# Patent

## Title
High concentration topical insecticide containing insect growth regulator

## Abstract

A topical insecticide is provided which can be safe to use and avoids many common deleterious side effects of conventional topical insecticides. The insecticide contains an insecticide and an insect growth regulator effective for killing fleas, flea larvae and flea eggs. The insecticide is formulated by dissolving an insecticidal (tetrahydro-3-furanyl) methylamine derivative and an insect growth regulator (IGR) in a solvent containing N-octyl pyrrolidone and/or N-methyl pyrrolidone to increase the solvency of the IGR component, thereby providing an insecticide having high insecticidal activity.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims the benefit of U.S. Provisional Application No. 60/795,674, filed Apr. 28, 2006. Priority is claimed to the application listed above, which is incorporated herein by reference.


BACKGROUND OF INVENTION
The invention relates generally to insecticides and more particularly to a topical insecticide, such as one suitable to use on house pets such as cats and dogs.
The infestation of animals with fleas is highly undesirable. Accordingly, it has become common to administer both topical and internal insecticides to livestock and pets. Topical applications can be desirable, in that many insecticides are acceptably safe when used topically, but not when used internally.
Various topical insecticides have drawbacks. Some require a large volume to be applied to the animal. This can cause considerable mess and can lead to an unpleasant smell. Also, when the animal is a house pet, there is a further complication in that the insecticide should be safe for human contact. It should also not lead to staining of furniture, carpeting and the like. Finally, even if safe, topical insecticides for house pets should not be irritating or lead to rashes, hair loss or exhibit other unpleasant side effects.
Accordingly, it is desirable to provide an improved topical insecticide, which overcomes drawbacks of the prior art.
SUMMARY OF THE INVENTION
Generally speaking, in accordance with the invention, a topical insecticide is provided which includes an insecticide in combination with an insect growth regulator. These ingredients are advantageously dissolved to a high concentration in a solution containing a quaternary ammonium salt, such as cetyltrimethylammonium chloride, tallowalkyltrimethylammonium chloride, or oleyldimethylammonium chloride. The insecticide formulation of the invention can be safe to use and avoids many common deleterious side effects of conventional topical insecticides. Accordingly, provided is an improved topical insecticide that overcomes drawbacks of the prior art, a method of preparing an insecticide and a method of controlling infestation with an insecticide.
The invention provides a topical insecticide that contains an insecticide and an insect growth regulator, which is advantageously effective to kill fleas, flea eggs, and flea larvae. The insecticide component preferably contains an insecticidal (tetrahydro-3-furanyl) methylamine derivative or a chloronicotinyl insecticide. It advantageously also includes an insect growth regulator (IGR) in a solvent component. Advantageous solvent solutions include those that contain water, ethyl lactate and/or a quaternary ammonium salt. The quaternary ammonium salt is preferably a hydrophobic ammonium salt such as oleyldimethylammonium chloride, tallowalkyltrimethylammonium chloride, and oleyldimethylammonium chloride.
It has been determined that an ammonium chloride with large numbers of carbon atoms, preferably about 16 or more, results in a more favorable solvent system. In a preferred embodiment of the invention, the solvent component advantageously contains a sufficient amount of the salt to increase the solvency of the IGR compared to the solvency of the IGR in the solvent without the salt. The selection of components in the solvent system allows for increased solubility of the insecticide and insect growth regulator thereby providing an insecticide having high insecticidal activity.
Active ingredients and insecticides in accordance with preferred embodiments of the invention are generally available as crystals and other solids. It has been determined that it is advantageous to dissolve or otherwise put these actives into a liquid form (e.g., mixture, emulsion, slurry, etc.) for use as topical spot products on animals. Topical spot products are more advantageous if the amount of liquid applied can be minimized. This should be balanced with the need for appropriate dosage to achieve the desired insecticidal effect. Therefore, it is desirable to use a solvent that will allow the solubilization of a high concentration of insecticide.
In a preferred embodiment of the invention, the insecticide contains 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran) and the IGR comprises pyriproxyfen and/or methoprene. In another preferred embodiment of the invention, the insecticide comprises a chloronicotinyl insecticide, preferably acetamiprid, imidacloprid, nitenpyram or clothianidin, and the IGR comprises pyriproxfen and/or methoprene.
Dinotefuran is an insecticide that kills adult fleas, and pyriproxyfen and methoprene are insect growth regulators that kill flea larvae and prevent flea eggs from hatching. Accordingly, the combination of an insecticide, such as acetamiprid or dinotefuran and an IGR, such as pyriproxyfen or methoprene, provides for an effective flea control system since only about 5% of the existing fleas on an animal are adults and the other 95% are in a juvenile state (eggs and larvae).
Dinotefuran and pyriproxyfen are hydrophilic and lipophilic, respectively. A solvent system that provides for solubilization of a high concentration of dinotefuran will typically not allow pyriproxyfen to solubilize. However, it has been determined that the addition of a quaternary ammonium salt such as cetyltrimethylammonium chloride, tallowalkyltrimethyl ammonium chloride, and oleyldimethylammonium chloride allows for an effective amount of pyriproxyfen to solubilize. Moreover, the salt can help prevent emulsification of the formulation. This advantageously produces an insecticide with high insecticidal activity.
Accordingly, it is an object of the invention to provide an improved topical insecticide.
Another object of the invention is to provide a method for controlling insect infestation.
Another object of the invention is to provide a topical insecticide that works more rapidly and/or more permanently than other insecticides and/or can include a lower total volume of insecticide applied.
Another object of the invention is to provide an improved method of making an insecticide.
Other objects and features will be in part apparent and in part pointed out.


DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the invention, topical insecticide formulations, which contain an insecticide and an insect growth regulator effective to kill fleas, flea eggs, and flea larvae are provided. Combining an insecticide effective against adult fleas with an insect growth regulator effective against flea eggs and larvae results in a highly effective insecticidal formulation.
In one preferred embodiment of the invention, the insecticide is formulated by dissolving an insecticidal (tetrahydro-3-furanyl) methylamine derivative and an insect growth regulator (IGR) in a solvent component comprising water, ethyl lactate and quaternary ammonium salt. The solvent component contains a sufficient amount of quaternary ammonium salt to increase the solvency of the IGR compared to the solvency of the IGR in the solvent without the quaternary ammonium salt and to increase the effectiveness of the insecticide compared to its effectiveness without the quaternary ammonium salt.
In a preferred embodiment of the invention, the active ingredient of the insecticide formulation is an amine derivative, having a nitro-methylene group, a nitroamino group or a cyanoamino group, which can be formulated to have low toxicity and excellent insecticidal activity. Active ingredients of insecticides and their method of formation in accordance with the preferred embodiments of the invention are discussed in U.S. Pat. Nos. 5,532,365; 5,434,181; 6,867,223; 6,984,662 and 7,132,448 the contents of which are incorporated herein by reference.
In another preferred embodiment of the invention, the insecticide comprises an insecticidal (tetrahydro-3-furanyl) methylamine derivative of the following formula (1). 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.




where X1, X2, X3, X4, X5, X6 and X7 each represent each a hydrogen atom or a 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 whole group), an alkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxy carbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms, an alkenylcarbonyl group having from 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 benzoyl group substituted by halogen atom(s), a 2-furanylcarbonyl group or an 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 whole group), a 1-pyrrolidinyl group, an alkenylamino group having 3 carbon atoms, an alkynylamino group having 3 carbon atoms, a methoxyamino group, an alkoxyalkylamino group having from 2 to 4 carbon atoms (in its whole group), a methylthio group or —N(Y1)Y2 (where Y1 represents an alkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms, an alkenylcarbonyl group having from 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 benzoyl group substituted by halogen atom(s), a 2-furanylcarbonyl group, an 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.
Intermediates for producing the compounds of the formula (1) are represented by a formula (2):




where X1, X2, X3, X4, X5, X6 and X7 each represent each 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 R11 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 formula (2) according to the invention are excellent compounds having a high insecticidal activity and broad insecticidal spectrum. Further, 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 hence are useful.
Specific examples of the alkyl group for X1, X2, X3, X4, X5, X6 and X7 in the above formulae (1) and (2) include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, a tert-butyl group, and the like, preferably a methyl group.
Specific examples of the alkyl group for R1 include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and the like.
Specific examples of the alkenyl group for R1 include a 1-propenyl group, a 2-propenyl group, and the like.
Specific examples of the alkoxyalkyl group for R1 include a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, an iso-propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, and the like.
Specific examples 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 examples of the alkylcarbonyl group for R1 include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-propylcarbonyl 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 examples of the alkenylcarbonyl group for R1 include a vinylcarbonyl group, a 1-methylvinylcarbonyl group, and the like.
Specific examples of the cycloalkylcarbonyl group for R1 include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, and the like.
Specific examples of the benzoyl group substituted by alkyl group(s) for R1 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) for R1 include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a 4-chlorobenzoyl group, a 3,4-dichloro-benzoyl group, a 4-fluorobenzoyl group, and the like.
Although R1 can take various substituents as described above, it is preferably a hydrogen atom, an alkylcarbonyl group having from 1 to 4 carbon atoms or a cyclopropylcarbonyl group.
Specific examples of the alkylamino group for R2 include a methylamino group, an ethylamino group, an n-propyl-amino group, an iso-propylamino group, an n-butylamino group, an iso-butylamino group, a sec-butylamino group, a tert-butylamino group, an n-pentylamino group, and the like, preferably a methylamino group.
Specific examples of the di-substituted alkylamino group for R2 include a dimethylamino group, a diethylamino group, an N-methyl-N-ethylamino group, an N-methyl-N-n-propylamino group, an N-methyl-N-n-butylamino group, and the like, preferably a dimethylamino group.
Specific examples of the alkenylamino group for R2 include a 1-propenylamino group, a 2-propenylamino group, and the like.
Specific examples of the alkynylamino group for R2 include a propargylamino group, and the like.
Specific examples of the alkoxyalkylamino group for R2 include a methoxymethylamino group, an ethoxymethylamino group, an n-propoxymethylamino group, an iso-propoxymethylamino group, a methoxyethylamino group, an ethoxyethylamino group, and the like.
Specific examples of the alkyloxycarbonyl group denoted by Y1 for R2 include a methyloxycarbonyl group, an ethyloxy-carbonyl group, an n-propyloxycarbonyl group, an iso-propyloxy-carbonyl group, and the like.
Specific examples of the alkylcarbonyl group denoted by Y1 for R2 include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a sec-butyl-carbonyl group, a tertbutylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and the like, preferably a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonyl group and a tert-butylcarbonyl group.
Specific examples of the alkenylcarbonyl group denoted by Y1 for R2 include a vinylcarbonyl group, a 1-methyl-vinylcarbonyl group, and the like.
Specific examples of the cycloalkylcarbonyl group denoted by Y1 for R2 include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclo-hexylcarbonyl group, and the like, preferably a cyclopropyl-carbonyl group.
Specific examples of the benzoyl group substituted byalkyl group(s) denoted by 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) denoted by Y1 for R2 include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a 4-chlorobenzoyl group, a 3,4-dichlorobenzoyl group, a 4-fluoro benzoyl group, and the like.
Specific examples of the alkyl group denoted by Y2 for R2 include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and the like, preferably a methyl group.
In the formula (1), compounds in which R1 and Y1 are concurrently an alkylcarbonyl group having from 1 to 4 carbon atoms or a cyclopropylcarbonyl group are preferred from the viewpoint of both insecticidal activity and production method.
In a preferred embodiment of the invention, the (tetrahydro-3-furanyl)methylamine derivative dissolved in the solvent component is dinotefuran. Dinotefuran is an insecticide that will kill adult fleas. Preferably, dinotefuran is dissolved in the formulation to a concentration range of about 5 to 20%, more preferably about 10 to 15%, and most preferably about 12 to 15%. All percentages, unless otherwise evident, are on a weight basis.
In another preferred embodiment of the invention, the insecticide is formulated by dissolving an insecticidally effective amount of a chloronicotinyl insecticide and an insect growth regulator (IGR) in a solvent component. The solvent component contains a sufficient amount of quaternary ammonium salt to increase the solvency of the IGR compared to the solvency of the IGR in the solvent without the quaternary ammonium salt and to increase the effectiveness of the insecticide compared to its effectiveness without the quaternary ammonium salt. In a preferred embodiment of the invention, the solvent component comprises ethanol and a quaternary ammonium salt. In another preferred embodiment of the invention, the solvent component comprises water, ethyl lactate and a quaternary ammonium salt.
In a preferred embodiment of the invention, the chloronicotinyl insecticide in the formulation is N-((6-chloro-3-pyridinyl)methyl)-N′-cyano-N-methyl-ethanimidamide (acetamiprid) and the insect growth regulator is pyriproxfen or methoprene. Acetamiprid is an insecticide that primarily kills adult fleas. Acetamiprid is disclosed in international applications PCT/JP90/01282 and PCT/EP93/01286, the contents of which are disclosed herein by reference.
In another preferred embodiment of the invention, the insect growth regulator is pyriproxyfen. In a preferred embodiment of the invention, pyriproxyfen is dissolved in the formulation to a concentration range of about 0.1 to 3%, more preferably about 0.5 to 3% and most preferably about 0.9 to 1.1%. In another preferred embodiment of the invention, the formulation comprises a dosage of at least about 10 mg of pyriproxyfen to an animal. Therefore, if the formulation contains 1% pyriproxyfen, an acceptable dosage would be about 10 mg or more in a 1 ml application.
In yet another preferred embodiment of the invention, the insect growth regulator is methoprene. In a preferred embodiment of the invention, methoprene is dissolved in the formulation to a concentration range of about 0.1 to 5%, more preferably about 0.5 to 5%, and most preferably about 3.0 to 5.0%. In another preferred embodiment of the invention, the dosage comprises at least about 30 mg of methoprene administered to the animal.
In one preferred embodiment of the invention, the insecticide is formulated by dissolving dinotefuran and pyriproxyfen in a solvent comprising water, ethyl lactate and a quaternary ammonium salt, preferably oleyldimethylammonium chloride. In another preferred embodiment of the invention, the insecticide is formulated by dissolving dinotefuran and pyriproxyfen in a solvent comprising ethanol and a quaternary ammonium salt, preferably oleyldimethylammonium chloride. Dinotefuran is an insecticide which kills adult fleas, acetamiprid is an insecticide that primarily kills adult fleas, and pyriproxyfen is an insecticide which kills flea larvae and flea eggs. By killing fleas in the adult and juvenile stages, the insecticide formulation of the invention is useful to improve the speed of result and decrease the reoccurrence of flea infestation compared to other insecticide formulations.
In another preferred embodiment of the invention, the insecticide is formulated by dissolving acetamiprid and pyriproxyfen in a solvent preferably comprising water, ethyl lactate and a quaternary ammonium salt, preferably oleyldimethylammonium chloride. In yet another preferred embodiment of the invention, the insecticide is formulated by dissolving acetamiprid and pyriproxyfen in a solvent preferably comprising ethanol and a quaternary ammonium salt, preferably oleyldimethylammonium chloride. Acetamiprid is an insecticide that primarily kills adult fleas, and pyriproxyfen is an insecticide which kills flea larvae and flea eggs. By killing fleas in the adult and juvenile stages, the insecticide formulation of the invention is useful to improve the speed of result and decrease the reoccurrence of flea infestation compared to other insecticide formulations.
High concentrations of dinotefuran and acetamiprid can be solubilized in a combination of water and ethyl lactate or ethanol. However, because dinotefuran is hydrophilic and pyriproxyfen is lipophilic, a solvent system which provides for solubilization of a high concentration of dinotefuran will not allow pyriproxyfen to solubilize properly. It has been determined that the addition of a quaternary ammonium salt such as an ammonium chloride, preferably with one or more carbon atoms, for example, cetyltrimethylammonium chloride, tallowalkyltrimethyl ammonium chloride and oleyldimethylammonium chloride, to the solvent component allows for an effective amount of pyriproxyfen to solubilize into the formulation without emulsification, thereby allowing for the delivery of high concentrations of hydrophilic and lipophilic insecticides in a single highly effective insecticidal topical solution.
Because pyriproxyfen is hydrophobic, it may be preferable to select a quaternary ammonium salt that is also hydrophobic in order to dissolve an effective amount pyriproxyfen into the insecticide formulation. Quaternary ammonium salts having a high number of carbon atoms in the alkyl chains such as cetyltrimethylammonium chloride, tallowalkyltrimethyl ammonium chloride and oleyldimethylammonium chloride, are preferably selected for use in the solvent component. Preferably, insecticidally effective amounts of dinotefuran and pyriproxyfen are incorporated into relatively low volumes. Such insecticide formulations are advantageously stable under various conditions of high and low temperature.
In another preferred embodiment of the invention, the preferred solvent component comprises a mixture comprising water, ethyl lactate and oleyldimethylammonium chloride, wherein the final concentration of oleyldimethylammonium chloride ranges from 0.5 to 20%, more preferably 0.5 to 5% oleyldimethylammonium chloride, and most preferably a final concentration of 1.0% oleyldimethylammonium chloride. When the solvent contains oleyldimethylammonium chloride, the ratio of water to ethyl lactate in the solvent is preferably approximately about 1:1 to 1:2.
Ethanol can also be added to the solvent component to improve solubility and to prevent high concentrations of dinotefuran or acetamiprid from crystallizing over time at low temperatures. In another preferred embodiment of the invention, the preferred solvent component comprises a mixture comprising water, ethyl lactate, ethanol and oleyldimethylammonium chloride, wherein the final concentration of oleyldimethylammonium chloride ranges from 0.5 to 20%, more preferably 0.5 to 5% oleyldimethylammonium chloride, and most preferably a final concentration of 1.0% oleyldimethylammonium chloride. When the solvent contains oleyldimethylammonium chloride, the ratio of water to ethyl lactate to ethanol in the solvent is preferably approximately about 1:1:1 to about 3:4:3, and all ratios in between. All ratios, unless otherwise evident, are on a weight basis.
In a preferred embodiment of the invention, the insecticide is formulated by dissolving dinotefuran and pyriproxyfen in a solvent comprising water, ethyl lactate and one of the above salts, such as oleyldimethylammonium chloride. Dinotefuran is dissolved in the formulation to a concentration range of about 5 to 20%, pyriproxyfen is dissolved in the formulation to a concentration range of about 0.5 to 3%, the concentration of oleyldimethylammonium chloride ranges from about 1 to 20%, and the concentration of ethyl lactate ranges from about 50 to 67%. Preferably, dinotefuran is dissolved in the formulation to a concentration of about 15%, pyriproxyfen is dissolved in the formulation to a concentration of about 1%, and the concentration of oleyldimethylammonium chloride is about 1%.
When the insecticide is formulated by dissolving dinotefuran and pyriproxyfen in a solvent comprising water, ethyl lactate and oleyldimethylammonium chloride, the ratio of dinotefuran to pyriproxyfen to oleyldimethylammonium chloride is preferably about 15:1:1, and the concentration of dinotefuran in the insecticide formulation does not exceed 15%. In other preferred embodiments, the ratio of dinotefuran to pyriproxyfen to oleyldimethylammonium chloride is preferably approximately about 10:1:1, 20:1:1 or 30:1:1 and all ratios in between, and the concentration of dinotefuran preferably does not exceed 15%.
For the application of about 0.5 to 1.33 ml of the insecticide to a companion animal weighing 9 pounds or less, it is preferable that the insecticide is formulated by dissolving approximately 150-200 mg of dinotefuran and approximately 10 mg of pyriproxyfen in a solvent comprising water, ethyl lactate and oleyldimethylammonium chloride to achieve a 90% kill rate for fleas.
In yet another embodiment of the invention, the preferred solvent component comprises a mixture comprising water, ethyl lactate and cetyltrimethylammonium chloride, wherein the final concentration of cetyltrimethylammonium chloride is approximately 19 to 20%, and more preferably, the final concentration of cetyltrimethylammonium chloride is approximately 20%. Ethanol can also be added to the solvent component to improve solubility.
Preferably, when the insecticide is formulated by dissolving dinotefuran and pyriproxyfen in a solvent comprising water, ethyl lactate and cetyltrimethylammonium chloride, dinotefuran is dissolved in the formulation to a concentration range of about 14 to 15%, pyriproxyfen is dissolved in the formulation to a concentration range of about 1 to 3%, the concentration of cetyltrimethylammonium chloride ranges from about 19 to 20%, and the concentration of ethyl lactate ranges from about 40 to 75%.
In yet another embodiment of the invention, the preferred solvent component comprises a mixture comprising water, ethyl lactate and tallowalkyltrimethyl ammonium chloride, wherein the final concentration of tallowalkyltrimethyl ammonium chloride ranges from approximately 19 to 20%, and more preferably, the final concentration of tallowalkyltrimethyl ammonium chloride is about 20%. Ethanol can also be added to the solvent component to improve solubility.
Preferably, when the insecticide is formulated by dissolving dinotefuran and pyriproxyfen in a solvent comprising water, ethyl lactate and tallowalkyltrimethyl ammonium chloride, dinotefuran is dissolved in the formulation to a concentration range of about 14 to 15%, pyriproxyfen is dissolved in the formulation to a concentration range of about 1 to 3%, the concentration of tallowalkyltrimethyl ammonium chloride ranges from about 19 to 20%, and the concentration of ethyl lactate ranges from about 40 to 75%.
In another embodiment of the invention, the insecticide is formulated by dissolving acetamiprid and pyriproxfen in a solvent comprising water, ethyl lactate and a quaternary ammonium salt such as cetyltrimethylammonium chloride, tallowalkyltrimethyl ammonium chloride and oleyldimethylammonium chloride. Acetamiprid is dissolved in the formulation to a concentration range of about 5 to 50%, pyriproxfen is dissolved in the formulation to a concentration range of about 0.5 to 3%, the concentration of the quaternary ammonium salt ranges from about 1 to 20%, and the concentration of ethyl lactate ranges from about 50 to 67%.
For the application of about 0.4 to 1.33 ml of the insecticide to a companion animal weighing 9 pounds or less, it is preferable that the insecticide is formulated by dissolving approximately 100 mg/ml of acetamiprid and approximately 10 mg/ml of pyriproxyfen in a solvent comprising water, ethyl lactate, ethanol and oleyldimethylammonium chloride to achieve a 90% kill rate for fleas.
Solvent Containing N-octyl Pyrrolidone and/or N-Methyl Pyrrolidone
In accordance with another preferred embodiment of the invention, the preferred solvent includes N-octyl pyrrolidone (NOP) and/or N-methyl pyrrolidone (NMP). The inventors determined that N-octyl pyrrolidone and N-methyl pyrrolidone, either alone or in combination, can increase the degree of dissolution of the insecticide components, more specifically, dinotefuran. The greater amount of dissolution can enhance efficiency of the insecticide composition by requiring less solvent to dissolve the same amount of insecticide compositions, increasing insecticide concentration and leading to lower volumes of material to be applied to the animal.
Preferably, the insecticide comprises N-octyl pyrrolidone in a concentration range of approximately 0-10%, more preferably approximately 5-7%, most preferably about 6%. Additionally, the insecticide can comprise N-methyl pyrrolidone in a concentration range of approximately 45-94%. Preferably, the insecticide comprises dinotefuran in a concentration range of approximately 5-40%, and pyriproxyfen in a concentration range of approximately 1 to 7%. All percentages, unless otherwise specified, are on a weight basis.
Formulation A: In one exemplary embodiment of the invention, the insecticide comprises dinotefuran in a concentration range of about 5-30%, pyriproxyfen in a concentration range of about 1-3%, N-octyl pyrrolidone in a concentration range of approximately 0.1-6% and N-methyl pyrrolidone in a concentration range of approximately 61-94%. All percentages, unless otherwise specified, are on a weight basis.
Formulation B: In one exemplary embodiment of the invention, the insecticide comprises dinotefliran in a concentration range of about 20-40%, pyriproxyfen in a concentration of about 1%, N-octyl pyrrolidone in a concentration of approximately 6% and N-methyl pyrrolidone in a concentration range of approximately 53-73%. All percentages, unless otherwise specified, are on a weight basis.
Formulation C: In one exemplary embodiment of the invention, the insecticide comprises dinotefuran in a concentration of about 30%, pyriproxyfen in a concentration range of about 1.5-7%, N-octyl pyrrolidone in a concentration of approximately 6% and N-methyl pyrrolidone in a concentration range of approximately 57-63%. All percentages, unless otherwise specified, are on a weight basis.
Formulation D: In one exemplary embodiment of the invention, the insecticide comprises dinotefuran in a concentration of about 35%, pyriproxyfen in a concentration range of about 1.5-7%, N-octyl pyrrolidone in a concentration of approximately 6% and N-methyl pyrrolidone in a concentration range of approximately 52-58%. All percentages, unless otherwise specified, are on a weight basis.
Formulation E: In one exemplary embodiment of the invention, the insecticide comprises dinotefuran in a concentration range of about 20-25%, pyriproxyfen in a concentration of about 2%, N-octyl pyrrolidone in a concentration of approximately 6%, N-methyl pyrrolidone in a concentration range of approximately 45-54% and water in a concentration of about 16-27%. All percentages, unless otherwise specified, are on a weight basis.
Formulation F: In one exemplary embodiment of the invention, the insecticide comprises dinotefuran in a concentration of about 35%, pyriproxyfen in a concentration of about 5%, N-octyl pyrrolidone in a concentration of approximately 6% and N-methyl pyrrolidone in a concentration of approximately 54%. All percentages, unless otherwise specified, are on a weight basis.
Formulation G: In one exemplary embodiment of the invention, the insecticide comprises dinotefuran in a concentration range of about 18-26%, pyriproxyfen in a concentration range of about 2-4%, N-octyl pyrrolidone in a concentration range of approximately 3-8%, N-methyl pyrrolidone in a concentration range of approximately 30-48% and propylene carbonate in a concentration range of approximately 30-38%. All percentages, unless otherwise specified, are on a weight basis.
Formulation H: In one exemplary embodiment of the invention, the insecticide comprises dinotefuran in a concentration of about 22%, pyriproxyfen in a concentration of about 3%, N-octyl pyrrolidone in a concentration of approximately 6%, N-methyl pyrrolidone in a concentration of approximately 34.74% and propylene carbonate in a concentration of approximately 34%. All percentages, unless otherwise specified, are on a weight basis.
In the preparation of a formulation in accordance with the invention for use on companion animals, there are several parameters that should be considered. These are:

    
    
        (a) Concentration high enough to minimize the volume of the topical applied to the animal (one would not want to put 20 ml, e.g., onto a small cat).
        (b) The formulation should be stable for one month at 130° F., 110° F., 40° F., room temperature and 0° F. This helps ensure that the formulation remains stable under the conditions that it could meet in commerce.
        (c) Safe to use on the animal—particularly non-irritating since the product is applied to the skin. Also safe if ingested by the animal; ingestion can occur when cats groom themselves.
        (d) Safe to use by the consumer.
        (e) Efficacious in use—should kill greater than 80% or even 90% of the fleas up to 28 days.
        (f) Efficacy would be reduced if crystallization occurred in the package.
        (g) Needs to be aesthetically pleasing—“no oily drop” on the animal when applied.
        (h) Fast drying to reduce the chance of the animal shaking off the liquid thereby reducing efficacy.
        (i) Microbiologically stable.
    
    


Other additives to the insecticidal formulation can include, but are not limited to, fragrances to improve odor and surfactants such as isopropyl myristate and sorbitan derivatives such as polysorbate 20 and spreading agents to increase performance. Polymers may also be used to provide enrobing of the insecticide to improve safety and adhesion to skin and hair. Examples of polymers that may be used include cationic cellulose, cationic guar, cationic acrylate polymers, agar, gelatin and alginate.
In practice, an effective amount of the insecticidal formulation as described herein may be applied to a companion animal, preferably a dog or cat, as a foaming shampoo, dip, aerosol spray, pump spray, lotion, emulsifiable concentrate, aqueous or liquid flowable, suspension concentrate and by any other methods suitable for administering topical compositions to animals.
In a preferred embodiment of the invention, the insecticidal formulation can be applied as a topical drop about once a month, preferably in the area between the shoulder blades and the base of the skull to kill fleas, flea larvae and flea eggs over a one-month period.
The following examples are given for purposes of illustration only and are not intended to be construed in a limiting manner.
EXAMPLES
Example 1
Preparation of 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran)
A mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol, 29.5 g of trifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml of dichloromethane was stirred for an hour at room temperature. Water was poured into the reaction solution to separate the organic layer, which was washed with 1 N 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% sodium hydride were 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 an hour. 20.0 g of the 3-tetrahydrofuranylmethyl triflate were added thereto, and the mixture was stirred at 50° C. for 2 hours. After cooling the mixture to room temperature, 50 ml of 2N hydrochloric acid were added thereto, followed by stirring at 50° C. for 2 hours. The resultant mixture was neutralized with sodium bicarbonate and extracted with dichloromethane, and the extract was dried and concentrated. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to obtain 7.8 g of 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran).
Example 2
Preparation of Insecticide Formulation Containing Dinotefuran, Pyriproxyfen, and Oleyldimethylammonium Chloride
0.5 g of oleyldimethylammonium chloride was added to 0.5 g of pyriproxyfen with heat (50 degrees C.) and dissolved. 20.75 g of water followed by 20.75 g of ethyl lactate was then added. 2.1 g of t-octylphenoxzypolyethoxyethanol containing 9 moles of ethlyene oxide (OP 9) was added. 7.8 g of dinotefuran was dissolved in the solution by stirring to produce a clear homogeneous solution followed by cooling to room temperature. The pH was adjusted with sodium carbonate solution to between 5.5 and 7.
Example 3
Stability of Dinotefuran/Pyriproxyfen Formulations
Few solvent systems allow for dinotefuran to remain in solution for one month at low temperatures. Further, solvent systems which allow for high concentrations of dinotefuran to be dissolved do not typically allow for the solubilization of pyriproxyfen. As shown in Table 1, it has been determined that including a quaternary ammonium salt in the solvent allows for an effective amount of pyriproxyfen to become and remain solubilized, thereby producing a stable formulation. The stability of the formulation is based on the criterion of no crystal formation at 0° F. during a 1 month period.







TABLE 1







Formulation Stability Studies (% are w/w)











%
%
Solvent
Quaternary



Dinotefuran
Pyriproxfen
System
Ammonium Salt
Stable





15
1
Water/Ethyl
Cetyltrimethylammonium
Yes




Lactate/Ethanol
chloride


15
1
Water/Ethyl
Cetyltrimethylammonium
Yes




Lactate
chloride


15
1
Water/Ethyl
tallowalkyltrimethyl ammonium
Yes




Lactate
chloride


15
1
Water/Ethyl
tallowalkyltrimethyl
Yes




Lactate/Ethanol
ammonium chloride


15
1
Water/Ethyl
Oleyldimethylammonium
Yes




lactate
chloride


15
1
Water/Ethyl
Oleyldimethylammonium
Yes




lactate/Ethanol
chloride


15
1
Water/Ethyl
None
No




lactate/Ethanol









It has been determined that the solubility of pyriproxfen in a solution containing dinotefuran can be increased by adding a quaternary amine such as an ammonium chloride salt, for example, cetyltrimethylammonium chloride, tallowalkyltrimethyl ammonium chloride and oleyldimethylammonium chloride compared to a similar formulation without the quaternary ammonium salt. The inclusion of a quaternary ammonium salt up to about 20% results in a formulation which is stable.
Example 4
Formulations containing varying ratios of solvent components were prepared using the procedure discussed in Example 2.
Table 2 contains the composition of the various formulations and demonstrates that the inclusion of a quaternary ammonium salt produces a stable solution containing dinotefuran and pyriproxfen. Stability of the formulation is based on the criterion of no crystal formation at 0° F. during a 1 month period.













TABLE 2






Ratio of








Solvent

%
%


Solvent System
Components
Quaternary Amines (20%)
Dinotefuran
Pyriproxfen
# of Days Stable
Observation





















Water/Ethyl
50/10/40
Cetrimonium chloride
15
1

Precipitation on


lactate/Ethanol





day 20


Water/Ethyl
30/40/30
Cetrimonium chloride
15
1
30
Clear solution


lactate/Ethanol


Myristamine
25/75
Cetrimonium chloride
15
1

Precipitation on


oxide/Ethyl





day 30


lactate


Ethyl
50/50
Cetrimonium chloride
15
1

Precipitation


lactate/Ethanol





overnight


Myristamine
50/50
Cetrimonium chloride
15
1

Precipitation on


oxide/Ethyl





day 11


lactate


Water/Ethyl
50/50
Cetrimonium chloride
15
1
42
Clear solution


lactate


Water/Ethyl
25/75
Cetrimonium chloride
15
1
37
Clear solution


lactate


Water/Ethyl
75/25
Cetrimonium chloride
15
1
35
Clear solution


lactate


Water/Ethyl
33.3/33.3/33.3
Cetrimonium chloride
15
1
36
Clear solution


lactate/Ethanol


Water/Ethanol
25/75
Cetrimonium chloride
15
1

Precipitation on








day 10


Water/Ethanol
75/25
Cetrimonium chloride
15
1

Clear solution








could not be made


Water/Ethyl
50/50
Cetrimonium chloride
15
1

Precipitation on


lactate





day 7


Water/Ethyl
50/50
Cetrimonium chloride
18
1

Precipitation on


lactate





day 25


Water/Ethyl
25/75
Cetrimonium chloride
18
1

Precipitation on


lactate





day 25


Water/Ethyl
33.3/33.3/33.3
Cetrimonium chloride
18
1

Precipitation on


lactate/Ethanol





day 7


Water/Ethyl
50/50
Cetrimonium chloride
20
1

Precipitation on


lactate





day 14


Water/Ethyl
25/75
Cetrimonium chloride
20
1

Precipitation on


lactate





day 20


Water/Ethyl
33.3/33.3/33.3
Cetrimonium chloride
20
1

Precipitation on


lactate/Ethanol





day 6


Water/Ethyl
50/50
Cetrimonium chloride
22
1

Precipitation on


lactate





day 10


Water/Ethyl
25/75
Cetrimonium chloride
22
1

Precipitation on


lactate





day 6


Water/Ethyl
33.3/33.3/33.3
Cetrimonium chloride
22
1

Precipitation on


lactate/Ethanol





day 6


Water/Ethanol
50/50
Cetrimonium chloride/OP-9
15
1

Precipitation on








day 6


Water/Ethanol
50/50
Tallowalkyltrimethyl
15
1

Precipitation on




ammonium chloride



day 28


Water/Ethyl
50/50
Tallowalkyltrimethyl
15
1
38
Clear solution


lactate

ammonium chloride


Water/Ethanol
25/75
Tallowalkyltrimethyl
15
1

Precipitation on




ammonium chloride



day 25


Water/Ethyl
25/75
Tallowalkyltrimethyl
15
1
35
Clear solution


lactate

ammonium chloride


Water/Ethyl
75/25
Tallowalkyltrimethyl
15
1
20
Clear solution


lactate

ammonium chloride


Water/Ethyl
50/10/40
Tallowalkyltrimethyl
15
1
30
Clear solution


lactate/Ethanol

ammonium chloride


Water/Ethyl
30/40/30
Tallowalkyltrimethyl
15
1

Precipitation on


lactate/Ethanol

ammonium chloride



day 27


Water/Ethyl
33.3/33.3/33.3
Tallowalkyltrimethyl
15
1

Precipitation on


lactate/Ethanol

ammonium chloride



day 33


Myristamine
50/50
Tallowalkyltrimethyl
15
1

Precipitation on


oxide/Ethyl

ammonium chloride



day 7


lactate


Myristamine
25/75
Tallowalkyltrimethyl
15
1

Precipitation on


oxide/Ethyl

ammonium chloride



day 27.


lactate


Ethyl
50/50
Tallowalkyltrimethyl
15
1

Precipitation


lactate/Ethanol

ammonium chloride



overnight


Water/Ethanol
75/25
Tallowalkyltrimethyl
15
1

Precipitation on




ammonium chloride



day 4


Water/Ethyl
50/50
Tallowalkyltrimethyl
18
1

Precipitation on


lactate

ammonium chloride



day 6


Water/Ethyl
25/75
Tallowalkyltrimethyl
18
1

Precipitation on


lactate

ammonium chloride



day 16


Water/Ethyl
75/25
Tallowalkyltrimethyl
18
1

Precipitation on


lactate

ammonium chloride



day 6


Water/Ethyl
33.3/33.3/33.3
Tallowalkyltrimethyl
18
1

Precipitation on


lactate/Ethanol

ammonium chloride



day 16


Water/Ethyl
50/50
Tallowalkyltrimethyl
20
1

Precipitation on


lactate

ammonium chloride



day 6


Water/Ethyl
25/75
Tallowalkyltrimethyl
20
1

Precipitation on


lactate

ammonium chloride



day 5


Water/Ethyl
75/25
Tallowalkyltrimethyl
20
1

Precipitation on


lactate

ammonium chloride



day 6


Water/Ethyl
33.3/33.3/33.3
Tallowalkyltrimethyl
20
1

Precipitation on


lactate/Ethanol

ammonium chloride



day 6


Water/Ethyl
50/50
Tallowalkyltrimethyl
22
1

Precipitation on


lactate

ammonium chloride



day 6


Water/Ethyl
25/75
Tallowalkyltrimethyl
22
1

Precipitation on


lactate

ammonium chloride



day 6


Water/Ethyl
75/25
Tallowalkyltrimethyl
22
1

Precipitation on


lactate

ammonium chloride



day 6


Water/Ethyl
33.3/33.3/33.3
Tallowalkyltrimethyl
22
1

Precipitation on


lactate/Ethanol

ammonium chloride



day 6


Water/Ethyl
50/50
Oleyldimethylammonium
15
1
41
Clear solution


lactate

chloride


Water/Ethyl
25/75
Oleyldimethylammonium
15
1
35
Clear solution


lactate

chloride


Water/Ethyl
33.3/33.3/33.3
Oleyldimethylammonium
15
1
36
Clear solution


lactate/Ethanol

chloride


Water/Ethyl
50/10/40
Oleyldimethylammonium
15
1
15
Precipitation on


lactate/Ethanol

chloride



day 15


Water/Ethanol
75/25
Oleyldimethylammonium
15
1

Precipitation on




chloride



day 29


Water/Ethanol
25/75
Oleyldimethylammonium
15
1

Precipitation on




chloride



day 5


Water/Ethyl
75/25
Oleyldimethylammonium
15
1

Precipitation on


lactate

chloride



day 12


Water/Ethyl
30/40/30
Oleyldimethylammonium
15
1
30
Clear solution


lactate/Ethanol

chloride


Ethyl
50/50
Oleyldimethylammonium
15
1

Precipitation


lactate/Ethanol

chloride



overnight


Myristamine
50/50
Oleyldimethylammonium
15
1

Precipitation on


oxide/Ethyl

chloride



day 7


lactate


Myristamine
25/75
Oleyldimethylammonium
15
1

Precipitation on


oxide/Ethyl

chloride



day 7


lactate


Water/Ethyl
50/50
Oleyldimethylammonium
18
1

Precipitation on


lactate

chloride



day 14


Water/Ethyl
25/75
Oleyldimethylammonium
18
1

Precipitation on


lactate

chloride



day 16


Water/Ethyl
33.3/33.3/33.3
Oleyldimethylammonium
18
1

Precipitation on


lactate/Ethanol

chloride



day 6


Water/Ethyl
50/50
Oleyldimethylammonium
20
1

Precipitation on


lactate

chloride



day 11


Water/Ethyl
25/75
Oleyldimethylammonium
20
1

Precipitation on


lactate

chloride



day 16


Water/Ethyl
33.3/33.3/33.3
Oleyldimethylammonium
20
1

Precipitation on


lactate/Ethanol

chloride



day 6


Water/Ethyl
50/50
Oleyldimethylammonium
22
1

Precipitation on


lactate

chloride



day 14


Water/Ethyl
25/75
Oleyldimethylammonium
22
1

Precipitation on


lactate

chloride



day 6


Water/Ethyl
33.3/33.3/33.3
Oleyldimethylammonium
22
1

Precipitation on


lactate/Ethanol

chloride



day 6









Example 5
Stability Data for Formulations B C D and E
The following examples of the insecticide composition in accordance with the embodiment of Formulations B, C, D and E were tested for color, appearance and uniformity in various temperatures, some over the duration of four days or more. The composition of these examples and the test results are provided below. The following examples are given for purposes of illustration only and are not intended to be construed in a limiting manner.
Sample Compositions:










FORMULATION B: (% concentration)









Composition Numbers












Ingredients
3061-41A
3061-41B
3061-41C
3061-53A
3061-53B















S-1638
20.000
25.000
30.000
35.000
40.000


n-Methyl
73.000
68.000
63.000
58.000
53.000


pyrrolidone


Agsolex 8
6.000
6.000
6.000
6.000
6.000


Nylar
1.000
1.000
1.000
1.000
1.000





TS#
TS#12848





12839



















FORMULATION C:









(% concentration)













Composition Numbers













Ingredients
3061-62A
3061-62B
3061-62C
3061-62D
3061-62E
3061-62F





S-1638
30.00
30.00
30.00
30.00
30.00
30.00


Nylar
1.50
2.00
2.50
3.00
3.50
4.00


Agsolex 8
6.00
6.00
6.00
6.00
6.00
6.00


n-Methyl pyrrolidone
62.50
62.00
61.50
61.00
60.50
60.00



TS#12840
TS#12841
TS#12842
TS#12843
TS#12844
TS#12845












Composition Numbers













Ingredients
3061-62G
3061-62H
3061-62I
3061-62J
3061-62K
3061-62L





S-1638
30.00
30.00
30.00
30.00
30.00
30.00


Nylar
4.50
5.00
5.50
6.00
6.50
7.00


Agsolex 8
6.00
6.00
6.00
6.00
6.001
6.00


n-Methl pyrrolidone
59.50
59.00
58.50
58.00
57.50
57.00



TS#12846
TS#12847



















FORMULATION D:









(% concentration)













Composition Numbers













Ingredients
3061-63A
3061-63B
3061-63C
3061-63D
3061-63E
3061-63F





S-1638
35.00
35.00
35.00
35.00
35.00
35.00


Nylar
1.50
2.00
2.50
3.00
3.50
4.00


Agsolex 8
6.00
6.00
6.00
6.00
6.00
6.00


n-Methyl pyrrolidone
57.50
57.00
56.50
56.00
55.50
55.00



TS#12849
TS#12850
TS#12851
TS#12852
TS#12853
TS#12854












Composition Numbers













Ingredients
3061-63G
3061-63H
3061-63I
3061-63J
3061-63K
3061-63L





S-1638
35.00
35.00
35.00
35.00
35.00
35.00


Nylar
4.50
5.00
5.50
6.00
6.50
7.00


Agsolex 8
6.00
6.00
6.00
6.00
6.00
6.00


n-Methyl pyrrolidone
54.50
54.00
53.50
53.00
52.50
52.00



TS#12855
TS#12856



















FORMULATION E: (% concentration)









Composition Numbers












Ingredients
3061-55A
3061-55B
3061-55K
















S-1638
20.000
25.000
20.000



n-Methyl pyrrolidone
54.000
51.000
45.000



DI H2O
18.000
16.000
27.000



Agsolex 8
6.000
6.000
6.000



Nylar
2.000
2.000
2.000










S-1638 is dinotefuran and Agsolex 8 is N-octyl pyrrolidone. Pyriproxyfen is also known as Nylar.
Test Results:
Table 3A shows the results of the stability testing at room temperature.









TABLE 3A









Room Temperature


















INITIAL
Day 4
Day 7
Day 10
Day 14
Day 17
Day 20
Day 24
Day 27
Day 30





















Comp # 3061-












41A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp #3061-


41B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp #3061-


41B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp #


3061-53A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


53B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


55A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


55B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


55K


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


62A


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62B


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62C


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62D


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62F


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62G


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62H


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62I


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62J


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62K


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62L


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63A


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63B


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63C


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63D


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63E


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63F


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63G


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63H


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63I


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63J


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63K


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63L


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes









Table 3B shows the results of the stability testing at 4° C.









TABLE 3B









4° C.


















INITIAL
Day 4
Day 7
Day 10
Day 14
Day 17
Day 20
Day 24
Day 27
Day 30





Comp # 3061-












41A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp #3061-


41B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp #3061-


41B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp #


3061-53A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


53B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


55A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


55B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
Clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
crystals


Comp # 3061-


55K


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
crystals
crystals


Comp # 3061-


62A


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62B


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62C


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62D


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62F


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62G


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62H


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62I


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62J


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62K


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62L


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63A


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63B


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63C


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63D


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63E


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63F


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63G


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63H


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63I


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63J


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63K


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63L


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes









Table 3C shows the results of the stability testing under freeze (0° F.)/thaw (F/T) conditions.









TABLE 3C









F/T


















INITIAL
Day 4
Day 7
Day 10
Day 14
Day 17
Day 20
Day 24
Day 27
Day 30





















Comp # 3061-












41A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp #3061-


41B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


41B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp #


3061-53A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


53B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
cloudy
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
crystals
crystals
crystals
crystals
crystals


Comp # 3061-


55A


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
yes
yes
yes


Comp # 3061-


55B


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
yes
yes
crystals
crystals
crystals


Comp # 3061-


55K


Color
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow
sl yellow


Appearance
clear
clear
clear
clear
clear
clear
clear
clear


Uniform?
yes
yes
yes
crystals
crystals
crystals
crystals
crystals


Comp # 3061-


62A


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62B


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62C


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62D


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62F


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62G


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62H


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62I


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62J


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62K


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


62L


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63A


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63B


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63C


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63D


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63E


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63F


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63G


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63H


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63I


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63J


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63K


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes


Comp # 3061-


63L


Color
sl yellow
sl yellow


Appearance
clear
clear


Uniform?
yes
yes









Example 6
Stability Data for Formulations G and H
The following examples of the insecticide composition in accordance with the embodiment of Formulations G and H were tested for uniformity under freeze/thaw conditions over a duration of four weeks. The composition of these examples and the test results are provided below. The following examples are given for purposes of illustration only and are not intended to be construed in a limiting manner.







TABLE 4A







Series A Compositions


Compositions are given in percent by weight.


















Positive
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp



Control
#1
#2
#3
#4
#5
#6
#7
#8
#9





















Dinoterfuran
20
20
20
20
20
20
20
20
20
20


Nylar
3
3
3
3
3
3
3
3
3
3


NMP
26
30
35
40
45
26
30
35
40
45


NOP
3
3
3
3
3
6
6
6
6
6


Propylene
48
44
39
34
29
45
41
36
31
26


carbonate


Crystals?
YES
YES
NO
NO
NO
YES
YES
NO
NO
NO
















TABLE 4B







Series B Compositions


Compositions are given in percent by weight.


















Positive
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp



Control
#1
#2
#3
#4
#5
#6
#7
#8
#9





















Dinoterfuran
22
22
22
22
22
22
22
22
22
22


Nylar
3
3
3
3
3
3
3
3
3
3


NMP
26
30
35
40
45
26
30
35
40
45


NOP
3
3
3
3
3
6
6
6
6
6


Propylene
46
42
37
32
27
43
39
34
29
24


carbonate


Crystals?
YES
YES
YES
NO
NO
YES
YES
NO
NO
NO
















TABLE 4C







Series C Compositions


Compositions are given in percent by weight.


















Positive
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp



Control
#1
#2
#3
#4
#5
#6
#7
#8
#9





















Dinoterfuran
25
25
25
25
25
25
25
25
25
25


Nylar
3
3
3
3
3
3
3
3
3
3


NMP
26
30
35
40
45
26
30
35
40
45


NOP
3
3
3
3
3
6
6
6
6
6


Propylene
43
39
34
29
24
40
36
31
26
21


carbonate


Crystals?
YES
YES
YES
YES
NO
YES
YES
YES
YES
NO
















TABLE 4D







Series D Compositions


Compositions are given in percent by weight.


















Positive
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp



Control
#1
#2
#3
#4
#5
#6
#7
#8
#9




















Dinoterfuran
30
30
30
30
30
30
30
30
30
30


Nylar
3
3
3
3
3
3
3
3
3
3


NMP
26
30
35
40
45
26
30
35
40
45


NOP
3
3
3
3
3
6
6
6
6
6


Propylene
38
34
29
24
19
35
31
26
21
16


carbonate












Crystals?
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
















TABLE 4E







Series E Compositions


Compositions are given in percent by weight.


















Positive
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp



Control
#1
#2
#3
#4
#5
#6
#7
#8
#9




















Dinoterfuran
20
20
20
20
20
20
20
20
20
20


Nylar
1
1
1
1
1
1
1
1
1
1


NMP
28
32
37
42
47
28
32
37
42
47


NOP
3
3
3
3
3
6
6
6
6
6


Propylene
48
44
39
34
29
45
41
36
31
26


carbonate












Crystals?
YES
NO
NO
NO
NO
YES
NO
NO
NO
NO
















TABLE 4F







Series F Compositions


Compositions are given in percent by weight.


















Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp



#1
#2
#3
#4
#5
#6
#7
#8
#9
#10




















Dinoterfuran
22
22
22
22
22
22
22
22
22
22


Nylar
1
1
1
1
1
1
1
1
1
1


NMP
28
32
37
42
47
28
32
37
42
47


NOP
3
3
3
3
3
6
6
6
6
6


Propylene
46
42
37
32
27
43
39
34
29
24


carbonate












Crystals?
YES
YES
NO
NO
NO
YES
YES
NO
NO
NO
















TABLE 4G







Series G Compositions


Compositions are given in percent by weight.


















Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp



#1
#2
#3
#4
#5
#6
#7
#8
#9
#10




















Dinoterfuran
25
25
25
25
25
25
25
25
25
25


Nylar
1
1
1
1
1
1
1
1
1
1


NMP
28
32
37
42
47
28
32
37
42
47


NOP
3
3
3
3
3
6
6
6
6
6


Propylene
43
39
34
29
24
40
36
31
26
21


carbonate












Crystals?
YES
YES
YES
NO
NO
YES
YES
YES
YES
NO
















TABLE 4H







Series H Compositions


Compositions are given in percent by weight.


















Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp
Comp



#1
#2
#3
#4
#5
#6
#7
#8
#9
#10




















Dinoterfuran
30
30
30
30
30
30
30
30
30
30


Nylar
1
1
1
1
1
1
1
1
1
1


NMP
28
32
37
42
47
28
32
37
42
47


NOP
3
3
3
3
3
6
6
6
6
6


Propylene
38
34
29
24
19
35
31
26
21
16


carbonate












Crystals?
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES









It can be seen that insecticides in accordance with the invention can remain liquids, without readily observable precipitation (e.g., visible crystal formation), at room temperature, preferably less than about 4° C. and more preferably under about 0° C. for more than 4 days, preferably more than 28 days.
It will thus be seen that the objects set forth above, among those made apparent from the preceding description, are efficiently attained and, since certain changes may be made in carrying out the above method and in the formulations set forth without departing from the spirit and scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described and all statements of the scope of the invention which, as a matter of language, might be said to fall there between. Particularly it is to be understood that in said claims, ingredients or compounds recited in the singular are intended to include compatible mixtures of such ingredients wherever the sense permits.

## Claims

1. A liquid insecticide formulated by combining components, comprising, by weight:
about 18% to 26% dinotefuran;
about 1% to 7% pyriproxyfen;
about 30% to 38% propylene carbonate;
about 30% to 94% N-methyl pyrrolidone; and
about 0.1% to 8% N-octyl pyrrolidone;
the liquid formulated so that the dinotefuran and pyriproxyfen remain in solution for over twenty-eight days when stored at a temperature under 4° C.

2. The insecticide of claim 1, comprising about 20% to 25% by weight dinotefuran.

3. The insecticide of claim 1, comprising about 2% to 4% by weight pyriproxyfen.

4. The insecticide of claim 1, comprising about 34% to 36% by weight N-methyl pyrrolidone.

5. The insecticide of claim 1, comprising about 5% to 7% by weight N-octyl pyrrolidone.

6. The insecticide of claim 1, comprising about 2% to 4% by weight pyriproxyfen, about 30% to 48% N-methyl pyrrolidone, and about 3% to 8% by weight of N-octyl pyrrolidone.

7. The insecticide of claim 1, comprising about 21% to 23% by weight dinotefuran, about 2% to 4% by weight pyriproxyfen, about 33% to 35% by weight propylene carbonate, about 34% to 36% by weight N-methyl pyrrolidone, and about 5% to 7% by weight N-octyl pyrrolidone.

8. A method of treating house pets, comprising applying an insecticidally effective amount of the insecticide of claim 1 onto the pet.

9. The method of claim 8, wherein the insecticide is applied to the pet as a topical spot on the pet.