MX2007002832A - Topical endoparasiticide and ectoparasiticide formulations. - Google Patents

Abstract

A topical formulation having significant parasiticidal activity effective against endoparasites and/or ectoparasites such as heartworms, mites, fleas, ticks, flies is provided, which can be safe to use and avoids the many common deleterious side effects of conventional topical formulations. The topical formulations comprise a combination of a macrocyclic lactone, a neo-nicotinoid and optionally, an insect growth regulator. The topical formulation can be packaged together or packaged so that the macrocyclic lactone and the neo-nicotinoid are stored separately prior to administering the topical insecticide formulation to the animal.

Description

TOPOPARTIC FORMULATIONS1TICIDES AND ECTOPARASITICIDES This application claims the benefit of the US provisional application number 60 / 607,900, filed on September 8, 2004, and is a partial continuation of the US application number 11 / 181,344, filed July 14, 2005, which is a continuation partial, and claims priority for the US application number 10 / 910,542, filed on August 3, 2004, which claims the priority benefit of the US provisional application number 60 / 493,796, filed on August 8, 2003, and the provisional application American number 60 / 554,563, filed March 19, 2004, and is also a partial continuation of US application No. 10 / 242,551, filed September 12, 2002, now US Patent No. 6,867,223, the content of which is incorporated herein by reference. BACKGROUND OF THE INVENTION This invention relates generally to topical formulations which may have significant parasiticidal activity such as insecticides, endoparasiticides, ectoparasiticides and acaricides in animal health, such as one suitable for use in domestic pets, such as dogs and cats. The infestation of companion animals with endoparasites and / or with ectoparasites such as heartworms, roundworms, hookworms, whipworms, fleas, ticks, flies, mites and the like, is highly undesirable, and as such, it is beneficial to include multiple drugs in the same formulation so that it is directed to a wider variety of parasites. Additionally, it has become common to administer both topical and internal insecticides to livestock and pets. Topical applications may be desirable, since many formulations are acceptably safe when used topically, but not when used internally. However, various typical pharmaceutical formulations have disadvantages. Some formulations require that a large volume be applied to the animal. This can cause considerable confusion and can lead to an unpleasant odor. Additionally, if the dose of a topical formulation has a large volume, it can be released when the animal is shaken, reducing the effectiveness of the formulation. Also, when the animal is a domestic pet, there is an additional complication in that the formulation has to be safe for human contact. Nor should it lead to coloring of furniture, carpeting and the like. Finally, even when they are safe, topical formulations should not be irritating or cause rashes, hair loss or other unpleasant side effects. Therefore, there is a need for an improved topical formulation for the treatment of endoparasites and ectoparasites that overcome the disadvantages of the prior art.

BRIEF DESCRIPTION OF THE INVENTION Generally, according to the invention, a topical formulation containing a macrocyclic lactone is provided, together with a neo nicotinoid and / or an insect growth regulator, particularly one for use in cats and dogs. The formulations according to the invention can be safe to use and avoid many harmful side effects of conventional topical formulations. The invention provides a topical formulation containing a combination of insecticides and insect growth regulators, which can be effective for killing endoparasites and ectoparasites such as heartworm, fleas, flea eggs, flea larvae, ticks, tick eggs , tick larvae, tick nymphs, mites and mosquitoes. The selection of the combination of insecticides and insect growth regulators produces a composition having high parasiticidal activity, thereby providing broad protection against a variety of endoparasites and ectoparasites with a single application of the topical formulation. The compositions originated here can also be useful to improve the speed of result and decrease the reappearance, compared with other formulations. The invention provides a topical formulation containing a combination of a first active ingredient, which contains a macrocyclic lactone, and a second active ingredient containing a neo nicotinoid. Preferably, the topical formulation also contains an insect growth regulator (IGR). In a preferred embodiment of the invention, the macrocyclic lactone in the composition contains at least one of ivermectin, selamectin, doramectin, moxidectin or eprinomectin. The neo-nicotinoid may contain a (tetrahyd ro-3-furanyl) methylamine derivative of the formula (I), as identified below. In another embodiment of the invention, the neo nicotinoid contains a chloronicotinyl insecticide, preferably acetamiprid. The insect growth regulator (I G R) preferably contains pyriproxyfen and / or methoprene. As used herein, the identification of an active ingredient, e.g., ivermectin, is intended also to refer to other pharmaceutically active forms of the active ingredient, such as esters, salts, chlorhydrates, acid or base forms, isomers, and so on. successively. In another embodiment of the invention, the topical formulation also contains a pyrethroid, such as permethrin or phenothrin, in order to provide additional miticidal efficacy and repel and kill mosquitoes. It has been determined that it is difficult to form a high concentration of dinotefuran or acetamiprid and permethrin or phenothrin, and is likely to result in an unstable solution when stored at room temperature for reasonable amounts of time. Therefore, it has been found preferable to produce a first formulation containing a macrocyclic lactone and a neo nicotinoid and a second formulation containing permethrin or phenothrin, and keeping these formulations separated until before, preferably immediately before, their application. Preferably, the topical formulation also contains an IGR, which may be packaged with the first or second formulation in yet another container. The first and second formulations are advantageously produced and packaged in a manner such that the first and second formulations can be prevented from interacting prior to the application of the formulation to the animal. Preferably, the first and second formulations can be stored separately from one another in a package or package containing two associated single chambers, preferably attached, to prevent mixing of the first and second formulations prior to administration of the first and second formulations. formulation to the animal. The first and second formulations can be advantageously packaged in a package or chamber that is opaque, in order to prevent photo degradation of the active ingredients in the formulations. Prior to administration, the packages containing the first and second formulations in their respective separate chambers are opened, and the first and second formulations are dispensed simultaneously or at least approximately at the same time, to the animal. Accordingly, it is an object of the invention to provide an improved topical formulation that is effective against a variety of parasites. Another object of the invention is to provide a method for controlling parasites. Another object of the invention is to provide a topical formulation that works more quickly and / or more permanently than other topical formulations. Another object of the invention is to provide an improved method for making an insecticide. Another object of the invention is to provide a new packaging system for insecticides. Other objects and characteristics will be partly evident and partly pointed out. Detailed description of the preferred modalities. According to the invention, insecticidal compositions are provided which contain a combination of a macrocyclic lactone, a neo nicotinoid, and preferably, an insect growth regulator, which are effective against endoparasites and ectoparasites such as heartworm, fleas, flea eggs, ticks and mites. The combination of active ingredients produces topical formulations that provide protection against endoparasites and ectoparasites using a single application of the formulation. Preferably, the insecticidal compositions of the invention contain a first active ingredient that contains macrocyclic lactone such as ivermectin, selamectin, doramectin, moxidectin or eprinomectin, combined with a second active ingredient containing a neo nicotinoid such as dinotefuran or acetamiprid, in an appropriate solvent solution. It should be noted that in embodiments in which the first active ingient network is dinotefuran and the second active ingredient is acetamiprid, it is not necessary to use a solvent containing ethyl lactate. Instead, it has been determined that an effective solvent for the solubilization of high concentrations of dinotefuran and acetamiprid contains ethanol. The treatment of different endoparasites and ectoparasites can be targeted by including a particular macrocyclic lactone in the formulation. Accordingly, in preferred embodiments of the invention, the topical formulation further comprises an insect growth regulator (IGR). The combination of the macrocyclic lactone and the neo nicotinoid with an IGR, preferably results in a topical formulation having effective insecticidal activity, for example, against flea larvae and flea eggs. In a preferred embodiment of the invention, the first component in the formulation contains a macrocyclic lactone such as ivermectin, selamectin, doramectin, moxidectin or eprinomectin, the second component is dinotefuran N - ((6-chloro-3-pyrridinyl) methyl) -N'-cyano-N-methyl-ethanamide (acetamiprid), and the IGR is pyriproxyfen and / or methoprene. In another preferred embodiment of the invention, the macrocyclic lactone in the formulation contains at least one of ivermectin, selamectin, doramectin, moxidectin and eprinomectin, the neo nicotinoid contains a derivative of (tetrahydro-3-furanyl) methylamine of the following formula (1), and the IGR contains pyriproxyfen and / or methoprene. The (tetrahydro-3-furanyl) methylamine derivatives of the formula (1) have an excellent insecticidal activity even in the absence of a pyridylmethyl group or a thiazolylmethyl group in their molecular structure.

Formula (1) wherein X1, X2, X3, X4, X5, X6 and X7 each represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; R1 represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, an alkenyl group having 3 carbon atoms, a benzyl group, an alkoxyalkyl group having from 2 to 4 carbon atoms (in its group whole), an alkoxycarbonyl group having from 1 to 3 carbon atoms, a carbonyl phenoxy group, an alkylcarbonyl group having from 1 to 6 carbon atoms, an alkenylcarbonyl group having from 2 to 3 carbon atoms, a cycloalkylcarbonyl group which has 3 to 6 carbon atoms, a benzoyl group, a group benzoyl substituted by alkyl group (s) having from 1 to 4 carbon atoms, a benzoyl group substituted by halogen atom (s), a 2-furanylcarbonyl group or a N, N-dimethylcarbamoyl group; R2 represents a hydrogen atom, an amino group, a methyl group, an alkylamino group having from 1 to 5 carbon atoms, a di-substituted alkylamino group having from 2 to 5 carbon atoms (in its entire group), a 1-pyrrolidinyl group, an alkenylamino group having 3 carbon atoms, an alkynylamino group having 3 carbon atoms, a methoxyamino group, an alkoxylamino group having from 2 to 4 carbon atoms (in its complete group), an methylthio group or -N (Y1) Y2 (wherein Y1 represents an alkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkoxycarbonyl group having from 1 to 6 carbon atoms, an alkenylcarbonyl group having 2 to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoyl group, a benzoyl group substituted by alkyl group (s) having from 1 to 4 carbon atoms, a substituted benzoyl group per halogen atom (s), a 2-f group uranylcarbonyl, a N, N-dimethylcarbamoyl group, a (tetrahydro-3-furanyl) methyl group or a benzyl group, and Y2 represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms); and Z represents = N-NO2, = CH-NO2 or = N-CN. The intermediates for producing the compounds of the formula (I) are represented by a formula (2): Formula (2) wherein X1, X2, X3, X4, X5, X6 and X7 each represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; R10 represents an alkyl group having from 1 to 5 carbon atoms or a benzyl group; and R1 1 represents an alkyl group having from 1 to 5 carbon atoms or a benzyl group. The (tetrahydro-3-furanyl) methylamine derivatives of the formula (1) and the formula (2) according to the invention are excellent compounds having a high insecticidal activity and broad insecticidal spectrum. In addition, agricultural chemicals containing the (tetrahydro-3-furanyl) methylamine derivatives of the formula (1) and (2) according to the invention, have outstanding characteristics as insecticides, and are therefore useful. Specific exes of the alkyl group for X1, X2, X3, X4, X5, X6 and X7 in the formulas (1) and (2) above include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group and the like, preferably a methyl group. Specific exes of the alkyl group for R1 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a group tert-butyl, an n-pentyl group, and the like. Specific exes of the alkenyl group for R1 include a 1-propenyl group, a 2-propenyl group, and the like. Specific exes of the alkyloxyalkyl group for R 1 include a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, an isopropoxymethyl group, a methoxyethyl group, an ethoxyethyl group and the like. Specific exes of the alkyloxycarbonyl group for R1 include a methyloxycarbonyl group, an ethyloxycarbonyl group, an n-propyloxycarbonyl group, an iso-propyloxycarbonyl group, and the like. Specific exes of the alkoxycarbonyl group for R1 include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropicarbonyl group, an n-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonyl group , an n-pentylcarbonyl group, an n-hexylcarbonyl group and the like. Specific exes of the alkenylcarbonyl group for R1 include a vinylcarbonyl group, a 1-methylvinylcarbonyl group, and the like. Specific exes of the cycloalkylcarbonyl group for R1 They include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group and the like. Specific exes of the benzoyl group substituted by Alkyl group (s) for R 1 include a 2-methoxybenxoyl group, a 3-methoxybenzoyl group, a 3-methoxybenzoyl group, a 4-methoxybenzoyl group, a 4-tert-butylbenzoyl group, and the like. Specific exes of the benzoyl group substituted by halogen atom (s) for R1 include a 2-chlorobenxoyl group, a 3-chlorobenxoyl group, a 4-chlorobenzoyl group, a 3,4-dichlorobenzoyl group, a group 4 -fluorobenzoyl, and the like. While R1 may take different substituents as described above, a hydrogen atom, an alkylenecarbonyl group having 1 to 4 carbon atoms or a cyclopropycarbonyl group is preferable. Specific exes of the alkylamino group for R2 include a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, a n-butylamino group, an isobutylamino group, a sec-butylamino group, a group tert-butylamino, a n-pentylamino group, and the like, preferably a methylamino group. Specific exes of the alkyl group substituted for R2 include a dimethylamino group, a diethylamino group, a N-methyl-N-ethylamino group, an N-methyl-Nn-propylamino group, and a N-methyl-Nn group -butylamino, and the like, preferably a dimethylamino group. Specific exes of the alkenylamino group for R2 include a 1-propenylamino group, and the like. The specific exes of the alkynylamino group for R2 they include a propargylamino group and the like. Specific examples of the alkoxyalkylamino group for R 2 include a methoxymethylamino group, an ethoxymethylamino group, an n-propyximethylamino group, an iso-propoxymethylamino group, a methoxyethylamino group, an ethoxyethylamino group and the like. Specific examples of the akoxycarbonyl group indicated as Y1 for R2 include a methyloxycarbonyl group, an ethyloxycarbonyl group, an n-propyloxycarbonyl group, an isopropyloxycarbonyl group and the like. Specific examples of the alkylcarbonyl group indicated as Y1 for R2 include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a sec-butylcarbonyl group, a tertiary group, butylcarbonyl, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and the like, preferably a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an iso-butylcarbonyl group , a sec-butylcarbonyl group and a tert-butylcarbonyl group. Specific examples of the alkenylcarbonium group indicated as Y1 for R2 include a vinylcarbonyl group, a 1-methyl-vinylcarbonyl group, and the like. Specific examples of the cycloalkylcarbonyl group indicated as Y1 for R2 include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a group cyclohexylcarbonium, and the like, preferably a cyclopropylcarbonyl group. Specific examples of the benzoyl group substituted by alkyl group (s) indicated as Y1 for R2 include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and the like. Specific examples of the benzoyl group substituted by halogen atom (s) indicated as Y1 for R2 include a 2-chlorobenzyl group, a 3. chlorobenzyl group, a 4. chlorobenzyl group, a 3,4-dichlorobenzyl group, a 4- group fluorobenzoyl, and the like. Specific examples of the alkyl group indicated as Y 2 for R 2 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tertiary group, butyl, an n-pentyl group, and the like, preferably a methyl group. In formula (1), compounds in which R1 and Y1 are concurrently an alkylcarbonyl group having 1 to 4 carbon atoms or a cyclopropylcarbonyl group are preferred from the viewpoint of both the insecticidal activity and the production method . In a preferred embodiment of the invention, the macrocyclic lactone contains at least one ivermectin, selamectin, doramectin, moxidectin or eprinomectin, the neo nicotinoid contains 1 -. { (tetrah id ro-3-furanyl) methyl} -2-nitro-3-methylguanidine (dinotefuran), and the insect growth regulator preferably contains pyriproxyfen or methoprene. The dinotefuran is an insecticide that kills adult pigs, and piriproxifen and methoprene are growth regulators of insects that kill flea larvae and prevent flea eggs from being incubated. Accordingly, the combination of dinotefuran and I GR such as pyriproxygen or methoprene provides an effective flea control system, since only about 5% of the fleas in an animal are adults, and the other 95% are in juvenile state (eggs and larvae). It has been determined that it is advantageous to dissolve or if not to place the active ingredients in a liquid form for use as products for topical application in animals. Of course, it will be understood that in certain embodiments of the invention, it may be advantageous to isolate the assets, such as by large portion (for example, sputtering), encapsulation, use of micelles, encapsulated microbeads and Similar. The products for topical application are more advantageous if the amount of fluid applied to the animal can be reduced to the minimum. This has to be balanced with the need for appropriate doses to achieve the desired pesticidal effect. ThusIt is desirable to include a high concentration of insecticide, so that the total volume of insecticide applied to the animal can be minimized. Preferably, the dinoteflu is dissolved in the formulation to a concentration of about 50 to 150 mg / mL, more preferably 1 00 to 150 mg / mL, and more preferably about 150 mg / mL. The dinotefuran can be dissolved in particularly effective solvent systems such as a combination of water and ethanol or of isopropanol, as described in pending U.S. Patent No. 1 0/242, 552, or in phenyl methanol or ethanol, as described in the patent. US number 6,588,374, or in combinations of ethyl and water lactate. The content of these references is incorporated herein by reference. The treatment of endoparasitic and ectoparasitic d iserentes is aimed at including particular macrocyclic lactones specific for the endoparasite or ectoparasite target in the topical formulation. The combination of the macrocyclic lactone and the neo nicotinoid with an insect growth regulator preferably results in a topical formulation having effective insecticidal and parasiticidal activity against a variety of endoparasites and ectoparasites. In another preferred embodiment of the invention, the topical formulation contains a pyrethroid such as 2,2-dimethyl-3- (2-methyl-1-propenyl) cydopropanecarboxylic acid (3-phenoxyphenyl) methyl ester. (phenothrin) or 3- (2, 2-dichloroethenyl) -2,2-dimethyl- (3-phenoxyphenyl) methyl ester of cyclopropanecarboxylic acid (permethrin) in order to provide additional miticidal efficacy and repel and kill mosquitoes. The compositions containing permethrin according to the invention are particularly advantageous for use in dogs, compared to their use in cats. It has been determined that it is difficult to form a high concentration of dinotefuran or acetamiprid and of permethrin or phenothrin, and this will likely result in a solution that can be unstable when stored at room temperature for reasonable amounts of time. Therefore, it has been found that it is preferable to produce a first formulation containing a macrocyclic lactone and a neo nicotinoid, and a second formulation containing permethrin or phenothrin. Preferably, the topical formulation further contains an IGR, which can be included in the first or second formulation or even separately in yet another container. The first and second formulations are produced and packaged in such a way that the first and second formulations are not allowed to interact prior to the application of the total formulation to the animal. In a preferred embodiment of the invention, the first and second formulations are stored separately from one another in a package or package having two associated chambers, preferably attached, but individual, to prevent the first and second formulations from mixing before of the administration of the first and second formulations to the animal. It should be noted that in embodiments wherein the formulation is packaged using separate chambers or containers, the percentage of active ingredient provided is the percentage of that active ingredient in a single solution. For example, 1 to 2% pyriproxyfen is the concentration of pyriproxyfen contained in the formulation in a single chamber instead of the concentration of piriproxifen in the total formulation of the combined chambers. Macrocyclic lactones can be unstable in both acid solutions and basic solutions. For example, ivermectrine is hygroscopic and therefore tends to be undesirably unstable. It has also been observed that macrocyclic lactones such as ivermectin are unstable in both acidic and basic solutions, and are susceptible to photo degradation and degradation by oxidation. Accordingly, in embodiments wherein the first active ingredient of the composition contains ivermectin, it is preferable that the first and second formulations be stored in an opaque package or container to prevent photo degradation of ivermectin during storage of the formulation. Even more preferably, the formulation will contain an antioxidant such as 2,6-ditertbutyl-4-methyl phenol (BHT) to prevent oxidative degradation of ivermectin during storage of the formulation for a reasonable amount of time. Before your administration, the containers containing the first and second formulations in their respective separate chambers are opened, and the first and second formulations are dispensed simultaneously or at least approximately at the same time to the animal. In a preferred embodiment of the invention, the first and second formulations can be packaged in a container that it has two associated chambers, preferably joined, but individual, to avoid mixing the formulations before the administration of the first and second formulations to the animal. Prior to administration, the container can be opened and the first and second formulations can be dispensed simultaneously or almost simultaneously to the companion animal. In another preferred embodiment of the invention, the insecticidal composition of the invention can be packaged in a package with a single dose. Single-dose containers make storage and dispensing more comfortable for animal owners. Preferably, the composition is packaged in a container comprising two associated, preferably attached, individual chambers, which are separated by a barrier, preferably plastic, coated with plastic or metal paper, such as aluminum foil. In a preferred embodiment of the invention, the first chamber and the second chamber are plastic tubes that are separate but are fused together. In another embodiment of the invention, the first and second chambers are constituted by opaque plastic in order to prevent the photo degradation of the active ingredients in the formulation. During packaging, the first formulation, which preferably contains a macrocyclic lactone such as ivermectin, selamectin, diramectin, moxidectin or eprinomectin and a neo nicotinoid, preferably dinotefuran or acetamiprid, can be placed in the first chamber. The second formulation, which preferably containing permethrin or phenothrin, can be placed in the second chamber. The topical formulation further contains an IGR such as a piroxifene or methoprene, which may be included in the first or second formulation, or in yet another container. Preferably, the first and second chambers can be separated by a barrier that prevents interaction of the first and second formulations. The entire container comprising the first and second formulations in separate chambers is sealed, preferably with a tab or cap, which is used to open the container prior to administration. After the container is sealed, the topical formulation can be stored safely in the container until the formulation is administered to the animal. Prior to the administration of the formulation to the animal, the container is opened by pulling out the tab or cap. In one embodiment of the invention, the container is opened by twisting the tab, which causes the breaking or tearing of the barrier separating the two chambers, thereby allowing the first and second formulations to be mixed prior to the administration of the formulation insecticide to the animal. After the two formulations are mixed, the two formulations are dispensed by squeezing or squeezing the container body, either simultaneously or sequentially. In another embodiment of the invention, a dual plunger system can be used for administer the formulation to the animal. Of course, it is understood that it is not necessary that the first and second formulations be mixed together prior to the administration of the topical formulation to the animal, accordingly, in another embodiment of the invention, the opening of the dual-chamber package does not produces the mixture of the first and second formulations. Instead of this, after the container is opened, the first and second formulations are dispensed onto the animal by squeezing or squeezing the container or containers, either simultaneously or sequentially. In one embodiment of the invention, the formulation is packaged with instructions, advising to mix the formulations. In other modalities, the instructions will instruct the user not to mix the formulation when applying it. Because the compositions according to preferred embodiments of the invention can be formulated with a relatively high concentration of active ingredients, a relatively small application of a point or line on the animal can effectively prevent and control the infestation with endoparasites and ectoparasites in the animal for approximately one to four weeks after its administration. Preferably, the topical formulation is non-toxic and does not irritate the animal's skin. In a preferred embodiment of the invention, the volume of total insecticidal formulation applied to a pet is in the range of about 0.5 to 10 mL, preferably approximately 2 to 5 mL, and much more preferably approximately 3 mL. In another embodiment of the invention, the volume of total insecticidal formulation applied in a small cat or puppy is in the range of about 0.5 to 1.5 mL. It should be noted that the total insecticidal formulation contains solvents and other additives, in addition to active ingredients and therefore, the volume of total insecticidal formulation applied to the animal does not contain only active ingredients. In preferred embodiments of the invention, the doses of active ingredients in a single application of the topical formulation comprise from about 0.16 to 4.80 mg of a macrocyclic lactone and from about 90 to 1350 mg of dinotefuran plus solvent, and preferably, from about 0.32 '. up to 3.2 mg of a macrocyclic lactone and approximately 180 to 900 mg of dinotefuran plus solvent. In a preferred embodiment of the invention, the formulation also contains an IGR such as pyriproxyfen or methoprene. In preferred embodiments of the invention wherein pyriproxyfen is added to the formulation, the dose of pyriproxyfen in the total volume of a single application of the formulation is from about 3.5 to 45 mg, and preferably, from about 7 to 30 mg. In embodiments of the invention wherein methoprene is added to the formulation, the dose of methoprene in the total volume of a single application of the formulation is from about 10 to 135 mg, and preferably, about 20 to 90 mg. The treatment of different endoparasites and ectoparasites can be directed including a particular macrocyclic lactone in the formulation. It should be understood that the invention is not limited by the modalities described herein. In a preferred embodiment of the invention, the insecticidal formulation contains ivermectin, dinotefuran and pyriproxyfen for the treatment of endoparasites and / or ectoparasites in cats and dogs. Of course, it should be understood that the actual amount of ivermectin in the formulation will vary depending on the size of the dog or cat. In a preferred embodiment, ivermectin ranges from about 0.2 to 1.75 mg per mL of formulation. In one embodiment of the invention, up to 8 mL of the total insecticidal composition can be administered to a dog weighing from 24 kg (55 pounds) to 54 kg (120 pounds), and preferably up to 6 mL. This composition will preferably contain at least about 1.6 to 4.8 mg of ivermectin, at least about 450 to 1350 mg of dinotefuran, and at least about 1-5 to 45 mg of pyriproxyfen. Even more preferably, the composition will contain about 3.2 mg of ivermectin, about 900 mg of dinotefuran, and about 30 mg of pyriproxyfen. In embodiments wherein the IGR is methoprene, the composition contains at least about 45 to 180 mg methoprene. In another preferred embodiment of the invention, approximately 6 to 8 mL of the total composition can be administered to a dog weighing from 24 kg (55 pounds) to 54 kg (120 pounds), the composition advantageously contains approximately 675 to 2025 mg of permethrin or approximately 2015 to 5050 mg of phenothrin, in order to provide additional miticidal efficacy and to repel and kill mosquitoes. In one embodiment of the invention, up to 4 mL of insecticide can be administered to a dog weighing from 10 kg (22 pounds) to 24 kg (55 pounds). This composition will preferably contain at least about 1.0 to 3.0 mg of ivermectin, at least about 300 to 900 mg of dinotefuran and at least about 10 to 30 mg of pyriproxyfen. Even more preferably, the composition will contain approximately 2.0 mg of vermectin, approximately 600 mg of dinotefuran, and approximately 20 mg of pyriproxyfen. In embodiments wherein the IGR is methoprene, the composition contains at least about 30 to 90 mg methoprene. In another preferred embodiment of the invention, the composition further contains from about 450 to 1350 mg of permethrin or approximately 1115 and 3345 mg of phenothrin in order to provide additional miticidal efficacy and to repel and kill mosquitoes. In one embodiment of the invention, up to 2.1 mL of insecticide can be administered to an animal weighing from 4 kg (9 pounds) to 10 kg (22 pounds). This composition will preferably contain at least about 0.4 to 1.2 mg of ivermectin, at least about 225 to 675 mg of dinotefuran, and at least about 5 to 1.5 mg of pyriproxyfen. Even more preferably, the composition will contain about 0.8 mg of ivermectin, about 450 mg of dinotefuran, and about 1.0 mg of pyriproxyfen. In another preferred embodiment, the composition further contains at least about 225 to 675 mg of permethrin or about 560 to 1 675 mg of phenothrin in order to provide additional miticidal efficacy and to repel and kill mosquitoes. It should be noted that formulations containing permethrin are for application to dogs only. In embodiments wherein the I G R is methoprene, the composition contains at least about 1-5 5 mg methoprene. In one embodiment of the invention, up to 1.5 mL of insecticide can be administered to animals weighing 4 kilos (9 pounds) or less. This composition will preferably contain at least about 0.1 to 0.60 mg of ivermectin, at least about 90 to 270 mg of dinotefuran, and at least about 3.5 to 1.2 mg of pyriproxyfen. Even more preferably, the composition will contain about 0.32 mg of ivermectin, about 1.80 mg of dinotefuran, and about 7 mg of pyriproxyfen. In embodiments wherein the IGR is methoprene, the composition contains at least about 10 to 30 mg of methoprene. In another modality Preferred, the composition further contains from about 150 to 450 mg of permethrin or from about 475 to 1425 mg of phenothrin in order to provide additional miticidal efficacy and to repel and kill mosquitoes. It should be noted that formulations containing permethrin are to be applied to dogs only. In another preferred embodiment of the invention, the insecticidal formulation contains selamectin, dinotefuran and pyriproxyfen for the treatment of endoparasites and / or ectoparasites in cats and dogs. It has been determined that an effective dose for selamectin contained in insecticidal formulations according to the invention is from about 7 mg to 14 mg per kilogram (3 to 6 mg per pound) of the animal's body weight. Therefore, the actual amount of selamectin in the insecticidal formulation will vary depending on the size of the dog or cat (eg, approximately 30 to 210 mg per mL of formulation). In a preferred embodiment of the invention, the insecticidal formulation contains moxidectin, dinotefuran and pyriproxyfen for the treatment of endoparasites and / or ectoparasites in cats or dogs. It has been determined that an effective dose for the moxidectin contained in insecticidal formulations according to the invention is about 0.46 mg per kg (0.2 mg per pound) of the animal's body weight. Therefore, the actual amount of moxidectin in the insecticide formulation will vary depending on the size of the dog or cat.

In another preferred embodiment of the invention, the insecticidal formulation contains doramectin, dinotefuran and piriproxifen for the treatment of endoparasites and / or ectoparasites in cats and dogs. It has been determined that an effective dose for the doramectin contained in insecticidal formulations according to the invention is about 0.04 mg per kg (0.02 mg per pound) of the animal's body weight. Therefore, the actual amount of doramectin in the insecticidal formulation will vary depending on the size of the dog or cat. In the preparation of a formulation for use in animals, there are several parameters that must be considered. These are: (a) Concentration high enough to minimize the volume of the topic applied to the animal (one might not want to put 20 mL, for example, a small dog). (b) Concentration sufficiently low to achieve effective transfer of the topical insecticide on the skin of the animal. (c) The formulation must be stable for six months at 4.4 ° C (40 ° F) and with 75% relative humidity, room temperature and -23 ° C (-10 ° F). This helps ensure that the formulation remains stable under the conditions it could be found in trade. (d) Safe to use in the animal to which it is directed, particularly non-irritant at least for the animal to which it is directed, since the product is applied to the skin. Also safe if it is ingested by the animal; Ingestion may occur when Pets are preening. (e) Safe for use by the consumer. (f) Effective when used. Must kill more than 90% of fleas and ticks for up to 28 days, and kill or eliminate the endoparasites. (g) Efficiency may be reduced if crystallization occurs in the package. (h) It is necessary that it be aesthetically pleasing, that it does not look oily on the animal when it is applied. (i) Quick drying to reduce the possibility of the animal removing the liquid, thus reducing the effectiveness, (j) Microbiologically stable. It may be advantageous for the insecticidal formulations of the invention, which contain an enzyme inhibitor or a synergist such as piperonyl butoxide, N-octylbicycloheptanedicarboximide, or triphenyl phosphate, which may increase the effectiveness of the formulation. Topical formulations also contain one or more compounds to increase the effectiveness and to reduce the irritation of pyrethroid insecticides on the skin of animals. The formulation may advantageously contain diffusing agents such as n-octyl pyrrolidone and dioctylsulfosuccinimide, fragrances and / or antioxidants. Other additives for the insecticidal composition include, but are not limited to, fragrances, surfactants and diffusers to increase performance, such as polyoxyethylene (20) sorbitan monolaurate (commercially available as a polysorbate 20 or Tween®20), and polyoxyethylene (20) sorbitan monooleate (commercially available as polysorbate 80 or Tween®80), and isopropyl myristate. Polymers such as agar, gelatin, alginate and cationic polymers such as cationic guar, cationic cellulose, cationic acrylates, and polyoxymethylene urea, can also be added to provide insecticide wrapping to improve safety and adhesion to the skin and hair. In practice, an effective amount of the insecticidal compositions as described herein can be applied to a companion animal, preferably a dog or a cat, such as a foaming shampoo, immersion bath, aerosol spray, pump spray, powder , lotion, emulsifiable concentrate, concentrate in aqueous suspension or liquid fluid, and by other methods suitable for administering topical compositions to animals. Formulations containing permethrin can not be applied to cats. The following examples are provided for purposes of illustration only, and are not intended to be construed as limiting. Examples Example 1. Preparation of 1 -. { (tetrahydro-3-furanyl) methyl) -2-nitro-3-methylguanidine (dinotefuran) A mixture containing 10.0 g of (tetrahydro-3-furanyl) methane, 29.5 g of trifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml of dichloromethane, was stirred for one hour at room temperature. The water was poured into the reaction solution to separate the organic layer, which was washed with 1N hydrochloric acid, water and a saturated saline solution, dried and concentrated to obtain 20 g of 3-tetrahydro-furanylmethyl triflate, 3.25 g of 60% ai sodium hydride was added to 12.5 g of 1,5-dimethyl-2-nitroiminohexahydro-1, 3,5-triazine and 60 mL of DMF at room temperature, followed by stirring for one hour. To this was added 20.0 g of the triflate of 3-tetrahydrofuranuylmethyl, and the mixture was stirred at 50 ° C for 2 hours. After cooling the mixture to room temperature, 50 mL of 2N hydrochloric acid was added thereto, followed by stirring at 50 ° C for 2 hours. The resulting mixture was neutralized with sodium bicarbonate and extracted with dichloromethane, and the extract was dried and concentrated. The residue thus obtained was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/1) to obtain 7.8 g of 1 { (tetrahydro-3-furanyl) methyl} -2-nitro-3-methylguanidine (dinotefuran). Example 2: Formulations with Ivermectin / Dinotefuran Ivermectin (0.05 g) was dissolved in ethanol in a clean container with agitation, until it completely dissolved. This solution was added to a chamber in the package in the appropriate volume based on the required dose. A second solution containing dinotefuran was prepared by adding 25 g of dinotefuran to 100 mL of phenyl methanol with stirring until dissolved. This solution was added to the other chamber in the package in the appropriate volume based on the required dose. Example 3. Preparation of compositions containing ivermectin, dinotefuran and pyriproxyfen A solution containing ivermectin was prepared using the methodology of Example 2 and placed in a chamber in the package in the appropriate volume based on the required dose. Pyriproxyfen (1 g) and Mackernium KP (1 g) were added to a clean container and gently warmed until the piroproxifen was liquefied. Water (27.6 g) was added with stirring, followed by the addition of ethyl lactate (55.4 g). Dinotefuran (15 g) was added and the solution was mixed and heated to 50 degrees C until the dinotefuran dissolved. The solution was cooled to room temperature and the pH was adjusted to 5.5 by the addition of sodium carbonate (0.15 g of a 25% aqueous solution). This solution was added to the other chamber in the package in the appropriate volume based on the required dose. Example 4. Preparation of compositions containing ivermectin, dinotefuran and methoprene. A solution containing ivermectin was prepared using the methodology of Example 2, and placed in a chamber in the package in the appropriate volume based on the required dose.

Methoprene (1 g) and Mackernium KP (1 g) were added to a clean vessel, and slowly heated. Water was added with stirring, followed by the addition of ethyl lactate (55.4 g). Dinotefuran (15 g) was added and the solution was mixed and heated to 50 degrees C until the dinotefuran dissolved. The solution was cooled to room temperature and the pH was adjusted to 5.5 by the addition of sodium carbonate (0.15 g of a 25% aqueous solution). This solution containing dinotefuran and methoprene was added to the other chamber of the package in the appropriate volume based on the required dose. Example 5. Preparation of compositions containing ivermectin, dinotefuran, permethrin and pyriproxyfen. Permethrin (6.5 g) was dissolved in ethanol in a clean vessel with stirring. Ivermectin (0.05 g) was added to this solution with stirring until it was completely dissolved. Preferably permethrin or phenothrin is added to the insecticidal formulations according to the present invention, in order to kill ticks and repel flies and mosquitoes. This solution containing permethrin and ivermethrin was added to one of the chambers in the package in the appropriate volume based on the required dose. Pyriproxyfen (1 g) and Mackernium KP (1 g) were added to a clean container, and slowly heated until the pyriproxyfen was liquefied. Water was added with stirring, followed by addition of ethyl lactate (55.4 g). Dinotefuran (15 g) was added and the solution was mixed and heated to 50 degrees C until the dinotefuran dissolved. The solution was cooled to room temperature, and the pH was adjusted to 5.5 by the addition of sodium carbonate (0.15 g of a 25% aqueous solution >). This solution was added to the other chamber in the package in the appropriate volume based on the required dose. Example 6. Preparation of compositions containing ivermectin, dinotefuran, phenothrin and pyriproxyfen Phenothrin (6.5 g) was dissolved in ethanol in a clean container with stirring. Ivermectin (0.05 g) was added to this solution with stirring until it was completely dissolved. The permethrin or phenothrin is preferably added to the insecticidal formulations according to the present invention, in order to mater ticks and repel flies and mosquitoes. This solution containing phenothrin and ivermectin was added to one of the chambers in the package in the appropriate volume based on the required dose. Pyriproxyfen (1 mg) and Mackernium KP (1 g) were added to a clean container, and warmed gently until the pyriproxyfen was liquefied. Water (27.6 g) was added with stirring, followed by the addition of ethyl lactate (55.4 g). Dinotefuran (15 g) was added and the solution was heated and heated to 50 degrees C until the dinotefuran dissolved. The solution was cooled to room temperature and the pH adjusted to 5.5 by the addition of sodium carbonate (0.15 g of a 25% aqueous solution). This solution is added to the other chamber in the package in the appropriate volume based on the required dose. Eiem plo 7. Com positions of moxidectin / dinotefuran. In a preferred embodiment of the invention, an insecticidal formulation containing moxidectin and dinotefuran was prepared using the methodology described in Example 3. Preferably, the total volume of the formulation is about 6 mL, it contains 1 1 to 24 mg of moxidectin and approximately 1 5% of dinotefuran, which is approximately 900 mg of dinotefuran for the treatment and prevention of fleas, prevention of heartworm, control of roundworms, hookworms and whipworms in dogs and cats. As used herein, it will be understood that the prevention of a specific parasite implies that the active ingredient prevents the parasite from having an effect, that is, the active ingredient prevents parasites from infecting the animal because the parasites kill themselves. as soon as they enter the animal. Additionally, it should be understood that controlling parasites implies that the active ingredient kills the parasites in an already infested animal. Preferably, the formulation further contains about 10 mg / mL of pyriproxyfen or about 30 mg / mL Methoprene to kill flea larvae and prevent flea eggs from being incubated. Even more preferably, the formulation also includes permethrin or phenothrin to kill ticks and repel mosquitoes and flies.

Example 8 Compositions with Selamectin / Dinotefuran In yet another preferred embodiment of the invention, an insecticidal composition containing selamectin and dinotefuran was prepared using the methodology described in Example 2. Preferably, the total volume of the formulation applied to the pet animal is of approximately 6 mL, which contains approximately 8% to 15% of dinotefuran and 2.6 to 12% of selamectin. In a preferred embodiment of the invention, the formulation contains from about 480 to 900 mg of dinotefuran and from 155 to 720 mg of selamectin dissolved in solvent, which is effective in killing fleas, to avoid incubating flea eggs, preventing r the heartworm, control and treat mites in the ear, sarcoptic mange, and control infestation by ticks due to Dermacentor variabilis in dogs. The formulation further advantageously contains about 60 mg (10 mg / mL) of pyriproxyfen, or about 180 mg (30 mg / mL) of methoprene, which provides additional efficacy against flea eggs. Example 9: Compositions Containing Selamectin, Dinotefuran, Permethrin and Pyriproxyfen In another embodiment of the invention, permethrin (489.1 g) was dissolved in safflower oil (435.9 g) in a clean vessel with stirring. Selamectin (75 g) was added to this mixture with stirring until it was completely dissolved. Preferably permethrin or phenothrin is added to the insecticidal formulations according to the present invention to obtain additional miticidal efficacy and for the treatment of mosquitoes and flies. This solution containing permethrin and selamectin was added to one of the chambers in the package in the appropriate volume based on the required dose. Piroproxifen (1.5 g) and Mackernium KP (1 g) were added to a clean container, and gently warmed until pyriproxyfen was liquefied. Ag ua (22.7 g) was added with stirring, followed by the addition of ethyl lactate (47.8 g). Dinotefuran (15 g) was added and the solution was mixed and heated to 50 degrees C until the dinotefuran dissolved. The solution was cooled to room temperature and the pH was adjusted to 5.5 by the addition of sodium carbonate (0.1 5 g of a 25% aqueous solution). This solution was added to the other chamber in the package in the appropriate volume based on the required dose. Thus, it will be seen that the objects set out above, among which are evident from the preceding description, are efficiently achieved, and since certain changes can be made to carry out the above method, and in the established composition, without departing from the spirit and scope of the invention, it is intended that all the matter contained in the previous description, is interpreted as illustrative and not in a limiting sense. It will also be understood that the following modalities are intended to cover all the generic and specific features of the invention described herein, and all declarations of the scope of the invention, which, as a matter of language, could be said to fall within them. Particularly, it will be understood that in said modalities, it is intended that the ingredients or compounds indicated in the singular include compatible mixtures of these ingredients where the sense allows it.

Claims (29)

REIVI ND ICATIONS

1 . A topical formulation containing a first active network containing a macrocyclic lactone and a second active ingredient containing a neo nicotinoid.

2. The topical formulation of claim 1, further characterized in that the first active ingredient contains ivermectin, selamectin, doramectin, moxidectin or eprinomectin.

3. The topical formulation of claim 2, further characterized in that the second active active ing contains an insecticidal derivative of (tetrahyd ro-3-furanyl) methylamine.

4. The topical formulation of claim 3, further characterized in that the second active network is dinotefuran.

5. The topical formulation of claim 4, further characterized in that the first active ingredient is ivermectin.

6. The topical formulation of claim 5, further characterized in that the formulation contains from about 0.2 to 1.75 mg of ivermectin per mL of total formulation volume and 1 00 to 150 mg of dinotefuran per mL of total volume of the formulation .

7. The topical formulation of claim 4, further characterized in that the first active active network is selamectin.

8. The topical formulation of claim 7, further characterized in that the formulation contains from about 30 to 210 mg of selamectin per mL of total formulation volume and from 100 to 150 mg of dinotefuran per mL of total volume of the formulation.

9. The topical formulation of claim 4, further characterized in that the first active ingredient is doramectin.

10. The topical formulation of claim 4, further characterized in that the first active ingredient is moxidectin. eleven . The topical formulation of claim 10, further characterized in that the formulation contains from about 0.2 to 1.75 mg / mL of moxidectin and from 100 to 150 mg / mL of dinotefuran. 12. The topical formulation of claim 1, further characterized in that the formulation further contains an insect growth regulator (IGR). 13. The topical formulation of claim 4, further characterized in that the formulation further contains a IGR. 14. The topical formulation of claim 13, further characterized in that the IGR is pyriproxyfen or methoprene. 15. The topical formulation of claim 14, further characterized in that the formulation also contains permethrin or phenothrin. 16. The topical formulation of claim 15, further characterized in that the macrocyclic lactone and the dinotefuran are packed in a first container, permethrin or phenothrin are packaged in a second container and the insect growth regulator is packaged either in the First container or in the second container, the first container is packaged in a form in which it is separated from the second container, in order to avoid interaction with the second container before administering the topical formulation. 17. The topical formulation of claim 16, further characterized in that the first and second containers are packed together, but separated by at least one barrier to prevent interaction of the first container with the second container. 18. The topical formulation of claim 1, further characterized in that the formulation is not irritating to cats and dogs and is effective in killing endoparasites and ectoparasites with applications of less than 10 mL. 19. A method for treating or preventing endoparasitic or ectoparasitic infestation in an animal, the method comprising applying the topical formulation of claim 1 to the animal. 20. The method of claim 19, further characterized in that the animal is a cat or a dog. 21. The topical formulation of claim 4, also characterized because the formulation is not irritating to cats and dogs, and is effective to kill endoparasites and ectoparasites with applications of less than 10 mL. 22. A method for treating or preventing endoparasitic or ectoparasitic infestation in an animal, the method comprises applying the topical formulation of claim 4 to the animal. 23. The method of claim 4, further characterized in that the animal is a cat or a dog. 24. The topical formulation of claim 14, further characterized in that the formulation is not irritating to cats and dogs and is effective in killing endoparasites and ectoparasites with applications of less than 10 mL. 25. A method for treating or preventing endoparasitic or ectoparasitic infestation in an animal, the method comprises applying the topical formulation of claim 14 to the animal. 26. The method of claim 25, further characterized in that the animal is a cat or a dog. 27. The topical formulation of claim 16, further characterized in that the formulation is not irritating to cats and dogs and is effective in killing endoparasites and ectoparasites with applications of less than 10 mL. 28. A method for treating or preventing endoparasitic or ectoparasitic infestation in an animal, the method comprises applying the topical formulation of claim 16 to the animal. 29. The method of claim 1 6, further characterizing because the animal is a cat or a dog.