MXPA00006039A - Aqueous insecticidal pour-on formulation - Google Patents

Abstract

A topically acceptable aqueous pour-on formulation adapted for localised external application to an animal, which format includes an effective amount of a water insoluble insect growth regulator (IGR), a suspending agent, a surfactant or mixture of surfactants, and an aqueous carrier

Description

TOPICAL AQUEOUS INSECTICIDE FORMULATION FIELD OF THE INVENTION The present invention relates to an aqueous topical formulation of water-insoluble insect growth regulator (IGR), and to a method for treating animals using this formulation.

ANTECEDENTS OF THE TECHNIQUE Traditionally, the animals have been treated in a general manner for the control of parasites, either by immersing the whole animal in a bath containing an effective agent against parasites or by spraying the entire surface of the body of the animal with said agent. Recently, it has been found that a number of effective substances against parasites can be applied by local application (the so-called "topical" application). Although the anti-parasite effective substance is supplied by local application, the active agent migrates to protect the animal's total external surface. By "local application" it is meant that the active ingredient is only applied to a minor portion of the animal's external surface, generally as a line or spot on the animal's back.

Formulations of the prior art (a) Non-aqueous topical formulations Various topical formulations are described in the Australian patents nos. 560078, 563723, and 546672. In most topical formulations, and in all topical water-insoluble IGR formulations known to the inventors, the active agent is dissolved in a non-aqueous solvent system to produce a suitable topical formulation. It has become apparent that non-aqueous topical formulations also possess a number of disadvantages. In particular, the formulation may present handling problems caused by the flammability or toxicity of the solvents, and lead to high levels of residue in the tissue in animals treated with the formulations. Formulations based on water immiscible solvents are drained in wet animals or washed by rain that occurs after treatment. When in contact with water, the active precipitates quickly from non-aqueous formulations based on water-miscible solvents. If this formulation is applied to a wet animal, or if the animal is exposed to rain before the treatment has dried on the animal, the active is precipitated from the solution and deposited on the back of the animal, the solvents being also washed by the rain. This prevents or prevents the dispersion of the active ingredient around the entire animal. This phenomenon is particularly important in the areas of the ventral side of the animal. This reduces the effectiveness of the solvent-based formulations only under these conditions. (b) Aqueous immersion formulations An aqueous immersion formulation of IGR is also known. However, said immersion formulation will not be suitable as a topical formulation neither in the diluted nor undiluted state for the following reasons.

• Undiluted immersion formulation This will not be satisfactory because: (i) in order to supply the same amount of assets per animal, the volume of doses will be very small. That is, 2 mL will be applied to most animals, which will be a matter of importance for accurate dosing by farmers. A very small dose volume will be very local to allow dispersion to all parts of the animal as described above. (ii) Due to the high levels of surfactants in an undiluted dipping formulation, the presence of water, particularly high precipitation, will cause the washing of active compound from the animal.

• Diluted immersion formulation This situation will arise when the aforementioned immersion formulation is diluted to achieve what is considered a satisfactory concentration of active. However, this will not be satisfactory for the following reasons: (i) if the immersion formulation were diluted in a container or tambo, the active would almost immediately begin to settle in the formulation due to the dilution of the suspending agent. This will create higher / lower dosing as described above. (ii) because the sedimented asset will no longer be associated with the dispersing / wetting agents, will be deposited essentially along the line of application and will not have means to disperse. With respect to the possibility of aqueous topical formulations, and based on non-aqueous topical formulations, those skilled in the art will believe that topical water-containing formulations containing water-soluble IGRs will not be effective due to problems with dispersion and stability. physical as indicated below.

• Dispersion It has generally been believed that a non-aqueous solvent is required both to dissolve the water-soluble IGR and to help disperse the active to reach all parasites on the animal. Without such dispersion, the asset will not reach all the parasites, and therefore will be ineffective. This dispersion, particularly with sheep, also involves the movement of the asset in the fatty layer of the wool. This is facilitated by the solvents that "push" the asset towards the layer while providing the physical dispersion described above.

• Physical stability Due to the insolubility of the IGR in water, it is necessary to "suspend" the active ingredient in the formulation so that it does not settle during rest. If such deposition occurs to an important degree, then it is difficult to re-disperse it to reach a precise dose scale for application to the animal. Therefore, there is indeed a cake of the active compound at the bottom of the container. This is one of the main reasons why many aqueous suspensions have problems. The result is that an animal treated with product from the top of the container receives a lower dose, while an animal treated with the product from the bottom of the container receives a higher dose. This can bring fatal consequences. Aqueous formulations of water insoluble IGR are described more precisely as suspensions. It is expected that when such formulations are applied to animals as topical, the suspended active will remain at the site of application, thus exacerbating the dispersion problems described above. Furthermore, it has been shown that when other water-insoluble actives are applied to animals such as sheep in an aqueous topical formulation, most of the active compound remains with the short fibers of the wool, away from the surface of the skin where it is necessary to control the parasites.

DETAILED DESCRIPTION OF THE INVENTION Surprisingly, it has been found that an aqueous topical formulation containing a water insoluble insect growth regulator (IGR) and a mixture of surfactants and wetting agents is effective in controlling lice in sheep. The formulation has the advantage over traditional non-aqueous solvent based formulations that it spreads rapidly and leads to very low levels of pesticide residue in the tissue in animals after application. A surprising demonstration of the effectiveness of this topical formulation is that at concentrations of 12.5 and 25.0 g / L diflubenzuron, when applied as a 20 ml dose along the back of the sheep, a 100% elimination of lice was reported in a period of 20 weeks. The majority of the lice (95%) were eliminated within 10 weeks subsequent to the application with the remaining being eliminated during the rest of the 20 week period. Surprisingly, it has also been found that applying the formulations of this invention to an already wet animal does not affect the efficiency of the formulation. Likewise, if it rains shortly after the formulations of the invention are applied, the efficiency rate of the active compound increases in comparison with situations where precipitation does not occur after the treatment. In both cases, it is believed that the surfactants promote the dispersion of the active compound on the surface of the animal. Therefore, in a first aspect, the present invention provides a topically acceptable aqueous topical formulation adapted for local external application to an animal, which formulation includes an effective amount of a water insoluble insect growth regulator (IGR), an agent in suspension, a surfactant or mixture of surfactants, and an aqueous vehicle. Due to the insolubility of IGR in water, it is necessary to suspend the active ingredient in the formulation so that it does not settle out during rest. Likewise, it is necessary to include in the formulation a sufficient amount of a suspending agent. In a second aspect, the present invention provides a method for controlling external parasites on an animal, said method includes the external application to an animal of an effective amount of an aqueous topical formulation adapted for local external application to an animal, said formulation includes a effective amount of an insoluble IGR in water, a suspending agent, a surfactant or mixture of surfactants, and an aqueous carrier. Any water-insoluble IGR can be used in the formulation according to the present invention. Suitable IGRs include diflubenzuron, triflumuron, fluazuron and methoprene. A particularly preferred IGR is diflubenzuron. For the formulation to be effective, the IGR must be suspended in the aqueous vehicle. Suitable suspending agents include xanthan gum, colloidal silica, bentonite, polyvinylpyrrolidone, cellulose derivatives and alginates. The particularly preferred suspending agent is xanthan gum. Any anionic or nonionic surfactant can be used in this formulation. A preferred anionic surfactant is alkylated naphthalene sulfonate, formaldehyde polymer, sodium salt. An effective amount of surfactant should be incorporated into the formulation to provide sufficient dispersion activity when applied to the animal. The preferred nonionic surfactants are alkyl polysaccharides; ethoxylates of alkylphenols. A preferred alkylphenol ethoxylate is ethoxylated from nonylphenol. Other ingredients may be suitably included, for example, wetting agents, thickeners, humectants, preservatives, pH regulators, foam antifoaming agents, diluents, excipients, adjuvants, and / or vehicles. Also active are those that have an immediate effect (ie ("annihilation"), dyes (washable, water soluble), antioxidants or UV stabilizers (eg, oxybenzone), and tixatropic agents.A preferred humectant is polyethylene glycol.

Thus, in a third aspect, the present invention provides a method for formulating a topically acceptable aqueous topical formulation adapted for local external application in an animal, said method comprising the formation of a first component by mixing a humectant and a nonionic surfactant. until it is homogeneous; add water and mix until homogeneous; add pH regulator and anionic surfactant; add insect growth regulator (IGR); forming a second component by mixing humectant and thickener; and combining said first and second component. Conveniently, the first and second components are diluted to a desired and final volume. In addition, conveniently, the IGR is milled to form a particle size between 2 and about 5 μm. The appropriate scales for the ingredients are as follows: a) Active 5 - 50g / L b) Surfactants (non-ionic) 10 - 100g / L c) Surfactants (anionic) 1 - 20g / L d) Wetting agent 1 - 20g / L e) Thickener 3 - 10g / L The "normal" relationship of the previous ones would be a): b): c): d): e) = : 6: 1: 1: 1. A more general description of the relationship would be active compound: surfactants / wetting agents / thickeners = 1: 2. These relationships are not expected to vary significantly with the type of active or surfactant. The most effective relationship is that of the most preferred formulation that has been "balanced" to optimize all of the above. The optimum pH for this formulation is in the pH 5-9 scale. A particularly preferred formulation using the scales of prior concentrations include diflubenzuron as the active; nonylphenol ethoxylate, alkylated naphthalene sulfonate, formaldehyde polymer, sodium salt, as the surfactant mixture; Sodium lauryl sulfate as the wetting agent and xanthan gum as the thickening or suspending agent. Conveniently, topical formulations include a coloring agent to allow the user to visually monitor the application of the formulation in the animal. The nature of the coloring agent is not important and a wide variety of suitable dyes and pigments will be known to those skilled in the art. Suitably, the ingredients are formulated as follows: a) half of the propylene glycol and the nonionic surfactant are mixed in a mixing vessel until homogeneous. Then add water and mix until homogeneous. Followed by the pH regulator and the anionic surfactant. Typically, the foam anti-foaming agent is added and the mixture is stirred, b) The active ingredient is added and mixed until it becomes homogeneous, c) The other half of the propylene glycol is mixed with the xanthan gum and then added, and Again the mixture is stirred until uniform mixing has occurred. The final volume is adjusted with water if necessary. The topical formulation can be formulated for application by a spray technique, for example, as an aerosol using a liquid or gas as a propellant. Depending on the effectiveness of the active agent used in particular, the formulation will generally contain from about 5 to about 50 g / L of the active agent. External parasites that can be treated according to the invention include ticks, fleas, flies (e.g., blue sheep flies, buffalo flies, nuisance flies), lice (e.g., sheep lice and cattle) and mites (for example. example, sheep mites). The mentioned insects and parasites are only indicative, and numerous other insects and parasites can be treated by the method of the present invention. Suitably, the compositions and method of this invention can be used to treat lice from the body of the sheep that are classified as follows: order- Phthiraptera, suborder- Mallophaga, family- Trichodectidae, genus- Damalinia (Bovicola, Tricholdectes), species- Bovicola ovis (Schrank). The animal is preferably a mammal, and can be selected from sheep, cattle, deer, goats, pigs, dogs and cats. The animal can also be a bird.

PREFERRED MODALITIES OF THE INVENTION Now the preferred embodiments will be described by way of non-limiting examples.

EXAMPLE 1 TABLE 1 Topical formulation of diflubenzuron for lice in sheep (25 q / L) EXAMPLE 2 Test details Target parasites Order- Phthiraptera, suborder- Mallophaga, family-Trichodectidae, genus- Damalinia (Bovicola, Trichodectes), species- Bovicola ovis (Schrank) and common name- lice from the body of sheep.

Test animals The sheep used in this study were a uniform line of merino rams heavily infected with lice. The method requires inspection of twenty parts each 10 cm long, along two contours on the left and right sides covering the wool growth regions of the animal. All live adult lice are counted in each of the 40 registered sites. Site counts are added together to give a total account for the animal. The evaluation of lice populations in this way also allows the production of a map, which shows how the lice are distributed in the body of the marked sheep.

TABLE 2 Test treatment Within 24 hours after shearing, treatments were applied as a single strip along the back of the sheep. The dosage rate applied was based on 20 mL of treatment per animal which is based on all test animals that are on the weight scale of 30.1 - 55 kg. The delivery apparatus for each formulation was a commercial applicator, fixed to deliver 1 x 20 mL doses to the back of the sheep. The gun was calibrated using a volumetric cylinder and checked twice before and once after treatment. To avoid the possibility of rain that would complicate the post-treatment situation, the sheep were kept in enclosures for a minimum of 48 hours. Then, on the morning of the 25th day of the trial, they were placed in their pens. Lice evaluations were done on all the sheep 2, , 10 and 20 weeks after treatment.

EXAMPLE 3 Effect of Diflubenzuron Formulations on Sheep Lice Concentrates and Lice Arithmetic Counts by Group (Standard Deviations)! TABLE 3 TABLE 4 EXAMPLE 4 Efficacy test Effect of diflubenzuron in 12.5 and 25.0 g / L of topical application formulations (head lice corrected counts) [results of Table 3 converted to% lice reduction] TABLE 5 EXAMPLE 5 Moistening test result TABLE 6 TABLE 7 Note that these reductions have been calculated using the mean head lice counts of group 5, that is, the lamb remains dry. The following equation was used to calculate the percentage of lice reductions. % reduction = [1- (untreated PT / PT treated x treated time T / untreated time T)] 1 x 100, where PT is the average number of lice, and T is the average number of lice in a time after the treatment.

EXAMPLE 6 Efficacy test in the enclosure (control of cattle lice) Efficacy of topical application of 25 g / L of diflubenzuron against lice of cattle.

TABLE 8 EXAMPLE 7 Field Effectiveness (prevention of blue-billed fly pickets) Fourteen field efficacy trials were conducted under a range of climatic conditions in the eastern states of Australia. The data generated showed that the 25 g / L diflubenzuron formulation gave a high level of protection against stings in the body and groins. Less than 0.1% of the 2316 treated sheep suffered pickets in the body and 0.35% pickets in the groin. The fly pressure was measured using two fly traps inside each pen that housed the treated sheep.

EXAMPLE 8 Efficacy trials in closures (studies of larval implants to demonstrate effectiveness against blue bighorn fly pickets, Lucilia Cuprina) Studies carried out in enclosures have shown that the aqueous product, when applied as a spray along the back of sheep with long wool, is effective against the larval stages of the blue sheep fly Lucilia cuprina.

EXAMPLE 9 Residues of tissue Studies on tissue residues were carried out following the technique of topical aqueous application to sheep and cattle. (Reference is made to page 1, lines 34 and 35 where it is mentioned that treatment with nonaqueous topical application formulations can lead to high tissue residues in animals treated with those formulations).

TABLE 9 TABLE 10 EXAMPLE 10 Comparative stability of formulations nominally containing 25 q / L of diflubenzuron and 25 g / L of triflumuron TABLE 11 TABLE 12 Results: The efficacy data show that pre-treatment or post-treatment to rain does not affect the effectiveness of the formulation, that is, the product will be resistant to rain. Insect growth regulators act to prevent the formulation of chitin during the moulting phase of insects.

They prevent the development of immature lice present in the fleece at the time of application and those that leave the eggs in the following weeks. Adult lice die naturally after a few weeks (may reach up to 14). The surprisingly rapid annihilation effect (95.7% lice reduction) of the formulation after post-treatment rain (22 days) is shown. Four of the six sheep of the group had no lice. This shows that surfactants help to spread the formulation when the product is applied wet. The foregoing describes only some embodiments of the present invention and those skilled in the art can make obvious modifications thereto without departing from the scope of the invention.

Industrial applicability It should be clarified that the present invention will find wide applicability in the areas of agriculture and veterinary science.

Claims (23)

NOVELTY OF THE INVENTION CLAIMS

1. An acceptable aqueous topical formulation adapted for local application external to an animal, said formulation comprising an effective amount of an insect insoluble growth regulator (IGR) in water, a suspending agent, a surfactant or a mixture of surfactants and a watery vehicle

2. The formulation according to claim 1, further characterized in that the insect growth regulator is diflubenzuron, triflumuron, fluazuron or methoprene.

3. The formulation according to claim 2, further characterized in that the regulator of insect growth is diflubenzuron.

4. The formulation according to any of claims 1 to 3, further characterized in that the suspending agent is xanthan gum, colloidal silica, polyvinyl pyrrolidone bentonite, cellulose derivatives or alginates.

5. The formulation according to claim 4, further characterized in that the suspending agent is xanthan.

6. The formulation according to any of claims 1 to 5, further characterized in that the surfactant is an anionic or nonionic surfactant.

7. The formulation according to claim 6, further characterized in that the anionic surfactant is an alkylated naphthalenesulfonate, formaldehyde polymer, sodium salt, and the nonionic surfactant is an alkylpolysaccharide or an ethoxylated alkylphenol.

8. The formulation according to any of claims 1 to 7, further characterized in that it comprises moisturizing agents, thickeners, humectants, preservatives, pH regulators, foam antifoaming agents, diluents, excipients, adjuvants and / or vehicles; active compounds that have an immediate effect; colorants; antioxidants and thixotropic agents.

9. The formulation according to claim 8, further characterized in that the humectant is polyethylene glycol.

10. The formulation according to claim 8 or claim 9, further characterized in that the insect growth regulator is about 5-50 g / L; the anionic surfactant is about 1-20 g / L; the nonionic surfactant is about 10-100 g / L; the moisturizing agent is about 1-20 g / L and the thickener is about 3- 0 g / L.

11. The formulation according to claim 10, further characterized in that the insect growth regulator is diflubenzuron; the surfactants comprise ethoxylated nonylphenol, and alkylated naphthalene sulphonate, formaldehyde polymer, sodium salt; the wetting agent is sodium lauryl sulfate; and the thickener or suspending agent is xanthan gum.

12. A method for controlling external parasites, said method including the external application to an animal of an effective amount of an aqueous topical formulation adapted for local external application to an animal, said formulation comprising an effective amount of an insect growth regulator (IGR) is soluble in water, a suspending agent, a surfactant or mixture of surfactants and an aqueous carrier.

13. The method according to claim 12, further characterized in that the insect growth regulator is diflubenzuron, trifluron, fluazuron or methoprene.

14. The method according to claim 13, further characterized in that the insect growth regulator is diflubenzuron.

15. The method according to claim 14, further characterized in that the formulation further comprises a coloring agent.

16. The method according to any of claims 12 to 15, further characterized in that the formulation is applied as a spray technique.

17. The method according to claim 16, formulated as an aerosol using a liquid or gas as a propellant.

18. - The method according to any of claims 12 to 17, further characterized in that the insect growth regulator is from about 5 to about 50 g / L.

19. The method according to any of claims 12 to 18, further characterized in that the parasites include ticks, fleas, flies, lice and mites.

20. The method according to claim 19, further characterized in that the flies may be blue sheep, buffalo fly or fastidious fly; head lice can be cattle or sheep lice; and mites are sheep mites.

21. A method for formulating an acceptable aqueous topical formulation, adapted for local external application to an animal, said method comprising the formation of a first component by mixing a humectant and a nonionic surfactant until they become homogeneous; adding water and mixing until they become homogeneous; the addition of pH regulator and anionic surfactant; the addition of insect growth regulator (IGR); the formation of a second component by mixing humectant and thickener; and the combination of said first and second components.

22. The method according to claim 21, further characterized in that the first and second components combined are diluted to a desired final volume.

23. The method according to claim 21, or claim 22, further characterized in that the insect growth regulator is milled to form a particle size of between about 2 and about 5 microns.