Topical endoparasiticide and ectoparasiticide formulations

Tag : triphenyl ester

Abstract
A topical formulation having significant parasiticidal activityeffective against endoparasites and/or ectoparasites such asheartworms, mites, fleas, ticks, flies is provided, which can besafe to use and avoids the many common deleterious side effects ofconventional topical formulations. The topical formulationscomprise a combination of a macrocyclic lactone, a neo-nicotinoidand optionally, an insect growth regulator. The topical formulationcan be packaged together or packaged so that the macrocycliclactone and the neo-nicotinoid are stored separately prior toadministering the topical insecticide formulation to the animal.
Description of the Invention
SUMMARY OF THE INVENTION

Generally speaking, in accordance with the invention, a topicalpharmaceutical formulation comprising a macrocyclic lactone,together with a neo-nicotinoid and/or an insect growth regulator,particularly one for use on cats and dogs, is provided.Formulations in accordance with the invention can be safe to useand avoids many common deleterious side effects of conventionaltopical formulations.

The invention provides a topical formulation that contains acombination of insecticides and insect growth regulators, which canbe effective to kill endoparasites and ectoparasites such asheartworm, fleas, flea eggs, flea larvae, ticks, tick eggs, ticklarvae, tick nymphs, mites and mosquitoes. The selection of thecombination of insecticides and insect growth regulators produces acomposition having high parasitical activity, thereby providingbroad protection against a variety of endoparasites andectoparasites with a single application of the topical formulation.The compositions derived herein can also be useful to improve thespeed of result and decrease the reoccurrence, compared to otherformulations.

The invention provides a topical formulation that contains acombination of a first active ingredient comprising a macrocycliclactone and a second active ingredient comprising a neo-nicotinoid.Preferably, the topical formulation further contains an insectgrowth regulator (IGR). In a preferred embodiment of the invention,the macrocyclic lactone in the composition comprises at least oneof ivermectin, selamectin, doramectin, moxidectin or eprinomectin.The neo-nicotinoid can comprise a (tetrahydro-3-furanyl)methylaminederivative of formula (1), as identified below. In anotherembodiment of the invention, the neo-nicotinoid comprises achloronicotinyl insecticide, preferably acetamiprid. The insectgrowth regulator (IGR) preferably comprises pyriproxyfen and/ormethoprene. As used herein, the identification of an activeingredient, e.g., ivermectin, is intended to also refer to otherpharmaceutically active forms of the active ingredient, such asesters, salts, hydrochlorides, acid or base forms, isomers and soforth.

In another embodiment of the invention, the topical formulationalso contains a pyrethroid such as permethrin or phenothrin inorder to provide additional acaricide efficacy and to repel andkill mosquitoes.

It has been determined that it is difficult to form a highconcentration of dinotefuran or acetamiprid and permethrin orphenothrin, and it is likely to result in a solution that can beunstable when stored at room temperature for reasonable amounts oftime. Therefore, it has been found preferable to produce a firstformulation comprising a macrocyclic lactone and a neo-nicotinoidand a second formulation comprising permethrin or phenothrin, andto keep these formulations separated until prior to, preferablyimmediately prior to application. Preferably, topical formulationalso contains an IGR, which may be packaged with either the firstor second formulation or in yet another container.

The first and second formulations are advantageously produced andpackaged in a manner so that the first and second formulations canbe prevented from interacting prior to application of theformulation to the animal. Preferably, the first and secondformulations can be stored separately from each other in a packageor container having two associated, preferably attached, butindividual chambers to prevent the mixing of the first and secondformulations prior to administration of the first and secondformulation to the animal. The first and second formulations can beadvantageously packaged in a container or chamber that is opaque inorder to prevent the photodegradation of the active ingredients inthe formulations. Prior to administration, the packages containingthe first and second formulations in their respective separatechambers are opened, and the first and second formulations aredispensed simultaneously or at least at about the same time, to theanimal.

Accordingly, it is an object of the invention to provide animproved topical formulation that is effective against a variety ofparasites.

Another object of the invention is to provide a method forcontrolling parasites.

Another object of the invention is to provide a topical formulationthat works more rapidly and/or more permanently than other topicalformulations.

Another object of the invention is to provide an improved method ofmaking an insecticide.

Another object of the invention is to provide a new insecticidepackaging system.

Other objects and features will be in part apparent and in partpointed out.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the invention, insecticidal compositions areprovided which contain a combination of a macrocyclic lactone, aneo-nicotinoid and preferably, an insect growth regulator, that areeffective against endoparasites and ectoparasites such asheartworm, fleas, flea eggs, ticks, and mites. The combination ofactive ingredients produces topical formulations that providesbroad protection against endoparasites and ectoparasites using asingle application of the formulation.

Preferably, insecticidal compositions of the invention comprise afirst active ingredient comprising a macrocyclic lactone such asivermectin, selamectin, doramectin moxidectin or eprinomectin,combined with a second active ingredient comprising aneo-nicotinoid such as dinotefuran or acetamiprid, in a suitablesolvent solution. It should be noted that in embodiments where thefirst active ingredient is dinotefuran and the second activeingredient is acetamiprid, a solvent comprising ethyl lactate andwater should not be utilized. Rather, it has been determined thatan effective solvent for the solubilization of high concentrationsof dinotefuran and acetamiprid comprises ethanol.

The treatment of different endoparasites and ectoparasites can betargeted by including a particular macrocyclic lactone in theformulation. Accordingly, in preferred embodiments of theinvention, the topical formulation further comprises an insectgrowth regulator (IGR). The combination of the macrocyclic lactoneand the neo-nicotinoid with an IGR preferably results in a topicalformulation having effective insecticidal activity against e.g.,flea larvae and flea eggs.

In one preferred embodiment of the invention, the first componentin the formulation comprises a macrocyclic lactone such asivermectin, selamectin, doramectin, moxidectin or eprinomectin, thesecond component is dinotefuran orN-((6-chloro-3-pyridinyl)methyl)-N'-cyano-N-methyl-ethanimidamide(acetamiprid), and the IGR is pyriproxyfen and/or methoprene.

In another preferred embodiment of the invention, the macrocycliclactone in the formulation comprises at least one of ivermectin,selamectin, doramectin, moxidectin and eprinomectin, theneo-nicotinoid comprises a (tetrahydro-3-furanyl)methylaminederivative of following formula (1) (see Original Patent), and theIGR comprises pyriproxyfen and/or methoprene. The(tetrahydro-3-furanyl)methylamine derivatives of the formula (1)(see Original Patent) have an excellent insecticidal activity evenin the absence of a pyridylmethyl group or a thiazolylmethyl groupin their molecular structure.

Intermediates for producing the compounds of the formula (1) arerepresented by a formula (2) -- see Original Patent.

In a preferred embodiment of the invention, the macrocyclic lactonecomprises at least one ivermectin, selamectin, doramectin,moxidectin or eprinomectin, the neo-nicotinoid comprises1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran), and the insect growth regulator preferably comprisespyriproxyfen or methoprene. Dinotefuran is an insecticide thatkills adult fleas, and pyriproxyfen and methoprene are insectgrowth regulators that kill flea larvae and prevent flea eggs fromhatching. Accordingly, the combination of dinotefuran and an IGRsuch as pyriproxyfen or methoprene provides for an effective fleacontrol system since only about 5% of the existing fleas on ananimal are adults and the other 95% are in a juvenile state (eggsand larvae).

It has been determined that it is advantageous to dissolve orotherwise put the actives into a liquid form for use as a topicalspot products on animals. It is of course, to be understood that incertain embodiments of the invention, it may be advantageous toisolate the actives, such as by granulation (e.g., spraygranulation), encapsulation, use of micelles, encapsulatedmicrobeads and the like. Topical spot products are moreadvantageous if the amount of liquid applied to the animal can beminimized. This should be balanced with the need for appropriatedosage to achieve the desired pesticidal effect. Therefore, it isdesirable to include a high concentration of insecticide so thatthe total volume of the insecticide applied to the animal can beminimized.

Preferably, dinotefuran is dissolved in the formulation to aconcentration of approximately 50 to 150 mg/ml, more preferably 100to 150 mg/ml, and most preferably, approximately 150 mg/ml.Dinotefuran may be dissolved in particularly effective solventsystems such as a combination of water and ethanol or isopropanol,as disclosed in pending U.S. Ser. No. 10/242,552 filed on Sep. 12,2002, now U.S. Pat. No. 6,814,030, or in phenyl methanol orethanol, as disclosed in U.S. Pat. No. 6,588,374, or in ethyllactate and water combinations. The contents of these referencesare incorporated herein by reference.

The treatment of different endoparasites and ectoparasites aretargeted by including particular macrocyclic lactones specific forthe target endoparasite or ectoparasite in the topical formulation.The combination of the macrocyclic lactone and neo-nicotinoid withan insect growth regulator preferably results in a topicalformulation having effective insecticidal and parasiticidalactivity against a variety of endoparasites and ectoparasites.

In another preferred embodiment of the invention, the topicalformulation comprises a pyrethroid such as2,2-Dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid,(3-phenoxyphenyl)methyl ester (phenothrin) orcyclopropanecarboxylic acid,3-(2,2-dichlorethenyl)-2,2-dimethyl-(3-phenoxyphenyl)methyl ester(permethrin) in order to provide additional acaricide efficacy andto repel and kill mosquitoes. Compositions containing permethrin inaccordance with the invention are particularly advantageous for useon dogs, compared to their use on cats.

It has been determined that it is difficult to form a highconcentration of dinotefuran or acetamiprid and permethrin orphenothrin, and it is likely to result in a solution that can beunstable when stored at room temperature for reasonable amounts oftime. Therefore, it has been found preferable to produce a firstformulation comprising a macrocyclic lactone and a neo-nicotinoidand a second formulation comprising permethrin or phenothrin.Preferably, the topical formulation further comprises an IGR, whichcan be included in the first or second formulation or evenseparately in yet another container. The first and secondformulations are produced and packaged in a manner so that thefirst and second formulations are not permitted to interact priorto application of the total formulation to the animal. In onepreferred embodiment of the invention, the first and secondformulations are stored separately from each other in a package orcontainer having two associated, preferably attached, butindividual chambers to prevent the mixing of the first and secondformulations prior to administration of the first and secondformulation to the animal.

It should be noted that in embodiments where the formulation ispackaged using separate chambers or containers, the percentage ofan active ingredient provided is the percentage of that activeingredient in a single solution. For example, 1 to 2% pyriproxyfenis the concentration of pyriproxyfen contained in the formulationin a single chamber rather than the concentration of pyriproxyfenin the total formulation of the combined chambers.

Macrocyclic lactones can be unstable in both acidic and basicsolutions. For example, ivermectin is hygroscopic and thereforetends to be undesirably unstable. It has also been seen thatmacrocyclic lactones such as ivermectin are unstable in both acidicand basic solutions and are susceptible to photodegradation andoxidative degradation. Accordingly, in embodiments where the firstactive ingredient of the composition comprises ivermectin, it ispreferable that the first and second formulations are stored in anopaque package or container to prevent the photodegradation ofivermectin during storage of the formulation. Even more preferably,the formulation will further comprise an antioxidant such as 2,6ditertiarybutyl-4-methyl phenol (BHT) to prevent the oxidativedegradation of ivermectin during storage of the formulation for areasonable amount of time.

Prior to administration, the packages containing the first andsecond formulations in their respective separate chambers areopened, and the first and second formulations are dispensedsimultaneously or at least at about the same time to the animal.

In one preferred embodiment of the invention, the first and secondformulations can be packaged in a container having two associated,preferably attached, but individual, chambers to prevent the mixingof the formulations prior to the administration of the first andsecond formulations to the animal. Prior to administration, thecontainer can be opened and the first and second formulations canbe dispensed simultaneously or nearly simultaneously to thecompanion animal.

In another preferred embodiment of the invention, the insecticidecomposition of the invention can be packaged in a single dosepackage. Single dose containers make storage and disposal moreconvenient for animal owners. Preferably, the composition ispackaged in a container encompassing two associated, preferablyattached but individual chambers, which are separated by a barrier,preferably plastic, plastic coated paper or metal, such as aluminumfoil. In one preferred embodiment of the invention, the firstchamber and the second chamber are plastic tubes that are separatebut fused together. In another embodiment of the invention, thefirst and second chambers are comprised of opaque plastic in orderto prevent the photodegradation of the actives in the formulation.

During packaging, the first formulation, preferably comprising amacrocyclic lactone such as ivermectin, selamectin, doramectin,moxidectin or eprinomectin and a neo-nicotinoid, preferablydinotefuran or acetamiprid can be placed in the first chamber. Thesecond formulation, preferably comprising permethrin or phenothrincan be placed in the second chamber. The topical formulationfurther comprises an IGR such as pyriproxyfen or methoprene, whichmay be included in the first or second formulation or in yetanother container. Preferably, the first and second chambers can beseparated by a barrier that prevents the interaction of the firstand second formulations.

The entire container containing the first and second formulationsin separate chambers is sealed, preferably with a tab or top, foruse in opening the container prior to administration. After thecontainer is sealed, the topical formulation can be safely storedin the container until administration of the formulation to theanimal.

Prior to administration of the formulation to the animal, thecontainer is opened by removing the tab or top. In one embodimentof the invention, the container is opened by twisting the tabthereby resulting in breaking or tearing of the barrier separatingthe two chambers, thereby allowing the first and secondformulations to mix prior to administration of the insecticideformulation to the animal. After the two formulations are mixed,the two formulations are dispensed by squeezing or collapsing thebody of the container either simultaneously or sequentially. Inanother embodiment of the invention, a dual plunger system can beemployed to administer the formulation onto the animal.

It is of course understood that the first and second formulationsneed not be mixed together prior to administration of the topicalformulation to the animal. Accordingly, in another embodiment ofthe invention, opening of the dual-chamber container does notresult in the mixing of the first and second formulations. Rather,after the container is opened, the first and second formulationsare dispensed onto the animal by squeezing or collapsing thecontainer or containers, either simultaneously or sequentially.

In one embodiment of the invention, the formulation is packagedwith instructions, advising to mix the formulations. In otherembodiments, the instructions will direct the user not to mix theformulation upon application. Because compositions in accordancewith preferred embodiments of the invention can be formulated witha relatively high concentration of active ingredients, a relativelysmall application of a spot or line on the animal can effectivelyprevent and control endoparasite and ectoparasite infestation onthe animal for approximately one to four weeks post-administration.Preferably, the topical formulation is non-toxic and does notirritate the animal's skin.

In a preferred embodiment of the invention, the volume of totalinsecticide formulation applied onto a companion pet is in therange of about 0.5 to 10 ml, preferably about 2 to 5 ml, and mostpreferably, about 3 ml. In another embodiment of the invention, thevolume of total insecticide formulation applied onto a small cat orkitten is in the range of about 0.5 to 1.5 ml. It should be notedthat the total insecticide formulation contains solvents and otheradditives in addition to active ingredients and therefore, thevolume of total insecticide formulation applied onto the animaldoes not comprise only actives.

In preferred embodiments of the invention, the dosages of activeingredients in a single application of the topical formulationcomprise approximately 0.16 to 4.80 mg of a macrocyclic lactone andapproximately 90 to 1350 mg dinotefuran plus solvent, andpreferably approximately 0.32 to 3.2 mg of a macrocyclic lactoneand approximately 180 to 900 mg dinotefuran plus solvent. In apreferred embodiment of the invention, the formulation furthercomprises an IGR such as pyriproxyfen or methoprene.

In embodiments of the invention where pyriproxyfen is added to theformulation, the dosage of pyriproxyfen in the total volume of asingle application of the formulation is approximately 3.5 to 45mg, and preferably, approximately 7 to 30 mg. In embodiments of theinvention where methoprene is added to the formulation, the dosageof methoprene in the total volume of a single application of theformulation is approximately 10 to 135 mg, and preferably,approximately 20 to 90 mg.

The treatment of different endoparasites and ectoparasites can betargeted by including a particular macrocyclic lactone in theformulation. It should be understood that the invention is notlimited by the embodiments described herein.

In a preferred embodiment of the invention, the insecticideformulation comprises ivermectin, dinotefuran and pyriproxyfen forthe treatment of endoparasites and/or ectoparasites on cats anddogs. It should of course be understood that the actual amount ofivermectin in the formulation will vary depending on the size ofthe dog or cat. In a preferred embodiment the ivermectin rangesapproximately 0.2 to 1.75 mg per ml of formulation.

In one embodiment of the invention, up to 8 ml of the totalinsecticide composition can be administered to a dog weighing 55 to120 pounds, and preferably, up to 6 ml. Such composition willpreferably comprise at least about 1.6 to 4.8 mg of ivermectin, atleast about 450 to 1350 mg dinotefuran, and at least about 15 to 45mg of pyriproxyfen. Even more preferably, the composition willcomprise approximately 3.2 mg of ivermectin, approximately 900 mgdinotefuran, and approximately 30 mg of pyriproxyfen. Inembodiments where the IGR is methoprene, the composition comprisesat least about 45 to 180 mg methoprene. In another preferredembodiment of the invention, approximately 6 to 8 ml of the totalcomposition can be administered to a 55 to 120 lb dog, whichadvantageously comprises approximately 675 to 2025 mg of permethrinor approximately 2015 to 5050 mg of phenothrin in order to provideadditional acaricide efficacy and to repel and kill mosquitoes.

In one embodiment of the invention, up to 4 ml of insecticide canbe administered to a dog weighing 22 to 55 pounds. Such compositionwill preferably comprise at least about 1.0 to 3.0 mg ofivermectin, at least about 300 to 900 mg dinotefuran, (and at leastabout 10 to 30 mg of pyriproxyfen. Even more preferably, thecomposition will comprise approximately 2.0 mg of ivermectin,approximately 600 mg dinotefuran, and approximately 20 mg ofpyriproxyfen. In embodiments where the IGR is methoprene, thecomposition comprises at least about 30 to 90 mg methoprene. Inanother preferred embodiment of the invention, the compositionfurther comprises approximately 450 to 1350 mg of permethrin orapproximately 1115 and 3345 mg of phenothrin in order to provideadditional acaricide efficacy and to repel and kill mosquitoes.

In one embodiment of the invention, up to 2.1 ml of insecticide canbe administered to an animal weighing 9 to 22 pounds. Suchcomposition will preferably comprise at least about 0.4 to 1.2 mgof ivermectin, at least about 225 to 675 mg dinotefuran, and atleast about 5 to 15 mg of pyriproxyfen. Even more preferably, thecomposition will comprise approximately 0.8 mg of ivermectin,approximately 450 mg dinotefuran, and approximately 10 mg ofpyriproxyfen.

In another preferred embodiment, the composition further comprisesat least about 225 to 675 mg permethrin or about 560 to 1675 mgphenothrin in order to provide additional acaricide efficacy and torepel and kill mosquitoes. It should be noted that formulationscontaining permethrin are for application to dogs only. Inembodiments where the IGR is methoprene, the composition comprisesat least about 15 to 45 mg methoprene.

In one embodiment of the invention, up to 1.5 ml of insecticide canbe administered to animals weighing 9 pounds or less. Suchcomposition will preferably comprise at least about 0.15 to 0.60 mgof ivermectin, at least about 90 to 270 mg dinotefuran, and atleast about 3.5 to 12 mg of pyriproxyfen. Even more preferably, thecomposition will comprise approximately 0.32 mg of ivermectin,approximately 180 mg dinotefuran, and approximately 7 mg ofpyriproxyfen. In embodiments where the IGR is methoprene, thecomposition comprises at least about 10 to 30 mg methoprene. Inanother preferred embodiment, the composition further comprises atleast about 150 to 450 mg permethrin or about 475 to 1425 mgphenothrin in order to provide additional acaricide efficacy and torepel and kill mosquitoes. It should be noted that formulationscontaining permethrin are for application for dogs only.

In another preferred embodiment of the invention, the insecticideformulation comprises selamectin, dinotefuran and pyriproxyfen forthe treatment of endoparasites and/or ectoparasites on cats anddogs. It has been determined that an effective dosage forselamectin contained in insecticide formulations according to theinvention is approximately 3 to 6 mg per pound of animal bodyweight. Therefore, the actual amount of selamectin in theinsecticide formulation will vary depending on the size of the dogor cat (for example, approximately 30 to 210 mg per ml offormulation).

In a preferred embodiment of the invention, the insecticideformulation comprises moxidectin, dinotefuran and pyriproxyfen forthe treatment of endoparasites and/or ectoparasites on cats anddogs. It has been determined that an effective dosage formoxidectin contained in insecticide formulations according to theinvention is approximately 0.2 mg per pound of animal body weight.Therefore, the actual amount of moxidectin in the insecticideformulation will vary depending on the size of the dog or cat.

In another preferred embodiment of the invention, the insecticideformulation comprises doramectin, dinotefuran and pyriproxyfen forthe treatment of endoparasites and/or ectoparasites on cats anddogs. It has been determined that an effective dosage fordoramectin contained in insecticide formulations according to theinvention is approximately 0.02 mg per pound of animal body weight.Therefore, the actual amount of doramectin in the insecticideformulation will vary depending on the size of the dog or cat.

In the preparation of a formulation for use on animals, there areseveral parameters that should be considered. These are: (a)Concentration high enough to minimize the volume of the topicalapplied to the animal (one would not want to put 20 ml, e.g., ontoa small dog). (b) Concentration low enough to achieve effectivetranslocation of the topical insecticide over the animal's skin.(c) The formulation should be stable for six months at 40.degree.F. and 75% relative humidity, room temperature and -10.degree. F.This helps ensure that the formulation remains stable under theconditions that it could meet in commerce. (d) Safe to use on theintended animal--particularly non-irritating to at least theintended animal, since the product is applied to the skin. Alsosafe if ingested by the animal; ingestion can occur when pets groomthemselves. (e) Safe to use by the consumer. (f) Efficacious inuse--should kill greater than 90% of the fleas and ticks up to 28days and kill or eliminate the endoparasites. (g) Efficacy would bereduced if crystallization occurred in the package. (h) Needs to beaesthetically pleasing--"no oily drop" on the animal whenapplied. (i) Fast drying to reduce the chance of the animal shakingoff the liquid thereby reducing efficacy. (j) Microbiologicallystable.

It can be advantageous for the insecticidal formulations of theinvention to contain an enzyme inhibitor or a synergist such aspiperonyl butoxide, N-octylbicycloheptenedicarboximide, ortriphenyl phosphate, which can increase the efficacy of theformulation. The topical formulations also contain one or morecompounds to increase the efficacy and to reduce the irritation ofpyrethroid insecticides to the skin of animals. The formulation canadvantageously contain spreading agents such as n-octyl pyrrolidoneand dioctylsulfosuccinimide, fragrances, and/or antioxidants.

Other additives to the insecticidal composition include but are notlimited to fragrances, surfactants and spreading agents to increaseperformance such as polyoxyethylene (20) sorbitan monolaurate(commerically available as polysorbate 20 or Tween.RTM. 20) andpolyoxyethylene (20) sorbitan monooleate (commerically available aspolysorbate 80 or Tween.RTM. 80), and isopropyl myristate. Polymerssuch as agar, gelatin, alginate, and cationic polymers such ascationic guar, cationic cellulose, cationic acrylates, andpolyoxymethylene urea may also be added to provide enrobing of theinsecticide to improve safety and adhesion to skin and hair.

In practice, an effective amount of the insecticidal compositionsas described herein may be applied to a companion animal,preferably a dog or a cat, as a foaming shampoo, dip, aerosolspray, pump spray, powder, lotion, emulsifiable concentrate,aqueous or liquid flowable, suspension concentrate and by any othermethods suitable for administering topical compositions to animals.Formulations containing permethrin cannot be applied to cats.

Claim 1 of 10 Claims
1. A topical formulation comprising a first active ingredientcomprising approximately 0.2 to 1.75 mg ivermectin per ml of totalvolume of formulation and a second active ingredient comprising 50to 150 mg dinotefuran per ml of total volume of formulation,wherein the formulation further comprises (I) permethrin orphenothrin and (ii) an insect growth regulator comprisingpyriproxyfen or methoprene, and wherein the first active ingredientand the second active ingredient are packaged with said permethrinor phenothrin, but isolated from interacting with said permethrinor phenothrin.
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