RU2802299C2 - Antiparasitic compositions to be used by pouring - Google Patents

Abstract

FIELD: medicine, veterinary medicine.

SUBSTANCE: claimed group of inventions discloses a liquid veterinary composition applied by pouring for use in the protection and treatment of parasitic infestations in cattle, containing an effective amount of at least one isoxazoline compound, where the isoxazoline compound is fluralaner or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle containing at least one skin penetration enhancer and a solvent system, wherein the skin penetration enhancer contains menthol, and the solvent system contains a pyrrolidone solvent and isopropyl alcohol and propylene glycol dicaprylate/dicaprate in an amount of 10 % w/v.

EFFECT: group of inventions also relates to a method of protecting cattle from ectoparasitic invasion and to the use of a liquid veterinary composition in the manufacture of a medicinal product for protecting cattle from ectoparasitic invasion and/or treating ectoparasitic invasion.

5 cl, 3 dwg, 6 tbl, 2 ex

Description

FIELD OF THE INVENTION

The present invention relates to veterinary compositions for controlling parasites in animals; the use of these compositions against parasites; and methods for the prevention or treatment of parasitic infections and infestations in animals.

BACKGROUND OF THE INVENTION

Various pests and parasites can infect or infect farm animals such as cattle, horses, pigs, sheep, as well as domestic animals such as cats and dogs. These pests and parasites pose a great danger to both animals and their owners.

Animal ectoparasites such as mites, mites, lice and flies are irritating to animals and can cause disease either by themselves or by transmitting pathogens carried by vector vectors. Farm animals such as cattle or sheep are susceptible to various parasites, such as mites, biting lice and lice, as well as hematophagous stinging flies and blowflies.

In particular, the main ectoparasites of cattle are mites, such as Rhipicephalus microplus (ringed tick) and R. decoloratus and R. annulatus . Tick infestation can lead to significant economic losses for livestock production due to deterioration in the quality of the hide, wool or sheepskin, poor meat/fabric quality, reduction in animal weight and reduced milk production.

In addition, ticks are also responsible for the transmission and spread of many diseases throughout the world. They carry bacterial (eg rickettsia), viral and protozoan diseases and cause tick paralysis and tick toxicosis.

Sheep and other domesticated farm animals are susceptible to infestation by a wide range of ectoparasites such as lice, blowflies, mites, denticle, sheep bloodsucker, and sheep psoroptosis. Of particular importance are the green blowflies, such as Lucilia cuprina, L. serircata, Chrysomyia rufifacies and Calliphora stygia , whose larvae are a parasite that can cause considerable distress and reduced productivity in infected sheep. At certain times of the year when blowflies are active, the adult fly lays its eggs on sheep. When these eggs hatch into larvae, they begin to feed on the flesh of the infected sheep, causing what is called fly-egg infestation or myiasis in sheep.

The administration of parasiticides to animals, in particular to farm animals such as cattle and sheep, is a very laborious job and causes stress and weight loss in the animals. It requires frequent processing of farm animals, which is undesirable, especially in feedlots and pastures.

Isoxazoline-substituted benzamide derivatives are known ectoparasiticides.

Isoxazoline-substituted benzamide derivatives were first described in WO 2005/085216 (Nissan Chem. Ind.) as pesticides with potential for veterinary insecticidal and acaricidal use, and subsequently their use as parasiticides has been further developed.

Meanwhile, many variants of isoxazoline pesticides have been described, for example, in: WO 2007/079162, WO 2008/122375, WO 2009/002809, WO 2009/024541, WO 2009/080250, WO 2010/070068, WO 2010/079 077, WO 2011/075591, WO 2011/124998, WO 2012/155352, WO 2012/155676, WO 2012/158396, WO 2015/048371, WO 2015/066277 and EP 2865369.

Several isoxazoline parasiticides have been described specifically for veterinary use in the prevention or treatment of ectoparasitic infestation. Examples are:

Fluralaner (CAS Registry Number: 864731-61-3), Afoxolaner (CAS Registry Number: 1093861-60-9), Lotilaner (CAS Registry Number: 1369852-71-0), and Sarolaner (CAS Registry Number: 1398609-39-6) .

While the compositions contain isoxazoline actives alone or in combination with other actives described in the above documents, there is a need for effective veterinary compositions and methods for protecting farm animals from ectoparasites in a specific manner. Accordingly, the invention solves at least one general problem and several specific problems.

Optimal compositions should be effective, have a fast onset and long duration of action to avoid the need for frequent repeat applications, be safe for the animal host and caregivers, and have the desired bioavailability and spectrum of action.

In addition, the optimal formulation should be reasonably easy to apply and have a limited tendency to wash off in the rain, remain effective on wet animals, dry for a reasonable amount of time without compromising the appearance of the animal, be soft on the animal's coat, have an acceptable level of skin irritation. animal and maintain its effectiveness on the animal under its normal conditions of life, for example, when exposed to the sun and water.

To control external parasites in farm animals such as sheep, cattle and other animals, including goats, pigs, horses and the like, it is common practice to use a localized topical application of a pour-on composition containing one or more active ingredients.

Veterinary pour-on formulations of NSAID compounds for the treatment of systemic anti-inflammatory diseases are described in US 2013/0310372.

WO 2012/089622 and WO2013/039948 describe compositions for topical administration of isoxazoline compounds.

Thus, there is a need in the art for isoxazoline topical compositions that overcome one or more of the above disadvantages.

SUMMARY OF THE INVENTION

1. The present invention relates to a liquid veterinary composition for use in the protection and treatment of parasitic infestation in animals, comprising an effective amount of at least one isoxazoline compound of formula (I)

Where

R ¹ =halogen, CF ₃ , OCF ₃ or CN; n=an integer from 0 to 3 inclusive; m=1 or 2; R ² =C ₁ -C ₃ haloalkyl; T=ring structure: 5- or 6-membered or bicyclic which is optionally substituted with one or more Y radicals; Y=methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C=S or two adjacent Y radicals together form a chain; Q=X-NR ³ R ⁴ , NR ⁵ -NR ⁶ -XR ³ , XR ³ or a 5-membered N-heteroaryl ring which is optionally substituted with one or more radicals; X=CH ₂ , CH(CH ₃ ), CH(CN), CO, CS; R ³ = hydrogen, halogenethyl, halogenpropil, haloenbutil, methoxymethyl, methoxyethyl, halogenmetoxymethyl, ethoximethyl, halogenetoxymethyl, proximethyl, ethylaminocarbonylomethyl, ethylaminocarbonyl ethylaminocarbonyl ethotoxyethyl, propynilaminocarbonomethyl, n-n-n-meblemino, gaglienethy Laminocarbonetil, halogenetylaminocarbonetil, tetrahydrofuril, methylaminocarbonylmetil, ( N, N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,

Where

Z ^A =hydrogen, halogen, cyano or halomethyl (CF ₃ );

R ⁴ = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanogen omethylaminocarbonylmethyl or haloethylaminocarbonylethyl;

R ⁵ =H, alkyl or haloalkyl; R ⁶ =H, alkyl or haloalkyl; or where R ³ and R ⁴ together form a substituent selected from the group consisting of:

And ,

or a pharmaceutically acceptable salt thereof, wherein the composition is administered as a drench or spot preparation and contains a pharmaceutically acceptable carrier containing at least one skin penetration enhancer and a solvent system, the skin penetration enhancer comprising menthol and the solvent system containing pyrrolidone solvent.

In one embodiment, the solvent system contains a volatile solvent.

In another embodiment, the composition contains an ester of glycerol.

In one embodiment, the composition is administered as a spot preparation.

In another embodiment, the composition is administered as a drench.

In one of the embodiments, the invention is a method of protecting farm animals, such as cattle or sheep, from ectoparasitic infestation, comprising the introduction of an effective dose of a liquid veterinary composition by pouring or spot application, as described in this application, to an animal in need of such protection .

In another embodiment, the invention is a method of treating a tick, pruritus, or lice infestation in a bovine animal, comprising administering an effective dose of a liquid veterinary composition by pouring or spotting, as described herein, to an animal in need of such treatment. .

In another embodiment, the invention is a method of administering a composition by pouring as described herein for use in any of the methods described above, comprising:

a) The introduction of the specified composition by means of a device for extracting the drug from the vessel; And

b) Administering an effective amount of said composition to an animal in need of such administration by pouring over the animal's back.

DESCRIPTION OF THE DRAWINGS

Figure 1 shows the therapeutic efficacy against ticks ( Rhipicephalus microplus ) in cattle that was obtained by administering pour-on formulations containing 5 mg/kg body weight of fluralaner to tick-infested cattle from day 1 to day 22. research. The graph shows compositions according to the invention No. 72 (T2) and No. 73 (T3) compared with alternative compositions for application by pouring (table 4 - No. 71 (T1) and No. 74 (T4) on day 0.

Figure 2 shows the long-term efficacy against ticks ( Rhipicephalus microplus ) in cattle obtained by administering pour-on compositions to tick-infested cattle from days 23 to 115 of the study.

Figure 3 shows, in one graph, the combined data on the daily control of ticks in percent from figures 1 and 2, described above, and the concentration of fluralaner in blood plasma.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to liquid veterinary compositions containing at least one isoxazoline compound, alone or in combination with other active substances, and their use in the control of parasites in farm animals.

Therefore, it is an object of the invention to provide a method for the prevention, treatment and control of parasites, in particular ectoparasitic infection or infestation in farm animals, in particular cattle and sheep, by drench or spot application of the composition of the present invention.

Preferred veterinary application by drench or spot application may be one that allows a single administration to provide effective protection to treated animals for an extended period of time, preferably for a period of 21 days or longer. In addition to the duration of action, the technical characteristics of the pharmaceutical composition, such as ease of use (applicability/viscosity), side effects (local tolerance) and residues of the composition in the body of the animal (in particular in farm animals) are important characteristics.

In accordance with the present invention, it has been found that the compositions of the invention generally exhibit one or more of these preferred technical characteristics.

In addition, it has been found that a single administration of such compositions generally provides potent activity against one or more ectoparasites while tending to provide rapid onset of action, long duration of action, and/or desirable animal and caregiver safety profiles. for the animals.

Surprisingly, such pour-on or topical formulations have been found to be (chemically) stable, ie the active ingredient does not degrade and there are no incompatibilities due to excipients. In addition, the compositions are easily administered to animals.

The expression "perfusion formulation" is understood to mean a ready-to-use concentrate intended for topical and topical application to an animal using a suitable device such as a measuring cup or sprayer, or an automatic microspray device.

The pour-on composition is usually applied by pouring in one or more lines or locally along the posterior midline (back) or the animal's shoulder blades. More typically, the composition is applied by pouring it along the back of the animal, following the spine.

This pour-on administration allows a small amount of the composition to be applied to the skin of the animal being treated, causing the active ingredient to migrate (spread) to protect the entire external surface of the animal and, if necessary, the active ingredient (depending on the molecule) to enter the body through skin and acts transdermally. Preferably, effective blood levels are achieved by administering a composition of the invention. Bovine skin is known to be particularly difficult for transdermal administration. Therefore, it was unexpected to obtain effective levels in the blood after administration by douche or spot application of the composition according to the invention. Even more surprising was the duration of the defense. Therefore, in one embodiment, the composition of the invention is administered to cattle and protects the cattle from ectoparasites for more than 2 weeks, preferably more than 4 weeks, preferably more than 6 weeks, 8 weeks, 10 weeks or 12 weeks.

The pour-on compositions may be in the form of a liquid, emulsion, foam, paste, aerosol, ointment, balm or gel. Typical compositions are liquid or semi-liquid dosage forms. Typically, the pour-on composition is liquid and has sufficient viscosity to prevent running off the animal's coat or skin by adhering sufficiently to the animal's coat/skin after administration, yet can be easily administered, for example, by displacing an appropriate amount out of the container at different temperatures.

Liquid dosage forms that can be used as a pour-on formulation are typically solutions, suspensions, or emulsions. A solution is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level. The slurry consists of insoluble solid particles dispersed in a liquid medium, with the solid particles comprising from about 0.5% to about 30% of the slurry. The liquid may be an aqueous liquid, an oily liquid, or both. An emulsion is a heterogeneous dispersion of one immiscible liquid in another; it depends on the emulsifier for stability.

To successfully prepare a pour-on or spot-on composition, the compound must be active when dissolved, dispersed or emulsified in a suitable solvent that is well tolerated by the animal's skin.

Preferably, for cattle, a volume of 30 ml is administered per animal, and for sheep, 10 ml or less of the perfusion composition. In one of the embodiments, the composition contains a component that increases the viscosity. In one of the embodiments. pour-on compositions are solutions of the active ingredient. In one embodiment, the pour solution comprises 50% w/v. the active ingredient, an isoxazoline compound, in particular fluralaner. In another embodiment, the concentration of the active ingredient is from 40 to 50% w/v. In another embodiment, the concentration is from 30 to 40%. The advantage of the composition according to the invention is that no precipitation of the active ingredient occurs and that effective blood levels are provided after administration by topical application or perfusion.

The expression "topically applied preparation" means a ready-made concentrate intended for topical and topical application to an animal in a small dose volume using a suitable device such as a pipette or syringe. Alternatively, a multi-dose applicator is used.

The spot application composition is usually administered by applying one or more drops along the dorsal midline (back) or shoulder blades of the animal. More typically, the composition is applied dropwise between the shoulder blades of the animal. Preferably, sheep are administered with a volume of 10 ml or less, and for cattle, 30 ml per animal of the spot composition. In one embodiment, the topical compositions are solutions of the active ingredient. In one embodiment, the spot application solution comprises 50% w/v. the active ingredient, an isoxazoline compound, in particular fluralaner. In another embodiment, the concentration of the active ingredient is from 40 to 50% w/v. In another embodiment, the concentration is from 20 to 40%. The advantage of the composition according to the invention is that no precipitation of the active ingredient occurs and that effective blood levels are obtained after administration by spot application or drenching.

In an alternative embodiment, in particular for sheep, a concentration of 1 to 10% w/v is used. active ingredient. Preferably 2-8% w/v, more preferably 2.5-5% w/v.

This spot-on administration ensures that a small amount of the composition is applied to the skin of the animal being treated, whereby the active ingredient migrates (spreads) to protect the entire external surface of the animal and, if desired, the active ingredient (depending on the molecule) enters the body by penetration through the skin and acts transdermally.

Topical compositions may be in the form of a liquid, emulsion, foam, aerosol, ointment, balm or gel. Typical compositions are liquid or semi-liquid dosage forms. Typically, the topical composition is a liquid and has a sufficient viscosity to allow it to run off the animal's coat or skin by adhering sufficiently to the animal's coat/skin after administration, and can be easily administered, for example, by displacing an appropriate amount from the container at various temperatures.

Liquid dosage forms that would be suitable for topical compositions are usually solutions, suspensions or emulsions. A solution is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level. The slurry consists of insoluble solid particles dispersed in a liquid medium, with the solid particles comprising from about 0.5% to about 30% of the slurry. The liquid may be aqueous, oily, or water-oily. An emulsion is a heterogeneous dispersion of one immiscible liquid in another; it depends on the emulsifier for stability.

To successfully prepare a pour-on or spot-on preparation, the compound must be active when dissolved, dispersed or emulsified in a suitable solvent that is well tolerated by the skin of the animal.

The compound must be easily absorbed through the skin of the animal if transdermal action is desired, and the composition as a whole must be well dispersed or distributed throughout the animal's body and have a relatively low viscosity upon such distribution.

It should also be taken into account that each compound has its own chemical and physical properties, which require special attention and limit the types of solvents, diluents, stabilizing agents and other excipients that can be used.

However, a difficulty in attempting to develop a transdermal pour-on formulation is that the skin has been described as a "black box" with respect to drug delivery. This is due to the lack of knowledge about the mechanisms of drug penetration through the epidermis and separation in the underlying layers. To date, the boundaries of such properties have not been defined; as a result, it is difficult to predict which compounds can be effectively delivered transdermally.

Transdermal systems that are effective for delivering one compound are almost always ineffective with other compounds. In addition, systems and devices that work in one species are usually ineffective in other species. In addition, as a result of the presence of the stratum corneum barrier, mass transfer through the skin is usually too slow for rapid massive systemic absorption. This explains why very few (or none) of commercially available human transdermal products are intended for immediate drug delivery or long-acting. Transdermal drugs that work in humans are in most cases not suitable for game animals, in particular for ruminants such as cattle. Bovine skin has been found to be very difficult to overcome with transdermal formulations. Therefore, one embodiment is a pour-on or spot-on composition for cattle.

The compositions of the invention allow or facilitate the penetration of the isoxazoline compound through the skin and effects on other parts of the body (eg, the entire body). Such a pour-on or spot-on composition can be prepared by dissolving, suspending or emulsifying isoxazoline in a suitable veterinary or pharmaceutically acceptable carrier.

The composition of the invention overcomes the disadvantage that the composition runs off wet animals or is washed away by rainfall after treatment. Upon contact with water, the active ingredient rapidly precipitates from previously existing compositions which are based on water-miscible solvents. If this composition is applied to a wet animal, or if the animal is exposed to rain before the drug has dried on the animal, the actives fall out of solution and are deposited along the back of the animal, the solvents are also washed away by the rain. This inhibits or prevents transdermal absorption, if necessary, and distribution of the active ingredient around the entire animal. This phenomenon is especially important for areas located in the lower part of the animal. It may reduce efficiency under these conditions.

Under realistic conditions, an optimal veterinary composition intended for use on farms for cattle or sheep, in particular for cattle, should have a shelf life of at least 12 months and preferably 24 months at 30°C, without exceeding the required to achieve this expiration date.

A "pharmaceutically or veterinarily acceptable carrier" means a carrier that is used in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes a carrier that is acceptable for veterinary use or pharmaceutical use.

In some embodiments, the topical veterinary composition comprises a pharmaceutically acceptable carrier, wherein the carrier comprises at least one diluent and at least one penetration enhancer.

The "isoxazoline" or "isoxazoline compound" used in the invention is the following compound:

(Formula I)

Where

R ¹ =halogen, CF ₃ , OCF ₃ or CN;

n=an integer from 0 to 3 inclusive;

m=1 or 2;

R ² =C ₁ -C ₃ haloalkyl;

T=ring structure: 5- or 6-membered or bicyclic which is optionally substituted with one or more Y radicals;

Y=methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C=S or two adjacent Y radicals together form a chain;

Q=X-NR ³ R ⁴ , NR ⁵ -NR ⁶ -XR ³ , XR ³ or a 5-membered N-heteroaryl ring which is optionally substituted with one or more radicals;

X=CH ₂ , CH(CH ₃ ), CH(CN), CO, CS;

R ³ = hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methylamino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, ( N, N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,

Where

Z ^A = hydrogen, halogen, cyano or halomethyl (CF3);

R ⁴ = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanogen omethylaminocarbonylmethyl or haloethylaminocarbonylethyl;

R ⁵ =H, alkyl or haloalkyl;

R ⁶ =H, alkyl or haloalkyl;

or where R ³ and R ⁴ together form a substituent selected from the group consisting of:

And .

In one embodiment, T is selected from

where in T-1, T-3 and T-4 the Y radical is hydrogen, halogen, methyl, halomethyl, ethyl or haloethyl.

In an embodiment, Q is selected from

where R ³ , R ⁴ , X and Z ^A are as defined above, and

In an embodiment in the isoxazoline of formula (I), (R ₁ )n, R ₂ , R ₃ , R ₄ , T, Y, Q, Z and X are as shown in Table 1.

Table 1:

(R ¹ ) _n R ² R ³ R ⁴ T Y Q Z X 3-Cl, 5-Cl _CF3 CH ₂ CF ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ OCH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - CO 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 - T-2 - Q-6 ^ZB -7 CO 3-Cl, 5-Cl _CF3 - - T-2 - Q-7 ^ZB -7 CO 3-Cl, 5-Cl _CF3 - - T-2 - Q-5 ^ZB -7 CO 3-Cl, 5-Cl _CF3 - - T-2 - Q-2 ^ZD -1 CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CC H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CN H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ CH ₃ T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ CH ₃ T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ SCH ₃ H T-21 - Q-1 - CO

Table 1 (continued):

(R ¹ ) _n R ² R ³ R ⁴ T Y Q Z X 3-Cl, 4-Cl, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH(CH ₃ ) ₂ H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)-cyclopropyl H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH ₂ CH ₃ H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 Cl Q-1 - CH ₂ 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 R ³ -1 (Z) H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 R ³ -1 (E) H T-1 CH ₃ Q-1 - CO

In an isoxazoline embodiment of formula (I), (R ₁ ) _n , R ₂ , R ₃ , R ₄ , T, Y, Q, Z and X are as shown in Table 2.

Table 2:

(R ¹ ) _n R ² R ³ R ⁴ T Y Q Z X 3-Cl, 5-Cl _CF3 CH ₂ CF ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ OCH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 - T-2 - Q-6 ^ZB -7 3-Cl, 5-Cl _CF3 - - T-2 - Q-7 ^ZB -7 3-Cl, 5-Cl _CF3 - - T-2 - Q-5 ^ZB -7 3-Cl, 5-Cl _CF3 - - T-2 - Q-2 ^ZD -1 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CC H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CN H T-3 CH ₃ Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ CH ₃ T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ SCH ₃ H T-21 - Q-1 - CO 3-Cl, 4-Cl, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH(CH ₃ ) ₂ H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)-cyclopropyl H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH ₂ CH ₃ H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 Cl Q-1 - CH ₂ 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 R ³ -1 (Z) H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 R ³ -1 (E) H T-1 CH ₃ Q-1 - CO

In one embodiment, the isoxazoline for use in the invention is a compound:

(formula II)

where R ^1a , R ^1b , R ^1c are independently of each other: hydrogen, Cl or CF ₃ .

Preferably R ^1a and R ^1c are Cl or CF ₃ and R ^1b is hydrogen,

T represents

where Y represents methyl, bromine, Cl, F, CN or C(S)NH ₂ ; n=1 or 2; and Q is as described above.

In an embodiment of isoxazoline as defined herein, R3 is H and ^R4 is: -CH ₂ -C(O)-NH-CH ₂ -CF ₃ , -CH ₂ -C(O)-NH- CH ₂ -CH ₃ , -CH ₂ -CH ₂ -CF ₃ or -CH ₂ -CF ₃ .

In a preferred embodiment of the pharmaceutical composition of the invention, isoxazoline is one or more substances selected from the group consisting of:

fluralaner, afoxolaner, lotilaner, sarolaner,

- (Z) -4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS No.: 928789 -76-8),

- 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thiethan-3-yl)benzamide (CAS number: 1164267-94 -0), which was described in WO 2009/0080250, and

- 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2, 2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS number: 1231754-09-8), which was described in WO 2010/070068.

Therefore, in a preferred embodiment of the pharmaceutical composition of the invention, isoxazoline is one or more substances selected from the group consisting of: fluralaner, afoxolaner, lotilaner and sarolaner.

In an embodiment of the pharmaceutical composition of the invention, the isoxazoline is fluralaner. In one embodiment of the pharmaceutical composition of the invention, the isoxazoline is an afoxolaner. In an embodiment of the pharmaceutical composition of the invention, the isoxazoline is a lotilaner. In one embodiment of the pharmaceutical composition of the invention, the isoxazoline is sarolaner.

In one embodiment of the pharmaceutical composition of the invention, isoxazoline is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino) methyl]-2-methylbenzamide (CAS number: 928789-76-8).

In one embodiment of the pharmaceutical composition of the invention, the isoxazoline is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thiethan-3 -yl)benzamide (CAS number: 1164267-94-0), which was described in WO 2009/0080250.

In one embodiment of the pharmaceutical composition of the invention, the isoxazoline is 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2 -oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS number: 1231754-09-8), which was described in WO 2010/070068.

In a more preferred embodiment of the pharmaceutical composition of the invention, the isoxazoline is fluralaner. Fluralaner has shown extended activity against ectoparasites in cattle and sheep after topical application. He showed exceptional efficiency and duration of the parasiticidal effect.

Isoxazoline for use in the invention also includes its pharmaceutically acceptable salts, esters and/or N-oxides.

A pharmaceutically acceptable salt of the isoxazoline compounds of formula (I) or (II) may be used due to one or more of the physical properties of the salt, such as pharmaceutical stability at various temperatures and humidity; crystalline properties; and/or the desired solubility in water, oil or other solvent. Acid and basic salts can usually be obtained, for example, by mixing the compound with an acid or base, respectively, using various methods known in the art.

In addition, reference to an isoxazoline compound applies equally to any of its polymorphic forms or stereoisomers.

Isoxazoline compounds can exist in various isomeric forms. Reference to a compound of the present invention, an intermediate thereof, and a compound corresponding to the use of the invention always includes all possible isomeric forms of such a compound.

In one embodiment, the racemic form of the isoxazoline compound is present in the composition of the invention. In another embodiment, the S-enantiomer is present. In a specific embodiment, the S-enantiomer of fluralaner is present.

Isoxazolines can be detected and quantified by liquid chromatography using standard equipment and procedures.

In one embodiment, the active substances of the isoxazoline(s) are present in the composition at a concentration of from about 0.5% to about 25% (w/v). In some embodiments, the isoxazoline actives are present in the composition at a concentration of about 1 to about 20% (w/v), about 1 to about 10% (w/v), about 2 to about 8% (w/v). ) or about 2, 3, 4 or 5% (w/v).

In another embodiment, the active substances of the isoxazoline(s) are present in the composition at a concentration of about 25-50% w/v. In another embodiment, the concentration is from 20 to 40% (w/v).

In other embodiments, the isoxazoline active agent(s) are present in the compositions at a concentration of about 1 to about 6% (w/v), about 2 to about 5% (w/v), or about 5% (w/v).

Additional active ingredients

In other embodiments, the implementation of the composition may additionally contain one or more additional active substances. In one embodiment, the compositions contain at least one macrocyclic lactone active, including, but not limited to, avermectins or milbemycins. In some embodiments, the active avermectin or milbemycin is eprinomectin, abamectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin.

In one embodiment, the composition contains one or more isoxazoline compounds and eprinomectin. In a specific embodiment, the composition of the invention contains fluralaner and eprinomectin.

In one embodiment, the composition comprises a combination of fluralaner with eprinomectin or fluralaner with moxidectin. In one embodiment, the composition comprises a combination of afoxolaner with eprinomectin or afoxolaner with moxidectin. In one embodiment, the composition comprises a combination of sarolaner with eprinomectin or sarolaner with moxidectin. In one embodiment, the composition comprises a combination of lotilaner with eprinomectin or lotilaner with moxidectin.

In another embodiment, the topical compositions of the invention comprise the combination of an isoxazoline active described herein with an insect growth regulator (IGR) active. Preferably the IGR insecticide is selected from one or more of the following: diflubenzuron, dicyclanil, lufenuron, novaluron, triflumuron, and cyromazine.

In another embodiment, the topical compositions of the invention comprise the combination of the isoxazoline active described herein with another (one or more) ectoparasiticidal compound(s). In one embodiment, such an ectoparasiticidal compound is a pyrethroid. In a specific embodiment, the topical composition of the invention comprises a combination of fluralaner, afoxolaner, sarolaner or lotilaner with a pyrethroid, in particular deltamethin or cypermethrin, flumethrin or permethrin or resmetrin or lambda-cyhalothrin, or a combination thereof. In a specific preferred embodiment, the composition comprises a combination of fluralaner and deltamethrin. Another preferred embodiment includes afoxolaner and deltamethrin.

In another preferred embodiment, the compositions of the present invention comprise avermectin or milbemycin and at least one endoparasiticide such as thiabendazole, oxibendazole, mebendazole, fenbendazole, flubendazole, oxfendazole, albendazole, triclabendazole, derquantel, febantel, levamisole, pyrantel, oxanthel , emodepsid, monepantel, atelocantel, morantel, praziquantel, epsiprantel, closantel, clorsulon, rafoxanide, and nitroxinil.

Typically, the additional active agent is included in the composition in an amount of from about 0.1% to about 50% w/v. More typically, the additional active agent may be included in an amount of from about 0.5% to about 25% w/v, about or from about 1% to about 10% w/v.

In other embodiments, an additional active agent (eg, as described above) may be included in the composition to deliver a dose of about 5 μg/kg body weight to about 50 mg per kg animal body weight. In other embodiments, the additional active agent may be present in an amount sufficient to deliver a dose of about 0.01 to about 30 mg/kg, about 0.1 to about 20 mg/kg, or about 0.1 mg/kg up to about 10 mg/kg animal weight. In other embodiments, the additional active agent may be present at a dose of from about 5 μg/kg to about 200 μg/kg, or from about 0.1 mg/kg to about 1 mg/kg of animal weight. In yet another embodiment of the invention, any of the additional active substances is included in a dose of from about 0.5 mg/kg to about 50 mg/kg.

It is understood that the ability of the active substance to be distributed topically or transdermally after administration by pouring depends on both the physico-chemical characteristics of the compound and the inactive excipients of the composition.

Examples of inactive excipients that affect transdermal distribution are skin penetration enhancers or "penetration enhancers". They are commonly used in compositions intended for the transdermal delivery of active compounds.

A skin penetration enhancer (or penetration enhancer) is a pharmaceutically acceptable carrier that promotes absorption or penetration of a compound through the skin into the bloodstream, other body fluids (lymph) and/or body tissues (adipose tissue).

As a skin penetration enhancer, the composition of the invention contains menthol.

Menthol is available as one of two enantiomers or as a racemate. The natural substance is a levorotatory form of (-)-menthol (or L-menthol). Synthetic menthol is racemic, consisting of equal amounts of (-)-menthol and (+)-menthol (or d-menthol). Preferably, levomenthol EP (European Pharmacopoeia) or 1-menthol (USP) is used in the composition of the invention. Alternatively, other terpenoids such as eucalyptol, camphor, D-limonene, nerolidol, 1,8-cineole and mixtures thereof are additionally present in the composition. Alternatively, a combination of menthol and eucalyptol is used.

In specific embodiments of the invention, menthol is present in an amount of from about 2 to about 20% w/v. compositions, in particular from about 5 to about 15% w/v. or, in particular, from about 6 to about 12% w/v. or about 10% w/v.

In one embodiment, the transdermal liquid formulation of the invention comprises two or more skin penetration enhancers.

Permeation enhancers are various classes of compounds, including certain solvents such as dimethyl sulfoxide (DMSO), isopropyl myristate, dipropylene glycol pelargonate, silicone oil, aliphatic esters, triglycerides and fatty alcohols pyrrolidones, ethanol, propylene glycol, ethyl acetate and dimethyl acetate, and others that can disrupt the barrier barrier. function of the stratum corneum of the epidermis.

Non-limiting examples of a suitable skin penetration enhancer include, but are not limited to, terpenoids such as menthol, eucalyptol, camphor, d-limonene, nerolidol, 1,8-cineol and mixtures thereof, saturated or unsaturated fatty acid esters, or propylene glycol diesters. or esters, diesters or triesters of glycerol, saturated or unsaturated fatty acids, saturated or unsaturated fatty alcohols, xylene, isopropyl myristate, or mixtures thereof.

In particular, the skin penetration enhancer is a combination of menthol with xylene and/or D-limonene and/or isopropyl myristate. In one embodiment, the skin penetration enhancer is menthol or eucalyptol, or a combination thereof. In another embodiment, the skin penetration enhancer is menthol.

Other substances have also been shown to increase the uptake of certain active substances through the skin. These include lipophilic compounds such as laurocapram (Azone); fatty acids or alcohols such as oleic acid, oleyl alcohol, linoleic acid, and the like; some fatty acid esters such as isopropyl myristate, methyl noanoate, methyl caprate and others. It is also known that mixtures of certain penetration enhancers with propylene glycol improve the delivery of certain active ingredients.

Other penetration enhancers are dimethyl isosorbide and glycol ethers such as diethylene glycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monomethyl ether, ethylene glycol monoethyl ether propylene glycol ether.

In specific embodiments, the skin penetration enhancer is present in an amount of from about 2% to about 90% w/v. transdermal liquid preparation, in particular from about 5 to about 80% w/v. or, in particular, from about 10 to about 70% w/v. In one embodiment, menthol is present at 10% w/v. In another embodiment, menthol is present at about 10% w/v and eucalyptol at 10% w/v.

The optional second skin penetration enhancer is particularly present in an amount of from about 2% to about 70% w/v. transdermal liquid preparation, in particular, from about 5 to about 50% w/v. or more specifically, from about 10 to about 40% w/v.

A pharmaceutically acceptable carrier includes a solvent system including suitable carriers or diluents commonly used in the composition, including solvents or mixtures of solvents.

Some solvents suitable for topical compositions can be characterized as having good spreading properties, while other solvents for topical compositions can be characterized by the ability to enhance the penetration of active substances through the skin barrier into the systemic circulation.

In certain embodiments of the invention, the compositions will contain mixtures of solvents that will improve the spreadability and/or the penetration enhancing ability of the composition.

In specific compositions of the invention, the solvent is present in an amount of from about 10% to about 90% by weight of the transdermal liquid preparation, in particular from about 20% to about 80%, from about 25% to about 70%, about 70% w/v, 60% mass/volume.

In one embodiment, the solvent system includes at least one pyrrolidone solvent and at least one volatile solvent, in particular a volatile alcohol solvent.

In another embodiment, the solvent system contains, in place of, or in addition to, a volatile solvent, one or more glycerol esters, propylene glycol esters, or other non-volatile solvent.

In another embodiment, the solvent system comprises one or more esters of glycerol and esters of propylene glycol.

In embodiments of the invention, the pyrrolidone solvent is present in amounts from about 5 to about 50% w/v. compositions, in particular from about 5 to about 40% w/v. or, in particular, from about 5, about 10 or about 35% w/v.

In particular, the pyrrolidone solvent includes 2-pyrrolidone, N-methylpyrrolidone (NMP), or mixtures thereof. In one embodiment, the pyrrolidone solvent is 2-pyrrolidone. In another embodiment, the pyrrolidone solvent is N-methylpyrrolidone (NMP).

In specific embodiments of the invention, 2-pyrrolidone or NMP is present in an amount of from about 5 to about 50% w/v. compositions, in particular, from about 5 to about 40% w/v. or, in particular, from about 5, about 10 or about 35% w/v.

In embodiments of the invention, the volatile solvent, in particular the alcohol solvent, is present in amounts from about 5 to about 60% w/v. compositions, in particular from about 5 to about 50% w/v. or, in particular, from about 20 to about 45% w/v. or, in particular, about 33-35%, about 54-55 or about 10% w/v.

In particular, a volatile solvent, specifically an alcoholic solvent, contains a volatile alcohol such as, for example, ethyl alcohol, methanol or isopropyl alcohol (isopropanol) or mixtures thereof. In one embodiment, the alcoholic solvent is isopropyl alcohol.

Volatile substances usually evaporate easily at normal temperatures and easily turn into vapors or gases. The European Union defines a volatile organic compound as “any organic compound having an initial boiling point less than or equal to 250°C (482°F) measured at standard atmospheric pressure of 101.3 kPa”.

In specific embodiments of the invention, isopropyl alcohol is present in an amount of from about 5 to about 60% w/v. compositions, in particular, from about 5 to about 50% w/v. or, in particular, from about 20% to about 45% w/v. or, in particular, about 33-35%, about 54-55% or about 10% w/v.

In another embodiment, the solvent system includes at least one pyrrolidone solvent and at least one volatile solvent, in particular an alcohol solvent and an additional solvent.

In another embodiment, the solvent system comprises at least one pyrrolidone solvent and at least one of glycerol esters, propylene glycol esters, or other non-volatile solvent.

Non-limiting examples of suitable solvents include, but are not limited to, solvents such as water, pyrrolidone solvent such as 2-pyrrolidone, N-methyl-2-pyrrolidone and/or mixtures thereof, and glycol ethers such as ethylene glycol monoethyl ether, monoethyl diethylene glycol ether or dipropylene glycol monoethyl ether, ethyl lactate, glycol ether such as diethylene glycol monoethyl ether (DEGMEE), glycerin, dimethyl isosorbide, triacetin, propylene glycol, glycol ethers such as polyethylene glycols (PEG) having an average molecular weight of 200 to 1000, dimethyl isosorbide , PEG esters of carboxylic acids and dicarboxylic acids and PEG esters of fatty acids, esters of glycerol including triacetin, caprylic/capric triglycerides (Miglyol 812®) and the like; ethers of glycerol, including glycerinformal; propylene glycol dicaprylate/dicaprate (Miglyol 840®), lauryl lactate, diisopropyl adipate (DIPA, also known as CERAPHYL 230), diisobutyl adipate, dimethyl isosorbide (DMI), acetyltributyl citrate, oleic acid; esters of carboxylic acids, including diacid esters, ketones, including acetone, methyl isobutyl ketone (MIK), methyl ethyl ketone, acetonitrile, C1-C12 alcohols, including benzyl alcohol, methanol, ethyl alcohol, isopropanol, isopropanol, (1,2-propanediol, isopropyl alcohol) and butanol; aromatic esters such as anisole; amides, including dimethylacetamide, monomethylacetamide and dimethylformamide; dimethyl sulfoxide (DMSO), ethylene glycol, propylene glycol, glycol carbonate, including but not limited to propylene carbonate and butylene carbonate; C1-C12 alkyl esters of carboxylic acids including butyl or octyl acetate and benzyl acetate; C1-C12 alkyl esters of dicarboxylic acids; aryl esters including benzyl benzoate, ethyl benzoate, and the like; and diethyl phthalate, dicarboxylic acid diester which is diethyl sebacate or diisopropyl dipinate, ethylene glycol (EG), propylene glycol (PG), liquid polyoxyethylene glycols (PEG) of various grades, including PEG 400, EG or PG monocaprylate, EG or PG caprylate, EG or PG monolaurate, EG or PG dicaprylate/dicaprate, diethylene glycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, or a combination thereof; an ether including, but not limited to, dimethyl isosorbide; an ester or disester including, but not limited to, triacetin, lauryl lactate, licerinformal, diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, dibutyl adipate, PG monocaprylate, PG caprylate, PG monolaurate, PG dicaprylate/dicaprate, isopropyl palmitate, or mixtures thereof.

In one embodiment, the composition does not contain any volatile solvent. In one embodiment, the composition contains fluralaner, penetration enhancer (menthol), solvent (pyrrolidone) and glyceryl monocaprylate, preferably in an amount of 20-80% v/v, without a volatile solvent.

The topical compositions of the present invention containing the isoxazoline active in a carrier containing a lipophilic solvent or lipophilic solvent system have been found to provide very high efficacy against ectoparasites over a long period of time. While not wishing to be bound by any theory, it is believed that the inactive excipients in the topical compositions of the invention help retain the isoxazoline active in the skin for longer periods of time while allowing the active to diffuse continuously into the circulatory system. at a rate that provides the desired concentration of the active substance in the bloodstream, which will be effective against ectoparasites for a longer period of time.

This is in contrast to methods used with typical topical formulations which are designed to rapidly transdermally pass compounds to obtain the desired biological effect, e.g. rapid anti-inflammatory action in the case of NSAIDs that do not require long acting, in particular in the case of farm animals, due to the risk of residue formation. .

As a carrier or diluent, vegetable oils such as soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grape seed oil, sunflower oil, etc. can be used; mineral oils such as, but not limited to, petroleum jelly, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons, including limonene, or alternatively, for example, medium chain triglycerides (such as C8-C12) such as Miglyol 812 or alternatively Miglyol 840, or mixtures thereof.

In one embodiment, the isoxazoline pour-on or spot-on composition contains glyceryl monocaprylate.

In another embodiment, the pharmaceutically acceptable carrier comprises C ₄ -C ₂₂ fatty acids or esters thereof, including esters with C ₆ -C ₂₀ long chain alcohols, C ₁ -C ₁₂ alcohols, C ₁ -C ₄ alcohols, or C ₃ - C ₈ alcohols; C ₁₀ -C ₁₈ saturated fatty acids or esters thereof, including esters with C ₆ -C ₂₀ long chain alcohols, C ₁ -C ₁₂ alcohols, C ₁ -C ₄ alcohols, or C ₃ -C ₈ alcohols; Unsaturated C ₁₀ -C ₁₈ fatty acids or esters thereof, including esters with C ₆ -C ₂₀ long chain alcohols, C ₁ -C ₁₂ alcohols, C ₁ -C ₄ alcohols, or C ₃ -C ₈ alcohols; monoesters or diesters of C ₆ -C ₁₆ aliphatic carboxylic acids and dicarboxylic acids, including esters with C ₆ -C ₂₀ long chain alcohols, C ₁ -C ₁₂ alcohols, C ₁ -C ₄ alcohols or C ₃ -C ₈ alcohols or their mixtures. In other embodiments, the carrier may include C ₁ -C ₁₀ , C ₁ -C ₈ or C ₁ -C ₆ alcohols or esters thereof.

In another embodiment, the compositions of the invention contain polar solvents. In another embodiment, the composition includes aromatic alcohols or their esters. In one preferred embodiment, the topical compositions of the invention may include isopropyl alcohol or benzyl alcohol as a diluent. In one embodiment, the topical compositions of the invention comprise isopropyl alcohol. Alternatively, with the exception of the ester of glycerol, the composition does not include a volatile solvent.

In preferred embodiments, the isoxazoline pour-on or spot-on composition comprises carriers selected from the group consisting of diethyl sebecate, dibutyl sebacate, mono- and diesters of saturated or unsaturated fatty acids of propylene glycol, or mono-, di- and triesters of glycerol with an alkyl chain length of from C8 to C14, saturated fatty acids with an alkyl chain length of C8 to C14, unsaturated fatty acids with an alkyl chain length of C14 to C22, saturated fatty alcohols with an alkyl chain length of C8 to C14, and unsaturated fatty alcohols with an alkyl chain length of C14 up to C22.

In other preferred embodiments, the isoxazoline pour-on or spot-on composition comprises carriers selected from the group consisting of mono- and diesters of saturated or unsaturated fatty acids of propylene glycol or mono-, di- and triesters of glycerol with an alkyl chain length of C8 to C14, saturated fatty acids with an alkyl chain length of C8 to C14, unsaturated fatty acids with an alkyl chain length of C14 to C22, saturated fatty alcohols with an alkyl chain length of C8 to C14, and unsaturated fatty alcohols with an alkyl chain length of C14 to C22 .

In one preferred embodiment, the isoxazoline pour-on or spot-on composition comprises the preferred carriers propylene glycol dicapriocaprate, glyceryl monocaprylate, and mixtures thereof.

In a preferred embodiment, the topical compositions of the invention containing the isoxazoline active agent(s) are dissolved in a pharmaceutically acceptable carrier containing one or more diluents. In some embodiments, the solvents include, but are not limited to, dimethyl isosorbide glycofurol, glycerinformal (methylidinoglycerol or glycerinformal), triacetin, liquid polyethylene glycols, including PEG 200 or 400, isopropyl palmitate diisopropyl dipinate, silicone fluid; propylene glycol (or other aliphatic dihydric alcohols), benzyl alcohol, propylene glycol esters including propylene glycol dicaprylate/dicaprate, propylene carbonate, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate and propylene glycol dilaurate; alkyl esters of dicarboxylic acids, including diethyl sebacate, diisopropyl sebacate; and esters or diesters of fatty acids, or a combination thereof.

In an embodiment of the invention, the compositions of the invention may include surfactants. Surfactants can be anionic, cationic, nonionic, or amphoteric surfactants.

Anionic surfactants include, but are not limited to, alkali metal stearates; calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulfates; sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids and the like.

Examples of the cationic surfactant include, but are not limited to, water-soluble quaternary ammonium salts of the formula; cetyltrimethylammonium bromide; and octadecylamine hydrochloride.

Non-ionic surfactants that can be used in the compositions include, but are not limited to, polyoxyethylene (pegylated) esters, including, but not limited to, sorbitol esters and fatty acid esters; polyethylene glycol stearate, polyoxyethylene castor oil derivatives, polyglycerol esters, polyoxyethylene fatty alcohols, polyoxyethylene fatty acids, and ethylene oxide-propylene oxide copolymers including, but not limited to, ethylene oxide-propylene oxide block copolymers such as poloxamers and the like (e.g., Lutrol® F and L grades from BASF, including Lutrol® F68, F87, F108 and F127).

Additional examples of surfactants include, but are not limited to, CAPRYOL™ 90 (propylene glycol monocaprylate), CAPRYOL™ PGMC (propylene glycol monocaprylate), which are oily liquids having an HLB (Hydrophilic-Lipophilic Balance) of 6 and 5, respectively. They can be applied topically as a co-surfactant in microemulsions and as a solubilizer/penetration enhancer. The HLB values used herein have the following general meanings: compounds with an HLB value <10 are generally lipid soluble (insoluble in water), and solvents with an HLB >10 are generally water soluble. Surfactants having an HLB of 4 to 8 are commonly used as antifoams. Surfactants having an HLB of 7 to 11 can be used as water/oil type emulsifiers. HLB from 12 to 16 generally indicates that the surfactant can be used in oil-in-water emulsions, and HLB from 11 to 14 indicates a wetting agent. HLB 12 to 15 is typical for detergents and HLB 16 to 20 is a solubilizer or hydrotrope. There is considerable overlap in ranges/uses, and it is well understood by one skilled in the art that a single HLB value cannot be used to predict whether a particular surfactant will be used for a particular purpose (e.g., antifoam, emulsifier, wetting agent, solubilizer, hydrotrope). Accordingly, in general, determining the appropriate system of solvent, active agent, surfactant(s) and other excipients necessarily involves non-routine experimentation and inventive effort.

The compositions may also include surfactants such as oleoyl macrogol glycerides (polyoxyl glycerides, eg LABRAFIL® M1944CS and LABRAFIL® M2125CS, both of which have an HLB of 4). These compounds can also be used, for example, as oil phase for emulsions, microemulsions and as penetration enhancers.

In another embodiment, the polyoxylglycerides may include polyethylene glycol caprylic/capric glycerides such as LABRASOL® (HLB 14). It is used topically as a surfactant in microemulsions and may also act as a solubility/penetration enhancer in topical formulations.

In another embodiment, the surfactant is LAUROGLYCOL™ 90 (propylene glycol monolaurate) having an HLB of 5. It is an additional surfactant for microemulsions in topical formulations and may also act as a solubilizer/penetration enhancer. compositions for topical use. In some embodiments, the surfactant is PLUROL® OLEIQUE CC497 (polyglyceryl oleate) having an HLB of 6.

In some embodiments of the invention, compositions are provided in which the carrier contains solvents that exhibit both good distribution and permeability characteristics. In other embodiments, the invention relates to compositions in which the carrier contains solvents that exhibit good distribution characteristics. In yet another embodiment of the invention, compositions are provided in which the carrier contains solvents that enhance the penetration of the active substance through the skin into the systemic circulation.

In some cases, solvents may have both good distribution and permeability characteristics. Propylene glycol dicaprylat/dicaprate, such as Miglyol 840, has both good distribution and permeation characteristics.

In specific embodiments, the propylene glycol dicaprylate/dicaprate is present in an amount of from about 2% to about 90% of the composition, in particular from about 5% to about 80% w/v. or, in particular, from about 10 to about 70% w/v.

Excipients that may also aid retention of the active in the skin for longer periods of time and may be included in the compositions of the invention include, but are not limited to, mixed esters of sucrose and carboxylic acids, including sucrose isobutyrate acetate (SAIB) and the like; low melting waxes, hydrogenated vegetable oils, caprylic/capric glycerides; esters of glycerol, including, for example, triacetin, glycerol monooleate, glycerol monolinoleate, glycerol stearate, glycerol distearate, and the like; triglycerides, including, for example, caprylic, capric/myristic/stearic triglyceride; thermoreversible polymers such as pluronics and poloxamers, including, for example, Lutrol F 127 alone or in admixture with other poloxamers; or their combination.

The addition of one or more additional other solvents may be desirable to change the viscosity of the composition to give the product appropriate characteristics for pour-on applications.

The viscosity of pourable compositions can be measured by methods known in the art.

Suitable viscosity modifying agents include, without limitation, water, ethanol, isopropanol, propylene glycol, dimethyl isosorbide, triacetin, or glycerin added in a suitable amount known to one of skill in the art.

Suitable exemplary polymers (“polymer substances”) for gelling and/or adhesion that can be used in the compositions of the invention include, but are not limited to, fumed silica, ethylcellulose, methylcellulose, methacrylic acid ester copolymers, carboxylated vinyl acetate, and polyvinylpropylene copolymers ( PVP)/vinyl acetate, Poloxamer 124, Poloxamer 188, Polybutene, Povidone K17 and Povidone K90. The compositions of the invention may contain other inert ingredients such as colorants, antioxidants, preservatives, pH stabilizers, chelating agents and viscosity modifying agents.

Preservatives such as parabens (methyl paraben and/or propyl paraben) are suitably used in the composition in amounts of from about 0.01 to about 2.0% w/v, and particularly preferably from about 0.05 to about 1.0%. weight/rev. Other preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury acetate, phenylmercury borate, phenylnitrate mercury , potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal and the like.

Representative chelating agents include, without limitation, disodium edetate and EDTA.

Antioxidants such as vitamin E, alpha tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, sodium metabisulfite, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), BHA and citric acid, monothioglycerol, tert-butylhydroquinone (TBHQ) and the like can be added to the composition of the invention.

Antioxidants are typically added to the composition in an amount of from about 0.01 to about 2.0% w/v, based on the total weight of the composition, with about 0.05 to about 1.0% w/v being particularly preferred.

It has been found beneficial to add at least one stabilizer to prevent degradation of any of the active ingredients in the compositions of the present invention.

In an embodiment, an additional component for the composition of the invention is a pharmaceutically acceptable coloring agent, such as a dye or pigment, or a combination of different dyes or pigments. This will allow visual control of the treated animals by determining the color of the stain on the back of the animal.

Dyes for use in the present invention are well known in this field. Such a dye, of course, should be allowed for introduction into feed for farm animals. Suitable colors are substances permitted under the US Federal Food, Drug, and Cosmetic Act (FD&C), such as FD&C Blue No. 1, FD&C Yellow No. 5, or natural food colors, such as chlorophyllin (green), or a mixture of any the substances described above. Preferred ranges include from about 0.01% to about 2% (w/v), more preferably from about 0.01% to about 0.5% (w/v).

Optionally, the composition may also contain an antifoam agent, such as, for example, an emulsion of simethicone 30% (USP), sodium oleate, sodium caprylate, or mixtures thereof. The antifoam agent is present in sufficient concentration to prevent foaming when the composition of the present invention is diluted with water. In the present invention, the simethicone emulsion may be present at a concentration of from about 0.2% w/v. up to about 1% w/v. In some embodiments, the simethicone emulsion is present at a concentration of about 0.5% w/v.

Optionally, flavoring may be added to any of the compositions of the invention.

Additional aspects regarding drug composition and various excipients can be found, for example, in Gennaro, A.R., et al., eds., Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins, 20th Ed., 2000).

In one embodiment, the liquid veterinary pour-on composition comprises:

a) from about 0.5% to about 15% w/v. isoxazoline compounds;

b) from about 5% to about 15% w/v. menthol;

c) from about 10% to about 50% w/v. isopropyl alcohol;

d) from about 10% to about 40% w/v. pyrrolidone solvent; and

e) from about 2% to about 50% w/v. propylene glycol dicaprylate/dicaprate.

In another embodiment, the liquid veterinary pour-on composition comprises:

a) from about 0.5% to about 15% w/v. an isoxazoline compound;

b) from about 5% to about 15% w/v. menthol;

c) from about 10% to about 40% w/v. pyrrolidone solvent; and

d) from about 2% to about 70% w/v. propylene glycol dicaprylate/dicaprate.

In another embodiment, the liquid veterinary pour-on composition comprises:

a) from about 0.5% to about 15% w/v. an isoxazoline compound;

b) from about 5% to about 15% w/v. menthol;

c) from about 10% to about 50% w/v. an ester of glycerol, in particular glyceryl monocaprylate;

d) from about 10% to about 40% w/v. pyrrolidone solvent; and

e) from about 2% to about 50% w/v. propylene glycol dicaprylate/dicaprate.

In a preferred embodiment, the liquid veterinary pour-on composition contains from about 2 to about 5% w/v. isoxazoline compounds, and the carrier contains about 10% w/v. menthol, from about 35 to about 55% w/v. isopropyl alcohol, from about 5 to about 35% w/v. 2-pyrrolidone and/or about 10% w/v. propylene glycol dicaprylate/dicaprate.

In an alternative embodiment, the composition contains from about 2 to about 5% w/v. isoxazoline compounds, and the carrier contains about 10% w/v. menthol, from about 5 to about 35% w/v. 2-pyrrolidone and/or about 10% w/v. propylene glycol dicaprylate/dicaprate.

In another preferred embodiment, the liquid veterinary pour-on composition contains from about 3 to 5% w/v. or about 2, about 3 or about 5% w/v. isoxazoline compounds, and the media contains about 35 or about 55% w/v. isopropyl alcohol and about 5% or about 35% w/v. 2-pyrrolidone or N-methylpyrrolidone (NMP).

In another preferred embodiment, the liquid veterinary pour-on composition contains from about 3 to 5% w/v. or about 2, about 3 or about 5% w/v. isoxazoline compounds, and the media contains about 35 or about 55% w/v. glyceryl monocaprylate and about 5% or about 35% w/v. 2-pyrrolidone or NMP.

Of particular note are compositions containing 5% w/v. fluralaner, optionally 0.5% eprinomectin, pyrrolidone diluent (preferably 2 pyrrolidone), L-menthol, miglyol 840 and glycerol monocaprylate.

Of particular note are compositions containing 5% w/v. fluralaner, optionally 0.5% eprinomectin, pyrrolidone diluent (preferably 2 pyrrolidone), L-menthol, miglyol 840 and isopropyl alcohol.

In the process for preparing the composition of the present invention, the excipients and the isoxazoline compound are mixed until all solids are dissolved. If necessary, additional solvent may be added to bring the composition to the final volume. Additives such as those listed above may also be included in the vessel and mixed with the composition. The order of adding the above excipients, solvents and additives is not standardized.

In other embodiments, the compositions of the invention may be in the form of oil-in-water or water-in-oil emulsions. In some embodiments, the oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifying agents include naturally occurring phosphatides such as soybeans, lecithin and esters or partial esters derived from fatty acids and hexitanhydrides such as sorbitan monooleate and the ethylene oxide condensation products of said partial esters such as polyoxyethylene sorbitan monooleate and the like. In some embodiments, the emulsions may also contain preservatives.

In another embodiment, the composition of the invention is in the form of a microemulsion. Microemulsions are well suited as a liquid carrier. Microemulsions are typically quaternary systems comprising an aqueous phase, an oil phase, a surfactant and a co-surfactant. They are usually translucent and isotropic liquids. Microemulsions consist of stable dispersions of microdroplets of an aqueous phase in an oil phase or, conversely, microdroplets of an oil phase in an aqueous phase. The size of these microdroplets is usually less than 200 nm (from 1000 to 100,000 nm for emulsions). The interfacial film consists of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules, which, by reducing the interfacial tension, allow the spontaneous formation of a microemulsion.

In one embodiment of the oil phase, the oil phase may be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides, or from triglycerides, or alternatively from mixtures of such compounds. In one embodiment of the oil phase, the oil phase contains triglycerides. In another embodiment of the oil phase, the triglycerides are medium chain triglycerides, eg C ₅ -C ₁₀ caprylic/capric triglyceride. In another embodiment, the oil phase will be in % v/v selected from the group consisting of about 1-20%; about 2 to about 15%; about 7 to about 10%>; and about 8 to about 9% by volume of the microemulsion.

The aqueous phase usually includes, for example, water or glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one embodiment of the glycol derivatives, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, and mixtures thereof. Typically, the aqueous phase will be from about 1 to about 10% v/v. or from about 1 to about 4% vol./about. in microemulsion.

Microemulsion surfactants typically include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, C ₈ -C ₁₀ polyglycolized glycerides, or polyglyceryl-6 dioleate, or a combination of these surfactants. In addition to these surfactants, co-surfactants include short chain alcohols such as ethanol and propanol. In addition, poloxamers and Pluronic F127 can be used as surfactants.

Some compounds are common to the three components described above, ie the aqueous phase, the surfactant and the co-surfactant. However, the practitioner, within his or her skill level, may use different compounds for each component of the same composition.

The pharmaceutically acceptable carrier may optionally contain a crystallization inhibitor, such as the crystallization inhibitors described below, or mixtures thereof, to inhibit crystal formation or precipitation of active components (eg, isoxazoline compounds).

A veterinarily and/or pharmaceutically acceptable carrier will typically contain a diluent or carrier in which the actives are dissolved. It will be apparent to those skilled in the art that the carrier or diluent for topical compositions must be capable of delivering active agents to the target site without them precipitating out of solution or forming crystals. In some embodiments, the carrier or diluent of the compositions will be suitable to avoid precipitation or crystallization of the actives. In other embodiments, the compositions may include a crystallization inhibitor component in addition to a carrier or diluent.

Crystallization inhibitors that are used for the invention include, but are not limited to:

(a) polyvinylpyrrolidone, polyvinyl alcohols, vinyl acetate-vinylpyrrolidone copolymers, 2-pyrrolidone, including N-methylpyrrolidone, dimethyl sulfoxide, polyethylene glycols, polyoxyethylene-polyoxypropylene copolymers, benzyl alcohol, mannitol, glycerin, sorbitol, or polyoxyethylene sorbitol esters; lecithin or sodium carboxymethylcellulose; or acrylic derivatives such as polymers derived from acrylic monomers, including polyacrylates or polymethacrylates; and the solvent described herein, which inhibits the crystallization of the active substance, and the like;

(b) anionic surfactants such as alkali metal stearates (eg sodium, potassium or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates, which include, but are not limited to, sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate; or fatty acids (eg coconut oil);

(c) cationic surfactants, such as water-soluble quaternary ammonium salts of the formula N R'R"R"'R""Y<~>, in which the radicals R are the same or different optionally hydroxylated hydrocarbon radicals and Y is an anion strong acids, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used;

(d) amine salts of the formula N HR'R'R'"Y<"> wherein the R radicals are the same or different optionally hydroxylated hydrocarbon radicals and Y<"> is an anion of a mineral or organic acid; octadecylamine hydrochloride is one of cationic surfactants that can be used;

(e) nonionic surfactants such as optionally polyoxyethylene esters of sorbitol, for example polysorbate 80 or polyoxyethylene alkyl ethers; polyethylene glycol stearate, polyoxyethylene castor oil derivatives, including hydrogenated castor oil and derivatives thereof, polyglycerol esters, polyoxyethylene fatty alcohols, polyoxyethylene fatty acids, or copolymers of ethylene oxide and propylene oxide;

(f) amphoteric surfactants such as substituted lauryl compounds of betaine; or

(g) a mixture of at least two compounds listed in points (a)-(f) above.

In one embodiment of the crystallization inhibitor, a pair of crystallization inhibitors will be used. Such pairs include, for example, a combination of a polymer type film-forming agent and a surfactant. Other pairs of crystallization inhibitors include polyethylene glycol and a non-ionic surfactant. Additional pairs of crystallization inhibitors are also contemplated, including other mixtures. These substances can be selected from the compounds described above as a crystallization inhibitor.

In some embodiments, the implementation of the crystallization inhibitor may be present in an amount of from about 1 to about 30% (w/v). Typically, the crystallization inhibitor may be present in an amount of about 1% to about 20% (w/v), about 1% to about 10% (w/v), or about 5% to about 15% (w/v). Acceptable inhibitors are inhibitors, the addition of which to the composition inhibits the formation of crystals of the active substances upon application of the composition. In some embodiments, the compositions may include compounds that function as crystallization inhibitors other than those described herein. In these embodiments, the suitability of a crystallization inhibitor can be determined by examining whether it will sufficiently inhibit crystal formation such that a sample containing 10% (w/v) isoxazoline active in a solvent as described above with 10 % (w/v) of the crystallization inhibitor produces less than 20, preferably less than 10 crystals when placed on a glass slide at 20° C. for 24 hours.

The pour-on compositions may also (or alternatively) contain one or more spreading agents. These substances function as carriers which help distribute the active ingredient over the coat or skin of the recipient animal. These may include, for example, isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides and/or fatty alcohols.

Various oil/solvent spreading combinations may also be suitable, e.g. oleic acid ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate and caproic acid esters of saturated fatty alcohols having a carbon chain of 12 to 18 carbon atoms, dicarboxylic acid ester solutions (e.g. dibutyl phthalate, diisopropyl isophthalate, diisopropyl adipic acid ester and di -n-butyl adipate) or solutions of aliphatic acid esters (e.g. glycols) In the case where the composition contains a spreading agent, it may also be effective to include a dispersant, such as, for example, pyrrolidin-2-one, N-alkylpyrrolidin-2 -one, acetone, polyethylene glycol or their ether or ester, propylene glycol or synthetic triglycerides.

In some embodiments, emollient and/or spreading and/or film-forming agents may be added to topical compositions of the invention. Softening agents, flow enhancers and film formers are well known in the art. In various embodiments, emollients, spreading agents, and film formers that can be used in topical compositions include the components listed in points (a) - (g) above, including polymeric derivatives such as polyvinylpyrrolidone, polyvinyl alcohols, and vinyl acetate copolymers. and vinylpyrrolidone; anionic surfactants; cationic surfactants; non-ionic surfactants; amphoteric surfactants; amine salts and combinations thereof. In one embodiment, the emollient is used in an amount of about 0.1 to about 10%, or about 0.25 to about 5% (w/v).

Topical application of the composition of the invention provides effective plasma concentrations. Topical application of the compositions of the invention provides effective transdermal delivery of the active substance through the skin into the systemic circulation and onto the surface of the animal at a concentration sufficient to provide excellent and long-term action against ectoparasites. The compositions of the invention achieve distribution of the active substance both locally in the animal's coat and transdermally into the bloodstream. In this embodiment, the topical compositions provide a high level of efficacy at surprisingly low plasma concentrations of the active isoxazoline agent.

In some embodiments of the invention, the compositions are designed to control the rate of penetration of an isoxazoline compound while maintaining effective plasma levels of the active substance for an extended period of time and significantly increasing the duration of its action.

The liquid formulation of the invention has the desired absolute systemic bioavailability to promote this excellent and long lasting action against ectoparasites. Bioavailability is determined by the amount of therapeutically active drug that enters the systemic circulation. It is denoted by the letter F. Absolute bioavailability measures the presence of an active drug in the systemic circulation after non-intravenous administration (i.e., after oral, transdermal, subcutaneous administration).

Absolute bioavailability corresponds to the dose-adjusted area under the curve (AUC) after non-intravenous administration divided by the AUC after intravenous administration. For example, the formula for calculating F for a drug administered subcutaneously (sc) is given below.

F = ([AUC] _by ⃰ _IV dose)/([AUC] _IV ⃰ dose _by )

In one embodiment, the isoxazoline compound in the composition of the invention has an absolute systemic bioavailability of 5 to 10% after administration by drench or spot application. In one embodiment, the absolute systemic bioavailability is 2 to 10%. In another embodiment, the absolute systemic bioavailability is 30 to 40%. In another embodiment, the absolute systemic bioavailability is 20 to 30%. In another embodiment, the absolute systemic bioavailability is greater than 30%.

Methods of treatment

In another aspect of the invention, there is provided a method of preventing or treating a parasitic infestation/infection in an animal, comprising administering to the animal a topical composition comprising an effective amount of at least one active isoxazoline agent together with a pharmaceutically acceptable carrier that is suitable for drenching and/or spotting. application to the skin of an animal. Compositions or compositions of the invention have a long-term effect against ectoparasites (eg, fleas and ticks) and, in some embodiments, may also be active against endoparasites that are harmful to animals.

In one embodiment, the invention provides methods for treating or preventing a parasitic infestation or infection in a companion animal, which comprises administering a topical composition comprising an effective amount of at least one active isoxazoline agent to the animal as a drench or spot preparation. Ectoparasites against which the methods and compositions of the invention are effective include, but are not limited to, fleas, ticks, itchs, mosquitoes, flies, and lice. In certain embodiments, where the compositions include one or more additional active substances that are active against internal parasites, the compositions and methods of the invention may also be effective against endoparasites, including, but not limited to, tapeworms, hookworms, hookworms, and roundworms in digestive tract of animals and humans.

Treated ectoparasites include, but are not limited to, fleas, ticks, itchs, mosquitoes, flies, lice, blowflies, and combinations thereof.

In another embodiment of the treatment against ectoparasites, the ectoparasite is a tick of the genus Boophilus/Rhipicephalus, Dermacentor, Ixodes, Boophilus, Ambylomma, Haemaphysalis, Hyalomma , in particular Boophilus (Rhipicephalus) , in particular microplus mites (ringed mites), R. decoloratus and R. annulatus .

Rhipicephalus microplus , R. decoloratus , and R. annulatus are single-host ticks, which means that all three stages of the life cycle occur on the same animal .

“Multiple host ticks” refers to ticks that fall to the ground after each stage and reattach to another host, host species may differ between different stages, and are, for example, Amblyoma cajennense, Ixodes holocyclus , i.e. paralyzing tick : H. longicornis , Rhipicephalus appendiculatus and Amblyoma haebraum , Dermacentor albipictus , Amblyoma maculatum , Amblyoma andersoni , Ixodes ricinus , Dermacentor marginatus .

Additional examples of ectoparasites include, but are not limited to, myiasis-causing flies, such as Dermatobia hominis (known as the Berne fly/Berne in Brazil) and Cochliomyia hominivorax (carrion green); myiasis in sheep, e.g. Lucilia sericata , Lucilia cuprina (known as blowfly found in Australia, New Zealand and South Africa).

Stinging flies, that is, flies whose adults are a parasite, such as Haematobia irritans (small cow fly), Haematobia allerans exiqua (cow fly), and Stomoxys calcitrans (common fly).

Lice suck the blood of their host and play a more important role in the transmission of pathogens. Vine-eaters or biting lice ingest the hair and skin and sometimes blood of their host, and important lice parasites are: cattle lice ( Bovicola bovis ), cattle long-nosed louse ( Linognathus vituli ), small blue cattle lice ( Solenopotes capillatus ), cattle short-nosed louse ( Haematopinus eurysternus ) and tail louse of cattle ( Haematopinus quadripertusus ) and sheep and goat lice ( Bovicola ovis ).

Important parasitic mites are, for example, Chorioptes bovis, Sarcoptes scabiei and Psoroptes ovis

The above list is not exhaustive, and other ectoparasites are well known in the art that are harmful to animals, especially farm animals, in particular ruminants, more specifically cattle or sheep. These include, for example, migrating Diptera larvae.

Surprisingly, the pour-on composition of the invention has been found to be effective in controlling one or more of these parasites.

In some embodiments of the invention, in particular when an isoxazoline compound is combined with another active ingredient, the composition can also be used to treat endoparasites such as helminths selected from the group consisting of Anaplocephala, Ancylostoma, Anecator, Ascaris, Capillaria, Cooperia , Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostumum, Ostertagia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris and Trichostrongylus , and other parasites.

In another preferred embodiment, the methods and compositions of the invention are used to treat or prevent parasitic infections and infestations in cattle or sheep. In the treatment of farm animals such as cattle or sheep, the methods and compositions are effective against, in particular, Rhipicephalus (Boophilus) microplus , Haematobia irritans (small cow's stallion), Stomoxys calcitrans (common's stallion), and (sheep's) myiasis caused by flies. , such as Lucilia sericata (European green blowfly), Lucilia cuprina (green blowfly or Australian sheep blowfly, known as blowfly found in Australia, New Zealand and South Africa) Chrysomya rufifacies (hairy blowfly), Chrysomya varipes ( green little blowfly), Calliphora stygia (brown blowfly), Calliphora augur (brown blowfly (eastern), Calliphora novicia (brown blowfly (western).

Important lice species in ruminants such as cattle and sheep that can be controlled with the compositions of the invention are Bovicola spp . and Linognathus spp (eg Bovicola ovis ).

The terms “treatment” or “treat” or “treatment” are intended to refer to the use or administration of a composition of the invention to an animal that has a parasitic, in particular ectoparasitic infestation, to kill a parasite or reduce the number of parasites infecting the animal being treated. It should be noted that the compositions of the invention can be used to prevent such parasitic (re)infestation.

Compositions of the invention are administered in (parasiticidally) effective amounts that are appropriate to control the parasite to the extent desired.

By "effective amount" is meant a sufficient amount of a composition of the invention to kill an infestation of a host animal or to reduce the number of parasites infecting the animal. In some embodiments, an effective amount of the active agent is at least 70% effective against the target parasite.

Efficacy is determined by methods known in the art, for example, in accordance with the guidelines of the World Association for the Advancement of Veterinary Parasitology (WAAVP) for the evaluation of ectoparasites. In other embodiments, an effective amount of the active agent is at least 80% or at least 90% effective against the target pests. Preferably, an effective amount of the active agent will achieve an effectiveness of at least 95%, at least 98% or 100% against the target parasites.

In each aspect of the invention, the compounds and compositions of the invention may be used to control infestations by a single parasite species or in animals that carry a combination of different parasite species.

Compositions of the invention may be administered continuously to treat or prevent parasitic infections or infestations. Thus, the compositions of the invention deliver an effective amount of the active compounds to an animal in need of such treatment to control the target parasite. Effective pest control may require one or more applications of the compositions of the invention. In one embodiment, only one administration is required to treat an existing parasitic infestation and to protect the animal from reinfestation.

Typically, a dose of about 0.001 to about 100 mg per kg of body weight, administered as a single dose or in divided doses over a period of 1 to 5 days, will be satisfactory, but there will certainly be instances where higher or higher doses are indicated. lower dosage ranges and are included within the scope of the present invention. It is within the normal practice of the practitioner to determine a particular dosage regimen for a particular host and parasite. A single dose is preferred.

In other embodiments, for the treatment of farm animals such as cattle or sheep, doses of the active isoxazoline agent administered may be from about 1 to about 30 mg/kg of body weight. More typically, doses administered will be from about 1 to about 20 mg/kg, or from about 1 to about 15 mg/kg. Preferably, the dose of active isoxazoline substance administered to farm animals is from about 1 to about 10 mg/kg of body weight.

The compositions according to the present invention are used in particular for ruminants such as cattle, sheep, goats, camels, llamas, in particular when they are farm animals, they are kept for meat and milk or wool or, alternatively, in as working animals.

In one embodiment, the animals are ruminants, such as cattle. Efficacy against parasites such as mites in cattle is very surprising because the skin of cattle makes it particularly difficult to obtain effective levels of isoxazoline compounds in the blood after administration by douche or spot application.

As used herein, ruminants are ruminant mammals of the genus Bos and include, but are not limited to, cattle, bulls, heifers, cows (milking and non-lactating), calves, bulls, and buffaloes. Particularly preferred are beef cattle, ie cattle kept for meat production. In another embodiment, the animals are sheep. In another embodiment, the animals are goats.

Used in this document and hereinafter, the term "long-acting" refers to the duration of activity, which is greater than 24 hours, preferably greater than a week. Preferably more than two weeks. Protecting cattle from tick infestation is a particularly preferred embodiment of the present invention.

What constitutes an "effective amount" for use in the invention is the amount, therapeutic dose, or amount of an isoxazoline compound as described herein, which is necessary to completely kill the parasites infecting such an animal, or at least to significantly reduce parasites that infect animals. Alternatively, it may refer to an amount, dose, or amount that can effectively control and/or reduce the presence of parasites in an animal or its environment, such as a building, building, farm, fields, etc.

In order to determine whether there has been an effective reduction in the infestation of an animal or an effective control and/or reduction of parasites in the environment of the animal and, accordingly, what constitutes such an effective amount, is easily determined by comparing the number of parasites on the animal or in the environment of the animal before and after the administration of the isoxazoline compound, as described in this document. Detection can be done by counting the number of parasites visible on the animal, or by counting parasites with a trap or other environmental detection device. The difference in the number of such counts performed before and after treatment indicates the effectiveness of the applied dose. In order to make such counts statistically valid, a certain minimum number of host animals or detection devices must be monitored.

The treatment or prophylactic effect of the inventive use of the isoxazoline compound described herein on a parasite may, for example, be ovicidal, larvicidal and/or supulticidal, or a combination thereof. The effect can manifest itself directly, i.e. killing parasites immediately or after a period of time, such as when molting occurs, or by influencing the duration or number of bites or the amount of blood or body fluid ingested by the parasite during bites. Alternatively, the effect may be on the number of offspring of the parasites, directly or in subsequent generations, for example by reducing the fertility or efficiency of laying eggs of the parasites, for example, in relation to the size, number or quality of eggs laid; hatchability; offspring viability; or gender ratio of offspring.

Alternatively, the impact on the economic performance of the animals can be monitored, such as, for example, differences in daily weight gain, feed conversion, or milk production.

Thus, although the goal is a reduction of 100% or close to 100%, nevertheless, a reduction in the number of parasites by about 5% may already amount to a significant reduction, because even such a modest reduction already reduces certain symptoms in affected animals and can restore animals to an improved economic level of production. The death of parasites is the preferred indicator of the effectiveness of treatment. Another effect may be the weakening of the reproduction of parasites, that is, a decrease in the number of offspring.

In a preferred embodiment, the reduction in infestation on the animal, or the level of control and/or reduction achieved, refers to the reduction in the number of parasites of a certain type in the following preferred order: at least 5, 10, 15, 20, 25, 30, 40 50, 60, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or even 100%.

In one embodiment, at least 90% mite efficacy is obtained compared to an untreated control group using the Abbot formula to calculate % control efficacy.

The treatment according to the invention may be available during the treatment period for one animal. It is more effective to treat a group of animals at the same time or all animals in the same stable, paddock, group, building or farm.

The term "treatment" and similar terms such as "treatment" or "treat" as used herein refer to administering an effective amount of isoxazoline as described for use in the invention to an animal that has an infestation, to a greater or lesser extent, parasites of one or more species.

"Protection" means that existing infestations in animals are attenuated and reduced and/or new infestations that appear after administration of the composition of the invention are controlled/attenuated/reduced or treated.

The term “(parasitic) infection or infestation” includes conditions associated with or caused by one or more (parasitic) pathogens; these conditions include clinical conditions (parasitosis) and subclinical conditions.

Subclinical conditions are generally those that do not lead directly to clinical symptoms in the parasitized animal, but result in economic loss. Such economic losses may result, for example, from reduced growth in young animals, decreased feeding efficiency, decreased weight gain in slaughter animals, decreased milk production in ruminants, or reduced sheep wool production.

The term "parasitosis" refers to clinically manifest pathological conditions and diseases associated with or caused by infection with one or more parasites, such as, for example, parasitic gastroenteritis or anemia in ruminants, such as sheep and goats, or colic in horses.

As used in the present invention, the term “reinfestation protection” covers the situation where an animal is exposed to a new parasite infestation because it either lives in an environment where live parasites are present or is in close contact with infested animals (or humans), respectively” at risk of being infected. Reinvasion is a repeated or subsequent invasion.

This means that an animal that is (essentially) free of parasites at a certain point is infested/infested with parasites (repeatedly) from external sources. The composition of the invention kills such newly emerging parasites before they can infect the animal, or alternatively, reduces the number of parasites to limit morbidity and damage to the animal by allowing few parasites.

In one embodiment, the composition demonstrates long-term efficacy and provides protection against parasites in farm animals for at least one month.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 50% against mites for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 70% against mites for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 90% against mites for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 50% against mites for at least 1 month, at least 2 months, at least 3 months, at least at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 70% against mites for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 90% against mites for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 50% against pruritus for at least 1 month, at least 2 months, at least 3 months, at least at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 70% against pruritus for at least 1 month, at least 2 months, at least 3 months, at least at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the compositions of the invention show a very long-term efficacy of at least 90% against pruritus for at least 1 month, at least 2 months, at least 3 months, at least at least 4 months, at least 5 months, or at least 6 months.

In another embodiment, the composition exhibits a long-term efficacy of at least 50% against mites, pruritus or lice over a period of at least 6 weeks.

In another embodiment, the composition exhibits a long-term efficacy of at least 70% against mites, pruritus or lice over a period of at least 6 weeks.

In another embodiment, the composition exhibits a long-term efficacy of at least 90% against mites, pruritus or lice over a period of at least 6 weeks.

Therefore, one embodiment of the invention is a method in which the composition of the invention is administered every month.

Therefore, in another embodiment of the invention, the composition of the invention is administered every six weeks.

Therefore, in another embodiment of the invention, the composition of the invention is administered every 2 months.

Therefore, in another embodiment of the invention, the composition of the invention is administered every 3 months.

In a preferred embodiment of the invention, the composition of the invention is administered as a single drug for one season.

Surprisingly, the topical compositions of the invention containing the isoxazoline active have been found to provide excellent efficacy against ticks at surprisingly very low plasma concentrations. In some embodiments, topical compositions of the invention containing selected solvents and excipients provide consistently low levels of active agent over an extended period of time.

In some embodiments, the plasma concentration of the active agent that is sufficient to achieve at least 90% efficacy against ticks is less than or equal to about 200 ng/mL, or less than or equal to about 150 ng/mL. In other preferred embodiments, the plasma concentration of active isoxazoline substance required to achieve 90% efficacy against ticks is less than or equal to about 100 ng/ml, less than or equal to about 75 ng/ml, or even less than or equal to about 50 ng/ml . In other embodiments, the plasma concentration of isoxazoline active required to achieve 90% efficacy against mites is about 75-100 ng/ml, about 50-75 ng/ml, or about 30-50 ng/ml.

In one embodiment, an effective dose of the composition protects cattle or sheep from infestation or re-infestation by mites, mites, lice and/or stinging flies for at least 21 days.

Therefore, in another embodiment of the invention, the pour-on composition is administered every 3 weeks or 21 days.

Without wishing to be bound by theory, it should be noted that the lower plasma concentration required to achieve 90% efficacy with the topical compositions of the invention may indicate that the compositions provide protection against ectoparasites by acting both on the animal's body surface and and systemically.

The improved efficacy of the topical compositions of the invention against these mite species at significantly lower plasma concentrations may provide longer lasting efficacy based on the ability of the inactive excipients in the compositions of the invention to deliver effective amounts of isoxazoline actives slowly into the bloodstream from the site of application.

In another embodiment of the invention, it has been surprisingly found that the topical compositions of the invention provide 90% effectiveness as early as 4 days after administration of the topical composition, and also provide long-term effectiveness. In other embodiments, topical compositions provide efficacy as early as 3 or 2 days or 1 day after administration.

The fast-acting and long-term protection provided by the compositions of the present invention is unexpected.

In another aspect of the invention, there is provided a kit for the treatment or prevention of a parasitic infestation in an animal, which comprises at least one isoxazoline active, together with a pharmaceutically acceptable carrier and a pour-on dispenser.

The volume of the composition for topical application by spot application or pour-on should be sufficient and should be safe and effective. The volume usually applied depends on the size and weight of the animal, as well as on the concentration of the active substance. It is preferable to apply a volume that allows accurate dosing but does not cause the composition to run off, in particular if the animal is moving.

The composition according to the invention provides a very high concentration of the isooxazoline compound in the composition and therefore provides a low volume of application.

In terms of the pour-on form of the composition, the volume may be on the order of about 0.3 to about 100 ml. In other embodiments, the pour-on volume of the composition may be from about 1 ml to about 100 ml, or from about 1 ml to about 50 ml. In other embodiments, the volume may be from about 5 to about 50 ml, or from about 10 to about 100 ml.

The composition for topical localized application by pouring is applied as a small volume of about 0.01 to 1 ml per kg, preferably about 0.05 to 0.1 ml per kg, with a total volume of 0.3 to 100 ml per animal, preferably limited to a maximum of about 50 ml depending on the target species.

In one embodiment, the application volume is 1 ml of the composition per 10 kg of animal body weight, resulting in a total application volume of 50 ml for 500 kg of cattle or 8 ml for 80 kg of sheep. These application volumes are optimal for the caretaker.

In another embodiment, the application volume is 1 ml of the composition per 20 kg of animal body weight, resulting in a total application volume of 25 ml for 500 kg of cattle or 4 ml for 80 kg of sheep.

The pour-on or topical compositions of the invention may be applied by any means known per se , e.g. applicator gun or measuring vessel, pipette, syringes, rollers, droppers, capsules, foil packs, vials, containers with twist-offs. , metered-dose aerosols or spray bottles and other single-dose and multi-dose containers.

In one embodiment, the compositions of the present invention are administered to an animal in need of such treatment via a drug evacuation vessel (PIBA) device. Such a device allows the healthcare worker to easily dispense liquids from standard bottles into (oral) syringes.

Upon administration of the composition, the practitioner opens the vial and presses the plastic adapter into the opening of the vial, and then secures the oral syringe into the connector of the adapter. The practitioner can then remove the dose of drug from the vessel and administer the dose. Then the vessel can be again closed with a lid for later use.

Currently, products for administration to an animal by drench generally require the administration of large volumes of the composition, and accordingly the method of administration described above is not suitable. Therefore, the present products for dousing application are administered either by means of a dispensing gun or a measuring vessel. Such routes of administration are less preferred for delivering precise, small volumes of drug.

Thus, the method of administration of the present invention using the PIBA application system provides more accurate and convenient administration of the inventive liquid preparation by pouring.

In one embodiment, the present invention relates to a method of administering a composition of the invention, comprising:

a) Introducing said composition into a device for extracting a drug from a vessel; and

b) Administering an effective amount of said composition to an animal in need by pouring over the animal's back.

This method consists of the following steps: determination of the animal's body weight and selection of the correct dose using a dosing vessel chamber that is calibrated in kilograms of body weight. Hold the vessel in a vertical position and at eye level while slowly and carefully squeezing the vessel to fill the dosing chamber to the selected mark. Pouring a measured volume onto the back of the animal along the midline, starting from the withers to the root of the base of the tail.

It is an aspect of the invention to provide a reusable container containing a topical pour-on composition of the invention from which accurate single dose aliquots of long-acting topical compositions can be administered.

The composition must remain stable under repeated exposure to the external environment, in particular oxygen and water. This embodiment may in particular be used with very long acting compositions of the invention which need to be administered to the animal infrequently, for example once every 1-6 months or the like.

Thus, composition stability is particularly important for multi-dose container applications where the compositions may be exposed to oxygen and water for multiple opening and closing cycles.

The compositions according to the invention are stable, which means that the active ingredient is practically not degraded during storage in the closed state and during several cycles of opening and closing the container.

The pour-on composition can also be applied to the animal by other conventional methods, including wiping the impregnated material over at least a small area of the animal, or applying it with a commercially available applicator, with a syringe, by spraying, or by using a spray split.

Definitions

As used herein, terms will have their usual meaning in the art, unless otherwise indicated.

In the present description and in the claims, terms such as “comprises”, “comprising”, “consisting of” and “having”, and the like, may mean “includes”, “comprising”, and the like; “consisting essentially of” or “consisting essentially of” is also non-exhaustive, allowing the presence of more than what is listed, provided that the essential or new characteristics of what is listed is not changed by having more than what is listed, but excludes options implementation of the prior art.

Used in the description and claims, the terms "about" and "approximately" mean that the value is in a statistically significant range. Such a range may typically be within 20%, more typically still within 10%, and even more typically within 5% of the set value or range. The tolerance covered by the terms "about" and "approximately" depends on the particular system under study and can be easily estimated by a person skilled in the art.

For the purposes of this detailed description, the following abbreviations and definitions apply. It should be noted that, as used herein, singular nouns encompass plural nouns unless the context clearly dictates otherwise.

The publications discussed in this document are provided solely for their disclosure. Nothing in this document should be construed as an admission of juxtaposition of publications with earlier priority. In addition, the publication dates provided may differ from the actual publication dates, which may need to be independently confirmed.

Where a range of values is provided, it is understood that every intermediate value is covered. The upper and lower limits of these smaller ranges may independently be included in the smaller ones, subject to any specifically excluded limit in the given range. Where the specified range includes one or both of the limits, ranges excluding both of these included limits are also included in the present invention. Any values that fall within the specified ranges are also considered.

The concentration ranges for the components of the described compositions are expressed in % by weight by volume of the final composition, unless otherwise indicated.

EXAMPLES

The invention is further described by way of the following non-limiting examples, which further illustrate the invention and are not intended to and should not be interpreted as limiting the scope of the invention.

As a non-limiting example, the isoxazoline compound fluralaner (compound A) has been investigated for topical delivery to farm animals such as cattle. In some compositions, the composition contains Compound A (fluralaner) and eprinomectin.

The compositions were prepared and evaluated for their effectiveness in controlling ectoparasites such as mites in cattle.

Table 3: Composition examples

Ingredient 72 73 123 124 37 76 77 14-082 14-086 Compound A 5.0 5.0 2.0 3.0 3.0 5.0 5.0 3.0 3.0 Eprinomectin - - - --- --- --- 0.5 0.5 0.5 --- 0.5 Eucalyptol 10.0 - - - --- --- --- 10.0 --- --- --- L-menthol 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Migliol 840 --- 10.0 10.0 10.0 10.0 --- 10.0 10.0 10.0 2-pyrrolidone 5.0 35.0 35.0 35.0 35.0 5.0 35.0 35.0 35.0 Isopropyl alcohol QS QS QS QS QS QS QS QS QS BHT - - - - - - --- --- 0.5 0.5 0.5 0.5

Table 3a: Composition for use in cattle by spot application

5006294-0005 5006294-0006 Component mg/ml Fluralaner 250 500 L-menthol 100 100 n-methyl-2-pyrrolidone 650 400

Table 3b: Composition for use in sheep by spot application

5006294-0002 5006294-0003 Component mg/ml Fluralaner 25 50 n-methyl-2-pyrrolidone 300 300 Dipropylene glycol monoethyl ether about 700 about 700

To prepare the compositions of the example, the carrier(s) or part of the carrier(s) were added to the mixing vessel, followed by the remaining excipients and actives. The mixture was stirred until all solids had dissolved. Although not included here, additives, such as those mentioned in the detailed description, are also included in the vessel and mixed with the composition. The order of addition was not critical.

Biological example 1

Efficacy against ticks of the genus Rhipicephalu s micro plus

The efficacy of two pour-on formulations of the invention containing Compound A was tested against infestation by mites of the genus Rhipicephalus microplus compared to two alternative pour-on formulations and an untreated control.

In each study group, five healthy cattle were used, aged from 6 to 15 months, weighing from 70 to 150 kg. Cattle in group 1 were not subjected to treatment/treatment (control). Cattle in group 2 were treated on day 0 with a pour-on formulation containing Compound A in an oily solution at a concentration of 5% (w/v) at a dose of 5 mg/kg; cattle in group 3 were treated on day 0 with a pour-on formulation containing Compound A at a concentration of 5% (w/v) in volatile solution I (pour-on formulation 2, see Table 1) at a dose of 5 mg/ kg; cattle in group 4 were treated on day 0 with a pour-on formulation containing Compound A at a concentration of 5% (w/v) of volatile solution II (pour-on formulation 3, see Table 1) at a dose of 5 mg/ kg; and cattle in group 5 were treated on day 0 with a pour-on formulation containing Compound A at a concentration of 5% (w/v) oily solution at a dose of 5 mg/kg.

Data from the tested investigational products are presented in Table 4:

No. % mass/volume Fluralaner BHT 2-pyrrolidone L-menthol Eucalyptol Kollidon HS-15 propylene glycol dicaprylocaprate Isopropyl alcohol 71- T1 5 NA 10.0 20.0 NA NA QS (about 60%) NA 72- T2 5 NA 5.0 100 100 NA NA QS (about 55%) 73- T3 5 NA 35.0 10.0 NA NA 100 QS (about 33%) 74-T4 5 NA NA 10.0 NA 10.0 QS (about 69%) NA

Before treatment, from day -28 to day -1, cattle were infected three times a week with about 3000 Rhipicephalus microplus larvae to form the current infestation. Cattle in groups 2, 3, 4 and 5 were treated with the respective compositions on day 0 by measuring the required amount of solution in a labeled disposable syringe and evenly applying the drug along the midline of the back of each animal from the withers to the root of the base of the tail.

After treatment, each animal was challenged with approximately 3000 R. microplus larvae 3 times a week. For group 1 (untreated control group), infection was continued for two weeks after treatment.

Starting on the first day after treatment (Day 1), fully engorged female ticks dropped from each animal were collected, counted and recorded daily during the animal study phase. The collection of ticks from the control group (C1) ended after the therapeutic efficacy period due to the fact that the animals would only be re-infected within two weeks of treatment.

In addition, the collected ticks were weighed as a group to measure the effect of the treatment on the increase in the mass of ticks compared to the control to assess the viability and reproductive capacity of the treated ticks.

The potency of the investigational veterinary product (IVP) was determined using the standard ADEQ assay method as described in Holdsworth, P.A., Kemp, D., Green, P., Peter, R.J., De Bruin, C., Jonsson, N.N., Rehbein, S. , Vercruysse, J. World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) guidelines for evaluating the efficacy of acaricides against ticks (Ixodidae) on ruminants. Veterinary Parasitology, 136 (2006) 29-43.

To determine the pharmacokinetic profile of Compound A (fluralaner) in plasma in cattle, blood samples from all treatment groups were collected before treatment and 1, 2, 5, 7, 9, 12, 14, 16 and 21 days after treatment. Thereafter, blood samples will be taken weekly (i.e., every 6-8 days) until the end of the animal study phase.

Figures 1 and 2 show the overall tick-counted % potency of the pour-on formulation against R. microplus 115 days post-treatment compared to the untreated control group.

Therapeutic daily mite efficacy (˃95%) was achieved 3 days after treatment with the T1 group, 10 days after the treatment with the T2 group, 4 days after the treatment with the T3 group, and 3 days after the treatment with the T4 group.

In the T1 group (5 mg fluralaner/kg body weight), the long-term tick control efficacy (˃ 95%) changed from 3 to 76 days post-treatment. The highest efficacy (100%) was maintained 9-55 days post-treatment, while the lowest efficacy (90.6) was observed 90 days post-treatment. The T1 group was excluded on day 98.

In the T2 group (5 mg fluralaner/kg body weight), the long-term daily tick control efficacy (˃95%) changed from 23 to 108 days post-treatment. The highest efficacy (100%) was maintained 35-42 days post-treatment, while the lowest efficacy (88.54) was observed 111 days post-treatment. The T2 group was excluded on day 117.

In the T3 group (5 mg fluralaner/kg body weight), the long-term daily tick control efficacy (˃95%) changed from 4 to 104 days post-treatment. The highest efficacy (100%) was maintained at 10-15 and 33-42 days post-treatment, while the lowest efficacy (65.27) was observed 110 days post-treatment. The T3 group was excluded on day 117.

In the T4 group (5 mg fluralaner/kg body weight), the long-term daily tick control efficacy (˃95%) changed from 3 to 72 days post-treatment. The highest efficacy (100%) was maintained 12-42 days post-treatment, while the lowest efficacy (65.25%) was observed 77 days post-treatment. The T4 group was excluded on day 84.

As shown in Figures 1 and 2, the pour-on compositions of the invention provide excellent efficacy against the mite of the genus Rhipicephalus microplus over an extended period of time.

The long-term efficacy of over 90% for a pour-on formulation against the mite of the genus Rhipicephalus microplus is significant compared to pour-on formulations known in the art.

The individual pharmacokinetic parameters of the compositions of the invention (ie C _max and AUC) are shown in Table 5 below. FIG. 3 shows the pharmacokinetic and efficacy results of this study in one graph.

Parameters (unit) group 1 2 3 4 Cmax (ng/ml) Mean ± standard deviation 10.7 ± 8.43 6.3 ± 6.63 11.5±8.19 24.6 ± 9.98 Tmax (days) Median (range) 5 (1-7) 1 (1-77) 14 (1-69) 7 (5-9) AUClast
(ng⃰day/ml) Mean ± standard deviation 153 ± 59.3 95 ± 32.8 221 ± 149.0 307 ± 145.8 MRTlast (days) Mean ± standard deviation 22.7 ± 4.08 33.5 ± 13.13 34.9 ± 15.09 12.4 ± 2.38

Biological example 2

The effectiveness of the pour-on composition against Haematobia irritans exiqua in cattle

The corral study was conducted on a commercial farm near Topaz in North Queensland, Australia. The aim of the study was to determine the therapeutic and residual efficacy of four experimental fluralaner pour-on formulations against natural cowfly ( Haematobia allerans exigua ) populations in cattle. The animals studied were commercial grade cattle that had remained on the farm during the study and had not been subjected to external treatment with a macrocyclic lactone, organophosphate, synthetic pyrethroid, or insect growth regulator during the previous 3 months. Data by treatment group are presented below:

Animals were selected to their groups on day 0. The untreated animals of group 1 were distilled into their own separate paddock prior to treatment. Treatment groups 2-5 were kept separately in small pens in the yards after selection until they were taken to the split for processing. Groups 3 and 5 (IVP2 and IVP 4) were treated with compositions according to the invention (see Table 1 Nos. 14-82 and 14-86). Groups 1 and 4 (IVP 1 and IVP 3) were treated with comparative pour-on formulations. These compositions are presented in the following table 6:

Composition % w/v IVP 1
14-080 IVP 2
14-082 IVP 3
14-084 IVP 4
14-086 Fluralaner 3.0 3.0 3.0 3.0 Eprinomectin --- --- 0.5 0.5 2-pyrrolidone 35.0 35.0 35.0 35.0 L-menthol 10.0 10.0 10.0 10.0 Migliol 840 10.0 10.0 10.0 10.0 Isopropyl alcohol --- QS --- QS Glyceryl monocaprylate QS --- QS --- BHT --- ---- 0.5 0.5

Each animal was kept in a machine with a head fixation mechanism during processing. Animals were treated according to their individual body weight recorded before treatment on day -1. The treatment was carried out with a 20 ml plastic syringe topically along the line of the back of the animal, starting from an area approximately 10 cm in front of the scapula and ending at the root of the base of the tail.

Each assessment consisted of counting the number of flies on one whole side of each of all animals in each individual group. Cow fly counts were performed on day -6 and day -1 to determine the distribution of the treatment. After drug administration (Day 0), flies were counted 1, 3, 7, 14, 21, 28 and 35 days post-treatment.

The numbers of cowflies in the pre-treatment group were the same between the groups and sufficient infestation was ensured. Numbers ranged from the arithmetic mean of 208.3 to 239.2 flies for the five treatment groups. The average number of cow flies per animal remained relatively constant in untreated control cattle during the first 3 days after treatment, ranging from a mean value of 233.3 to 278.3. Between 21 and 35 days after treatment, the number of flies increased to an average of 526.7.

Calculations showed that the fly infestation on the farm was sufficient during the study.

On post-treatment day 1, all four IVP-treated groups had an average number of flies that was significantly lower than the untreated control group.

Group 3 treated with IVP 2 had statistically higher numbers than the other treated groups; however, control was still relatively high at 82.6% effective. The rest of the IVPs reached >97.7% efficiency on the first day.

In group 4, treated with IVP 3, fluralaner plus eprinomectin, by perfusion, 100% control was achieved on day 3 and day 14; however, there was no statistical difference in the mean number of flies between groups 4, 2, and 3 at these assessment times. Efficacy for group 4 was ≥99.0% up to day 21. On days 28 and 35, a moderate level of efficacy was still evident with control of 93.3% and 80.9%, respectively.

The rest of the formulations maintained high levels of efficacy >93.9% up to 21 days. The effectiveness of all compositions decreased on days 28 and 35 to moderate levels. On day 35, cattle treated with all compositions had a significantly lower arithmetic mean number of flies than the untreated control group.

There was no difference between the IVP-treated groups, in which efficacy varied between 76.3% for group 5 and 80.9% for group 4.

The IVP formulations provided a high level of efficacy against natural populations of cowflies when administered as a therapeutic agent by upholstering.

The invention is further described with the aid of the following numbered paragraphs.

1. Liquid veterinary composition for use in the treatment and protection against parasitic infestations of an animal, containing an effective amount of at least one isoxazoline compound of formula (I)

(Formula I)

Where

R ¹ =halogen, CF ₃ , OCF ₃ or CN;

n=an integer from 0 to 3 inclusive;

m=1 or 2;

R ² =C ₁ -C ₃ haloalkyl;

T=ring structure: 5- or 6-membered or bicyclic which is optionally substituted with one or more Y radicals;

Y=methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C=S or two adjacent Y radicals together form a chain;

Q=X-NR ³ R ⁴ , NR ⁵ -NR ⁶ -XR ³ , XR ³ or a 5-membered N-heteroaryl ring which is optionally substituted with one or more radicals;

X=CH ₂ , CH(CH ₃ ), CH(CN), CO, CS;

R ³ = hydrogen, halogenethyl, halogenpropil, haloenbutil, methoxymethyl, methoxyethyl, halogenmetoxymethyl, ethoximethyl, halogenetoxymethyl, proximethyl, ethylaminocarbonylomethyl, ethylaminocarbonyl ethylaminocarbonyl ethotoxyethyl, propynilaminocarbonomethyl, n-n-n-meblemino, gaglienethy Laminocarbonetil, halogenetylaminocarbonetil, tetrahydrofuril, methylaminocarbonylmetil, ( N, N-dimethylamino)carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl

Where

Z ^A =hydrogen, halogen, cyano or halomethyl (CF ₃ );

R ⁴ =hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl or haloethylaminocarbonylethyl;

R ⁵ =H, alkyl or haloalkyl;

R ⁶ =H, alkyl or haloalkyl;

or where R ³ and R ⁴ together form a substituent selected from the group consisting of:

And ,

or a pharmaceutically acceptable salt thereof, wherein the composition is administered as a drench and comprises a pharmaceutically acceptable carrier containing at least one skin penetration enhancer and a solvent system, the skin penetration enhancer containing menthol and the solvent system containing a pyrrolidone solvent.

2. Liquid veterinary composition according to paragraph 1, where T is selected from

where in T-1, T-3 and T-4, the radical Y=hydrogen, halo, methyl, halomethyl, ethyl or haloethyl, and where Q is selected from

where R ³ , R ⁴ , X and Z ^A have the meanings defined above, and

3. Liquid veterinary composition according to paragraphs 1 or 2, where the solvent system contains a volatile solvent.

4. Liquid veterinary composition according to paragraphs 1 or 2, where the composition contains from about 2 to about 20% w/v. volatile solvent.

5. A liquid veterinary composition according to any one of paragraphs 1-3, wherein the volatile solvent is an alcoholic solvent.

6. Liquid veterinary composition according to any one of paragraphs 1-4, where the composition contains from about 5 to about 60% w/v. alcohol solvent.

7. Liquid veterinary composition according to any one of paragraphs 1-5, where the alcoholic solvent is isopropyl alcohol.

8. Liquid veterinary composition according to paragraphs 1 or 2, where the composition contains an ester of glycerol.

9. Liquid veterinary composition according to paragraphs 1 or 2, where the glycerol ester is selected from mono- and diesters of saturated or unsaturated fatty acids of propylene glycol or complex mono-, di- and triesters of glycerol with an alkyl chain length from C8 to C14, saturated fatty acids with alkyl chain length from C8 to C14, unsaturated fatty acids from alkyl chain length from C14 to C22, saturated fatty alcohols from alkyl chain length from C8 to C14 and unsaturated fatty alcohols from alkyl chain length from C14 to C22, or mixtures thereof.

10. The liquid veterinary composition of claim 8 wherein the glycerol ester is selected from the group consisting of propylene glycol dicapriocaprate, glyceryl monocaprylate and mixtures thereof.

11. Liquid veterinary composition according to any one of paragraphs 8-10, where the composition contains from about 5 to about 70% w/v. ester of glycerol.

12. The liquid veterinary composition of any one of 8-11, wherein the glycerol ester is glyceryl monocaprylate.

13. The liquid veterinary composition of any one of 1-12, wherein the isooxazoline compound is fluralaner.

14. A liquid veterinary composition according to any one of items 1-13, wherein the composition contains from about 1% to about 20% (w/v) of an isoxazoline compound.

15. A liquid veterinary composition according to any one of items 1-14, wherein the composition contains from about 20% to about 50% (w/v) of an isoxazoline compound.

16. Liquid veterinary composition according to any one of paragraphs 1-15, where the composition contains from about 2 to about 20% w/v. menthol.

17. A liquid veterinary composition according to any one of paragraphs 1-16, wherein the pyrrolidone diluent is 2-pyrrolidone, N-methyl-2-pyrrolidone, and/or mixtures thereof.

18. Liquid veterinary composition according to any one of paragraphs 1-17, where the composition contains from about 5 to about 50% w/v. pyrrolidone solvent.

19. A liquid veterinary composition according to any one of paragraphs 1-18, further comprising propylene glycol dicaprylate/dicaprate.

20. Liquid veterinary composition according to any one of paragraphs 1-19, where the composition contains from about 5 to about 80% w/v. propylene glycol dicaprylate/dicaprate.

21. Liquid veterinary composition according to any one of paragraphs 1-20, where the composition contains from about 5 to about 50% w/v. pyrrolidone solvent and from about 5 to about 80% w/v. propylene glycol dicaprylate/dicaprate.

22. Liquid veterinary composition according to paragraphs 1-7, including:

a) from about 0.5% to about 15% w/v of at least one isoxazoline compound;

b) from about 5% to about 15% w/v. menthol;

c) from about 10% to about 50% w/v. isopropyl alcohol;

d) from about 10% to about 40% w/v. pyrrolidone solvent; And

e) from about 5% to about 80% w/v. propylene glycol dicaprylate/dicaprate.

23. Liquid veterinary composition according to paragraph 22, where the composition contains from about 2 to about 5% isoxazoline compounds, and the carrier contains about 10% w/v. menthol, from about 35 to about 55% w/v. isopropyl alcohol, from about 5 to about 35% w/v. 2-pyrrolidone and/or about 10% w/v. propylene glycol dicaprylate/dicaprate.

24. Liquid veterinary composition according to any one of paragraphs 1-7, where the composition contains about 2, about 3 or about 5% w/v. an isoxazoline compound; and the media contains about 35 or about 55% w/v. isopropyl alcohol and about 5% or about 35% w/v. 2-pyrrolidone.

25. Liquid veterinary composition according to paragraphs 1-7, where the composition contains from about 20 to about 50% isoxazoline compounds, and the carrier contains from about 5 to about 15% w/v. menthol, from about 35 to about 55% w/v. isopropyl alcohol, about 5 to 40% (w/v) 2-pyrrolidone, and/or about 10 to 70% (w/v) propylene glycol dicaprylate/dicaprate.

26. Liquid veterinary composition according to paragraphs 1-7, where the composition contains about 2, about 3 or about 5% w/v. an isoxazoline compound; and the media contains about 35 or about 55% w/v. isopropyl alcohol and about 5% or about 35% w/v. 2-pyrrolidone.

27. The liquid veterinary composition of any one of 1-26, wherein the isoxazoline compound is selected from the group consisting of fluralaner, afoxolaner, lotilaner, and sarolaner.

28. A liquid veterinary composition according to any one of paragraphs 1-27 for use in the manufacture of a medicament for controlling parasites, wherein the animal is a bovine or ovine animal.

29. A liquid veterinary composition according to any one of paragraphs 1-28, wherein the ectoparasitic infestation is a tick and/or lice infestation.

30. A method for protecting cattle from ectoparasitic infestation, comprising administering an effective dose of a liquid veterinary composition according to any one of paragraphs 1-27 to an animal in need of such protection.

31. The use of a liquid veterinary composition according to any one of claims 1 to 27 in the manufacture of a medicament for the protection of cattle against ectoparasitic infestation and/or the treatment of ectoparasitic infestation, preferably against tick or lice infestation.

32. The use of a liquid veterinary composition according to any one of claims 1 to 27 in the manufacture of a medicament for the protection of sheep against ectoparasitic infestation and/or the treatment of ectoparasitic infestation, preferably against screwworm infestation.

Claims (5)

1. A pour-on liquid veterinary composition for use in the protection and treatment of parasitic infestations in cattle, comprising an effective amount of at least one isoxazoline compound, wherein the isoxazoline compound is fluralaner or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier containing at least one skin penetration enhancer and a solvent system, wherein the skin penetration enhancer contains menthol, and the solvent system contains a pyrrolidone solvent and isopropyl alcohol and propylene glycol dicaprylate/dicaprate in an amount of 10% w/v. 2. Liquid veterinary composition applied by pouring according to claim 1, characterized in that the pyrrolidone solvent is 2-pyrrolidone, N-methyl-2-pyrrolidone or mixtures thereof. 3. A method of protecting a bovine animal from an ectoparasitic infestation, comprising administering an effective dose of a liquid veterinary composition applied by pouring according to claim 1 or 2 to an animal in need of such protection. 4. Use of a liquid veterinary pour-on composition according to claim 1 or 2 in the manufacture of a medicament for the protection of cattle against ectoparasitic infestation and/or the treatment of ectoparasitic infestation. 5. Use according to claim 4, wherein the ectoparasitic infestation is a tick or lice infestation.