AU2017200250B2

AU2017200250B2 - A Tick Treatment

Info

Publication number: AU2017200250B2
Application number: AU2017200250A
Authority: AU
Inventors: Dudley Gradwell
Original assignee: Anidea Ltd
Current assignee: Anidea Ltd
Priority date: 2016-01-28
Filing date: 2017-01-13
Publication date: 2020-08-27
Anticipated expiration: 2037-01-13
Also published as: ZA201700689B; AU2017200250A1

Abstract

The invention relates to use of fluazuron in the production of a subcutaneous injection medicament for treating or preventing ticks in cattle with fluazuron in the amount of 5 about 3 mg per kg to about 7.5 mg per kg of animal body weight. 10 15 20 12 Figure 1 :Fluazuron levels in serum .. .................. ......... ......... ................... ................. ............................................................................. . i ............ .. . ....................... ... .... . ..... AS .k t .. .N ............ .. ................. ............... . ... ... .. ... .. ... ... .. ... .. .. ... ... .... ... ..k ................... .................. .. .. .. .. ... .. .. .. ... .. .. .. ... .. .. .. ... .. .. .. .... .. .. .. .. .. .. ... .. .. .. .. .. ... .. .. .. .. .. .

Description

Figure 1

:Fluazuron levels in serum

.. .................. ......... ......... ................... ................. .........................................

. i............ .. .......................

. ....... . ..... AS .k t

...N............ .. ............... ............. . ...... .. ... .. ... ... .. ... ..

.................k ............... .................. ....

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TITLE A Tick Treatment

BACKGROUND Cattle suffer from tick infestation in many parts of the world. The parasite affects cattle by taking large quantities of blood, and also in by spreading diseases such as babesiosis and anaplasmosis.

It is known to treat ticks in cattle by applying the growth regulator fluazuron as a pour on product. This is administered in two bands, one on each side of the animal between the shoulders and rump at doses of 1.5 to 3 mg/kg. The product is taken in orally by animals licking themselves, and each other, as part of their normal grooming behaviour. It is usually necessary to administer the product up to three times in order to achieve tick control for one season.

It is an object of a preferred embodiment of the invention to go at least some way towards treating or preventing tick infestation in cattle. While this object applies to the preferred embodiment, it should not be seen as a limitation on the claims. The object of the invention per se is simply to provide a useful choice.

The term "comprising" if and when used in relation to a combination of features should not be taken as excluding the possibility of there being additional unspecified features. Additional features may or may not be present and therefore the term should not be interpreted exclusively.

SUMMARY OF THE INVENTION

In one aspect, the invention involves the use of fluazuron in the production of a subcutaneous injection medicament for treating or preventing ticks in cattle with fluazuron in the amount of about 2.5 mg/kg to about 7.5 mg/kg of animal body weight.

Optionally the fluazuron is in the amount of about 3 mg/kg to about 7.5 mg/kg of animal body weight. Optionally the medicament is for treating or preventing ticks in cattle with fluazuron in the amount of about 3.5 mg/kg to about 6.5 mg/kg of animal body weight.

Optionally the medicament is for treating or preventing ticks in cattle with fluazuron in the amount of about 4.5 mg/kg to about 5.5 mg/kg of animal body weight.

Optionally the medicament is for treating or preventing ticks in cattle with fluazuron in the amount of 5mg per kg of animal body weight.

Optionally the medicament is in a concentration of 100 g to 400 g fluazuron per litre.

Optionally the medicament is in a concentration of approximately 1OOg to approximately 250g fluazuron per litre.

Optionally the medicament is in a concentration of 250g fluazuron per litre.

Optionally the medicament is in a concentration of 1OOg fluazuron per litre.

Optionally the medicament comprises: * N-methyl-pyrrolidone and/or 1-Methyl-2-pyrrolidone as solvent; and * emulsifier (eg polyoxyethylene (20) sorbitan monooleate).

Optionally the fluazuron is the only active ingredient.

Optionally the medicament includes one or more pesticides (for example selected from levamisoles, macrocyclic lactones (eg eprinomectin) and fluckicides).

In a further aspect, the invention involves a method of treating or preventing ticks in cattle, comprising subcutaneously injecting an individual with a medicament to deliver about 2.5 mg to about 7.5 mg fluazuron per kg of body weight.

Optionally the method involves injecting the individual with about 3.5 mg/kg to about 6.5 mg/kg fluazuron per kg of body weight.

Optionally the method involves injecting the individual with about 4.5 mg/kg to about 5.5 mg/kg fluazuron per kg of body weight.

Optionally the method involves injecting the individual with about 5mg fluazuron per kg of body weight.

Optionally the medicament is in a concentration of 250g fluazuron per litre.

Optionally the medicament is injected in the amount of 1 ml/50 kg of body weight.

Optionally the medicament is in a concentration of 1OOg fluazuron per litre.

Optionally the medicament is injected in the amount of 2 ml/50 kg of body weight.

Optionally the medicament comprises: • N-methyl-pyrrolidone or 1-Methyl-2-pyrrolidone as solvent; and • emulsifier (eg polyoxyethylene (20) sorbitan monooleate).

Optionally the fluazuron is the only active ingredient.

Optionally the medicament is injected to provide fluazuron blood levels of at least 15ug/litre for at least 60 days.

References in this document to amounts or concentrations of fluazuron are to fluazuron per se. However it should be understood that they are intended to include other chemical forms of fluazuron, if any, with the weight amounts adjusted accordingly to provide a substantially equivalent amount of active ingredient.

DRAWING

Some forms of the invention will now be described by way of example and with reference to figure 1, which illustrates the results of a fluazuron trial on cattle.

DETAILED DESCRIPTION

One embodiment of the invention provides a medicament for achieving sustained high blood levels of fluazuron by using stable injections to achieve prolonged tick control in bovines, for example in dairy cows or other cattle. Previously known cattle pour-on formulations are prepared at concentrations of 25 g/l fluazuron and are administered topically at doses of 1.5 to 3 mg/kg of animal body weight. By contrast, the present invention embraces an injection formulation comprising 250g fluazuron per litre for injecting cattle at doses of 1ml per 50kg of animal body weight, or 5mg fluazuron per kg animal body weight. In a further embodiment of the invention the formulation has fluazuron at 100gm / litre for injecting an animal with 2ml per 50 kg of animal body weight. Injection doses between these amounts are also within the scope of the invention.

It has been found, quite surprisingly, that sub cutaneous injection of cattle with a medicament to deliver 5mg fluazuron per kg animal body weight in a single administration provides good treatment and protection against ticks over an extended period. While the exact mechanism of action is not yet fully understood, it is believed that when fluazuron is delivered in this way it is stored in the animals' tissues, especially fatty tissue, and is gradually released back into the bloodstream to provide prolonged treatment and protection against ticks.

Prototype Formulation

In a particularly preferred embodiment of the invention a prototype formulation for cattle injection was made to have the following components:

Component Amount Function (% by weight)

Fluazuron 25 Active ingredient

Sorbitan-Poe(20) 10 Emulsifier monooleate

Methyl paraben 0.2 Preservative

N-methyl-pyrrolidone 64.8 Solvent

The formulation was prepared by placing 300g of N-methyl-pyrrolidone or 1-Methyl-2 pyrrolidone (NMP) in a vessel and adding 50g of Sorbitan Poe(20) Monoleate with mixing until dissolved. An amount of 126.26g of Fluazuron (99%) was then also added with mixing until dissolved. Additional NMP was mixed in to bring the formulation up to 500ml.

Stability

The prototype formulation was analysed and found to contain 25.84% by weight of fluazuron, with a density of 1.119 g/ml. Separate samples were stored at 25°C and 40°C, in each case for for 3 and 6 months. They were tested at the end of these periods, and in each case they had substantially retained their flurazon content. In other words they remained within the desired paremeters of 22.5% - 27.5% by weight flurazon, and 25.74% - 25.76% by weight flurazon, respectively. As these are standard test temperatures the results indicated that the formulation was stable.

Trials

The prototype formulation was subcutaneously injected into two cattle in the front of the shoulder on the upper part of the neck. No abnormal signs or evidence of pain were seen during or after injection. When observed 1 hour after the injection the animals were eating normally and showed no signs of discomfort. They were observed and inspected for a further 12 days and throughout that period there was no evidence of swelling at the injection site or any other adverse effects.

A confidential controlled field trial was conducted in the Gauteng Province in the Rayton area of South Africa. It compared the prototype formulation with a current 2.5% by weight market pour-on fluazuron formulation. In this regard a total of 80 cattle were used as test subjects. A count for blue ticks (Rhipicephalus decoloratus) was done on each animal and they were ranked from highest to lowest in terms of the number of ticks present. The 23 animals with the highest tick numbers were randomly divided into three groups of 8, 8 and 7. They had all been running on the same farm for their whole life. The animals were treated as follows:

Group 1: 8 cattle were treated topically with a 2.5% fluazuron pour-on (Acatak Pour-On, South African registration No. G2422) on day 'O' at a dose of 6ml/50kg body weight (equivalent to 3 mg flurazon per kg of body weight).

Group 2: 8 cattle were injected with the prototype formulation (25% fluazuron) on day 'O' at a dose of 1ml/50kg body weight (equivalent to 5 mg flurazon per kg of body weight).

Group 3: 7 cattle were left untreated, as a control.

Some of the remaining animals with high tick counts were also treated with the prototype formulation and allowed to run with the test animals; in the same paddocks. This was done to protect them against infection from tick borne disease.

Blood was collected from all the animals in groups 1 and 2 for serum analysis of the levels of fluazuron at various time points. Blood was only collected from the 7 control animals at day '0'. One animal from group 2 was removed from the study as it was discovered it had not in fact been treated (due to an identification error).

Figure 1 shows the results of the trial in terms of the average concentration of fluazuron in the blood at various time points. The x axis represents the number of days into the trial, with the marker "TO" indicating day 0, and "T+138" indicating day 138, etc. The prototype formulation is indicated as "25% injection" and the pour-on formulation is indicated as "Acatak". It is evident from figure 1 that with the prototype formulation high levels of fluazuron remained in the blood for extended periods of time; ie the large amount was not removed from the body early, as one would have expected.

To elaborate, figure 1 indicates that topical fluazuron was metabolised by the body rapidly after the initial dosage spike. The amount went to almost zero at around day 103. The injection on the other hand had a substantial plateaued fluazuron concentration between days 103 and 212. One would have expected the injection to show a rapid drop to the 'x axis' as occurred in the topical formulation, but that did not happen. This is consistent with storage of fluazuron in the fatty tissue.

In terms of tick count, the number of live blue ticks was counted for each animal in the three groups at days 26, 53, 83 and 103. The average number of ticks eradicated for groups 1 and 2 at each time interval, compared to the control group, was as follows:

Group Day 26 Day 53 Day 83 Day 103 (% erradicated) (% erradicated) (% erradicated) (% erradicated)

1 82 23 -82 -210

[2 45 9E5 [87 81

As can be seen, by day 53 the prototype formulation of the invention (group 2) had achieved 95% eradication of ticks, whereas the known pour-on formulation had only achieved 23% eradication. The protection provided by the pour-on formulation peaked at about 26 days and tailed off rapidly after that, which is consistent with known practices of having to apply a pour-on formulation frequently in order to maintain protection. Sometime between 26 and 53 days the ticks in the pour-on group had re-established themselves and actually increased in number. By contrast, at day 103 the prototype formulation of the invention (see group 2) was still providing good therapy.

Further Embodiments

In some preferred embodiments of the invention the formulation is prepared and administered by subcutaneous injection to deliver, on average, fluazuron blood levels of at least 15ug/litre for at least 60 days, using storage of the active component in the fat tissue of an animal to help achieve this.

In further embodiments of the invention the injection formulation may be modified to have one or more additional active ingredients, such as a suitable broad spectrum parasiticide; preferably one which dissolves relatively readily in N-methyl-pyrrolidone when at a concentration of 0.25 to 2% by weight, if necessary with suitable co-solvents such as propylene glycol. Examples include abamectin, ivermectin, moxidectin, eprinomectin, doramectin and selamectin. In some embodiments the additional active(s) may comprise levamisole or suitable salts thereof, and/or a flukicide such as clorsulon and/or nitroxynil.

While some preferred forms of the invention have been described by way of example it should be appreciated that modifications and improvements can occur without departing from the inventive principle and/or the accompanying provisional claims.

Claims

1. The use of fluazuron in the production of a subcutaneous injection medicament for treating or preventing ticks in cattle with fluazuron in the amount of 3.5 mg per kg to about 7.5 mg per kg of animal body weight.

2. A use according to claim 1, wherein the medicament is for treating or preventing ticks in cattle with fluazuron in the amount of 3.5 mg per kg to about 6.5 mg per kg of animal body weight.

3. A use according to claim 1, wherein the medicament is for treating or preventing ticks in cattle with fluazuron in the amount of about 4.5 mg per kg to about 5.5 mg per kg of animal body weight.

4. A use according to claim 1, wherein the medicament is for treating or preventing ticks in cattle with fluazuron in the amount of 5mg per kg of animal body weight.

5. A use according to any one of the preceding claims, wherein the medicament is in a concentration of 100 g to 400 g fluazuron per litre.

6. A use according to any one of the preceding claims, wherein the medicament is in a concentration of approximately 100 g to approximately 250g fluazuron per litre.

7. A use according to claim 6, wherein the medicament is in a concentration of approximately 250g fluazuron per litre.

8. A use according to claim 6, wherein the medicament is in a concentration of 1Og approximately fluazuron per litre.

9. A use according to any one of the preceding claims, wherein the medicament comprises: * N-methyl-pyrrolidone and/or 1-Methyl-2-pyrrolidone as solvent; and * emulsifier (eg polyoxyethylene (20) sorbitan monooleate).

10. A use according to any one of the preceding claims wherein the fluazuron is the only active ingredient.

11. A use according to any one of the preceding claims, wherein the medicament comprises one or more additional pesticide(s).

12. A use according to claim 11, wherein the additional pesticide(s) is/are selected from levamisoles, macrocyclic lactones and fluckicides.

13. A method of treating or preventing ticks in cattle, comprising subcutaneously injecting an individual with a medicament to deliver 3.5 mg to about 7.5 mg fluazuron per kg of body weight.

14. A method according to claim 13, involving injecting the individual with 3.5 mg/kg to about 6.5 mg/kg fluazuron per kg of body weight.

15. A method according to claim 13, involving injecting the individual with about 4.5 mg/kg to about 5.5 mg/kg fluazuron per kg of body weight.

16. A method according to claim 13, involving injecting the individual with about 5mg fluazuron per kg of body weight.

17. A method according to any one of claims 13-16, wherein the medicament is injected to provide fluazuron blood levels of at least 15ug/litre for at least 70 days.

18. A method according to any one of claims 13-17 wherein the fluazuron is the only active ingredient.

19. A method according to any one of claims 14 to 18 comprising one or more additional pesticide(s).

20. A method according to claim 19, wherein the additional pesticide(s) is/are selected from levamisoles, macrocyclic lactones and fluckicides.

21. A method of treating or preventing ticks in cattle, comprising administering to an animal a flurazon formulation, eg on a daily basis, so there are sufficient blood levels of flurazon to at least substantially protect the animal for at least 60 days.