0.22 0.33 0.39 0.44 0.16 0.31 0.56 0.53 Animal No 1 No 2 0.69 1.61 1.21 1.07 0.14 0.31 0.87 0.82 11 ■ 0.36 0.77 0.81 1.14 Comparative Example 1 A formulation was prepared with the composition of Example 1 except that the ethylene glycol diacetate 5 was omitted when this formulation was applied to three sheep by the procedure of Example 8 at an application dose of 4 ml tissue hardening on the animal was noted after six days.

Comparative Example 2 10 A formulation was prepared with the composition of Example 4 except that the ethylene glycol diacetate was omitted. When this formulation was applied to three sheep by the procedure of Example .8 at an application dose of 4 ml, the tissue at the site of application be-15 cane dry and hard after six days.

Claims (13)

- 13 - 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 8 at an application dose of 4 ml. After six days the tissue at the site of application was dry and cracking hard occurred. <2 o& r"2£ 202526 WHAT i •- CLAJM IS: 14

1. A pour-on composition for controlling or eradicating endoparasite infestations in animals comprising 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 to Cj 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 alky1)esters of C2 to Cg dicarboxylic acids, di (C2 to Cg alkanoyl) esters of C2 to Cg dilrydric 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, and . 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 where- -in the C„ to C, dicarboxylic acids are adipic acid and r " sebacid acid and the C2 to Cg dihydric alcohols are ethylene glycol, propylene glycol, diethylene glycol and 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 2 5% w/v.

6. A pour-on composition according to claim 5 wherein the carrier forms 70 to 98% w/v of the composition 7 £..\ •> J ■SC2526 - 15 - 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-butoxy-ethanol 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 nolar 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 aquiaolar proportions.

12. A method of controlling or eradicating endo-parasite infestations from animals which method comprises applying to a portion of said animal a composition as claimed in any one of claims 1 to 12.

13. Pour-on composition as claimed in any one of claims 1 to 11 substantially as herein described with reference to the examples. ' I C| tfcti m