KR102193090B1 - Topical localized isoxazoline formulation - Google Patents

Abstract

The present invention is a topical formulation comprising an isoxazoline compound and a pharmaceutically or veterinarily acceptable liquid carrier vehicle comprising N,N-diethyl-3-methylbenzamide as a solvent, and controlling parasitic infection in animals And an improved method for prevention.

Description

Topical isoxazoline formulation {TOPICAL LOCALIZED ISOXAZOLINE FORMULATION}

The present invention provides a topical localized formulation comprising an isoxazoline compound and a pharmaceutically or veterinarily acceptable liquid carrier vehicle. In addition, the present invention provides an improved method for controlling and preventing parasitic infection in animals.

Many pests and parasites can invade or infect livestock such as cattle, horses, pigs, sheep and companion animals such as cats and dogs. These pests and parasites are a major damage to both animals and their owners.

Ectoparasites such as mites, mites, lice, flies and fleas can cause disease by irritating animals and carrying pathogens that are transmitted by themselves or by vectors.

New economic methods and compositions for the prevention, treatment and control of parasites in warm-blooded animals continue to be studied.

Various patent applications for a new family of insecticidal isoxazoline compounds; For example, US patent application US 2007/0066617, and international patent applications WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075, WO 2010/070068, WO 2010/079077, WO 2011/075591 and WO 2011/124998.

Since these isoxazoline compounds were originally invented for use in the agricultural field, there is a need to identify specific formulations that allow their veterinary use, ie safe administration to effectively control parasites in animals.

One known and convenient method of administering extracorporeal anthelmintic compounds to animals is topical administration, for example as spot-on or pour-on.

However, prior art formulations and conventional topically applied in vitro anthelmintic formulations using a solvent proposed for an isoxazoline compound have difficulty in applying an effective amount of an isoxazoline compound while having an acceptable aesthetic. In particular, high doses of conventional topical formulations can lead to oozing of the product and a moist appearance of the hair after administration, and formulations with high concentrations may result in insolubility (crystallization) of the active ingredient, skin irritation as well as undesirable product characteristics such as poor quality. Viscosity, insufficient expansion, poor evaporation and insufficient penetration can result.

Therefore, what is needed in the present technology is a formulation for topical application of an isoxazoline compound, which avoids the aforementioned drawbacks.

The present invention provides topical formulations for the administration of isoxazoline compounds that overcome the drawbacks of the prior art. The formulations of the present invention deliver an effective amount of an isoxazoline compound with an acceptable aesthetic after topical application administration.

In one embodiment the invention comprises an effective amount of at least one isoxazoline compound of formula (I) and a veterinarily acceptable liquid carrier vehicle comprising N,N-diethyl-3-methylbenzamide as a solvent, It relates to topical formulations for the treatment or prevention of parasitic infections in animals.

<Formula I>

In the above formula,

R ¹ is halogen, CF ₃ , OCF ₃ , CN,

n is an integer of 0 to 3, preferably 1, 2 or 3,

R ² is C ₁ -C ₃ -haloalkyl, preferably CF ₃ or CF ₂ Cl,

T is a 5- or 6-membered ring, which is optionally substituted by one or more radicals Y,

Y is methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C=S, or two adjacent radicals Y together form a chain, in particular a 3 or 4 membered chain;

Q is an X-NR ³ R ⁴ or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;

X is CH ₂ , CH(CH ₃ ), CH(CN), CO, CS,

R ³ is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylamino Carbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, ( N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

이고,

ego,

Wherein Z ^A is hydrogen, halogen, cyano, halomethyl (CF ₃ );

R ⁴ is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl , Methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or Haloethylaminocarbonylethyl; or

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

및

And

In one embodiment the liquid carrier vehicle comprises N,N-diethyl-3-methylbenzamide as the only solvent. In another embodiment at least one additional veterinarily acceptable co-solvent is present.

In one embodiment the composition further comprises an effective amount of a macrocyclic lactone compound and/or a phenoxycarb, lupe selected from ivermectin, moxidectin, milbemycin oxime, selamectin, emamectin, latidectin and lepimectin or a salt thereof. Insect growth regulator compounds selected from nuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, methoprene and pyriproxyfen.

Another aspect of the invention is a method for the treatment or prevention of parasitic infections in animals, comprising the spot-on or pour-on administration of the topical formulation of claim 1.

These and other embodiments are disclosed in or are apparent from and encompassed by the following specific content.

1 is a plasma concentration of Compound A after spot-on administration of formulations A, U, D, O, F and G to beagle dogs.
2 is a plasma concentration of Compound A after spot-on administration of formulations A, V and I to beagle dogs.
3 is a plasma concentration of Compound A after spot-on administration of formulations A, N, and R to beagle dogs.
Figure 4 shows the plasma concentration of Compound A after spot-on administration of Formulation Q to beagle dogs.
5 is a plasma concentration of Compound A after spot-on administration of formulations C and H to beagle dogs.
6 is a plasma concentration of Compound A after spot-on administration of formulations N and C to beagle dogs.
Figure 7 shows the plasma concentrations of compound A and moxidectin after spot-on administration of formulation G to beagle dogs.

The topical formulations according to the present invention comprise an isoxazoline compound of formula (I) and a veterinarily acceptable liquid carrier vehicle comprising N,N-diethyl-3-methylbenzamide as a solvent.

<Formula I>

In the above formula,

R ¹ is halogen, CF ₃ , OCF ₃ , CN,

n is an integer of 0 to 3, preferably 1, 2 or 3,

R ² is C ₁ -C ₃ -haloalkyl, preferably CF ₃ or CF ₂ Cl,

T is a 5- or 6-membered ring, which is optionally substituted by one or more radicals Y,

Y is methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C=S, or two adjacent radicals Y together are chain CH-CH=CH-CH, N-CH=CH-CH, CH-N =CH-CH, CH-CH=N-CH, or CH-CH=CH-N, HC=HC-CH, CH-CH=CH, CH=CH-N, N-CH=CH;

Q is X-NR ³ R ⁴ or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals Z ^A , Z ^B , Z ^D ;

X is CH ₂ , CH(CH ₃ ), CH(CN), CO, CS,

R ³ is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylamino Carbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, ( N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

이고,

ego,

Wherein Z ^A is hydrogen, halogen, cyano, halomethyl (CF ₃ );

R ⁴ is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl , Methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or Haloethylaminocarbonylethyl; or

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

및

And

In one preferred embodiment in formula I T is selected from the formula

In the above formulas, the radical Y in T-1, T-3 and T-4 is hydrogen, halogen, methyl, halomethyl, ethyl, and haloethyl.

In a preferred embodiment in formula I Q is selected from the formula

In the above formula, R ³ , R ⁴ , X and Z ^A are as defined above.

이고,Z ^B is

ego,

이다.Z ^D is

to be.

Preferred compounds of formula I are:

Particularly preferred compounds of formula I are:

More preferred compounds have the formula II

<Formula II>

In the above formula,

R ^1a , R ^1b , R ^1c are independently of each other hydrogen, Cl or CF ₃ , preferably R ^1a and R ^1c are Cl, R ^1b is hydrogen, and T is

이고,

ego,

In the above formula, Y is methyl, bromine, Cl, F, CN or C(S)NH ₂ ,

Q is as described above.

In another preferred embodiment R ³ is H and R ⁴ 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 one embodiment the compound of formula I is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N -[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS registration number [864731-61-3]).

In another embodiment the compound of formula I is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N -[(Methoxyimino)methyl]-2-methylbenzamide (CAS registration number [928789-76-8]).

Particularly preferred compounds are

(화합물 A)이다.

(Compound A).

Particularly preferred compounds of formula II are:

*

Isoxazoline compounds are known in the art, and such compounds and their use as anthelmintic agents include, for example, US patent application US 2007/0066617 and international patent applications WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075, WO 2010/070068, WO 2010/079077, WO 2011/075591 and WO 2011/124998, the disclosures of which and references cited therein are incorporated herein by reference. Compounds of this class are known to possess excellent activity against ectoparasites such as ticks and fleas.

Isoxazoline compounds can exist in a variety of isomeric forms. References to isoxazoline compounds always include all possible isomeric forms of such compounds. Unless otherwise specified, compound structures that do not exhibit a particular form are intended to include compositions of all possible conformational isomers of the compound, as well as compositions containing fewer than all possible conformational isomers. In some embodiments, the compound is a chiral compound. In some embodiments, the compound is a non-chiral compound.

Isoxazoline compounds of formula I are, for example, among the methods described in patent applications US 2007/0066617, WO 2007/079162, WO 2009/002809, WO 2010/070068 and WO 2010/079077, 2011/075591 and WO 2011/124998 It can be prepared according to one or another method, or according to any other method within the skill of a person skilled in the art of chemical synthesis. In the chemical preparation of the products of the present invention, it is believed that one skilled in the art in particular makes use of the "Chemical Abstracts" and the entire contents of the documents cited therein at will.

The formulation according to the invention is effective for the treatment of ectoparasites in mammals for a long period of time, in particular fleas and ticks in small mammals such as dogs and cats. Advantageously, the formulations of the present invention retain the desired physical properties over time without loss of efficacy of the active substance. In addition, the formulation of the present invention exhibits a sufficient viscosity, which allows maintenance of the composition when administered topically to the skin or hair of an animal.

In addition, the formulations of the present invention have advantageous product properties, ie they are stable and cosmetically acceptable.

Cosmetic acceptability depends on the odor of the hair and skin (absence of), the humidity of the hair and skin at the application site, the overall appearance of the dogs' coat, in particular signs, such as dryness, stiff appearance, fragility, insensitivity, This includes hair loss and the appearance of hair residues near the site of administration.

This cosmetic acceptability is very important for products for topical application administration to companion animals such as dogs and cats, as pet owners will not allow long lasting changes in the appearance of their pet's fur after administration. .

Although the administration of the isoxazoline compound is cosmetically acceptable, it was possible to identify a topical formulation that allows long-acting efficacy against ticks and fleas as the formulation according to the present invention.

Topical application formulations are understood to refer to ready-to-use formulations in the form of spot-on, pour-on or spray-on formulations. The expression spot-on or pour-on method is understood to refer to a ready-to-use concentrate intended to be applied topically and topically on an animal. Preparations of this kind are intended to be applied directly to a relatively small area of the animal, preferably to one or several points on the animal's back and breech or along the line between the back and breech.

Spot-on administration is concentrated for intermittent application at a point on the animal, usually at a position 1, 2, 3, 4, or 5 (point) between the two shoulders (if more than one point is preferably the lower back). It is a topical application administration of a solution, suspension, microemulsion or emulsion. Alternatively, the product is administered by administration in one line.

Pour-on formulations are typically applied by pouring into one or several lines, or as a spot-on along the dorsal midline (back) or shoulder of the animal. More typically, the formulation is applied by infusion along the animal's back, spine. Pour-on formulations are more common for parasite control in domestic animals such as cattle, pigs, sheep and horses. The pour-on formulation of the present invention may be in the form of a liquid, emulsion, foam, paste, aerosol, ointment, plaster or gel. Typically, the pour-on formulation is a liquid.

Also, other conventional methods include wiping off material immersed on at least a small area of the animal, or applying using a commercially available applicator, using a syringe, by spraying, or by using a spray race. The formulation can be applied to animals by the method of.

Pour-on or spot-on formulations are generally advantageously from about 1 to about 50%, 10 to 40%, 20 to 35%, 25 to 30% about 20%, 25, in a proportion of about 0.01 to about 70%. %, 28%, 30%, 33%, 50% (percentage as weight per volume = W/V) may contain the isoxazoline compound of formula (I).

Topical formulations enable or facilitate the penetration of the isoxazoline compound into the skin and act on other parts of the body (eg, the entire body). Such pour-on or spot-on formulations can be prepared by dissolving, suspending or emulsifying isoxazoline in a suitable veterinary acceptable carrier.

In one embodiment the topical formulation is N,N-diethyl-3-methylbenzamide (DEET, previously N,N-diethyl-meta-toluamide or N,N-diethyl-m -Referred to as toluamide). In one embodiment at least one additional veterinarily acceptable co-solvent is present. N,N-diethyl-3-methylbenzamide is a well known chemical compound that has been used as a long-term insecticide. Various synthetic methods for their preparation are well known in the art.

Pour-on or spot-on formulations are generally advantageously about 1 to about 50%, preferably about 5 to about 37%, 8 to 28%, 10 to 23%, 15 to 20% about 5%, 7 %, 9%, 10%, 11%, 14%, 15%, 17%, 18%, 20%, 23%, 28%, 33%, 37%, 44% (percentage as weight per volume = W /V) may include N,N-diethyl-3-methylbenzamide.

Cosolvents for liquid carriers include pharmaceutically acceptable solvents known in the art of formulation.

Such solvents are, for example, diethyl phthalate fatty acid esters such as acetone dichloromethane, glycofurol, acetonitrile, n-butyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, diethyl ester or diisobutyl adipate, water , Alkanol, benzyl benzoate, dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, silicone, dimethylacetamide, 2,2-dimethyl-4-oxy-methylene-1,3-dioxolane, N,N -Dimethylalkanamide (e.g. N,N-dimethylformamide), limonene, eucalyptol, dimethyl sulfoxide, -alkylpyrrolidone (e.g. N-methylpyrrolidone, 2-pyrrolidone), liquid polyoxyethylene glycol , Methylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, butyl diglycol, dipropylene glycol, propylene carbonate, butylene carbonate, paraffin (e.g. white mineral oil, normal paraffin, isoparaffin), alkylbenzene, Alkylnaphthalene, glycerin, glycerol triacetate, sorbitol, triacetin, aromatic hydrocarbons, dearomatized aliphatic compounds, alkylbenzene, alkylnaphthalene, ketones such as methyl ethyl ketone, cyclohexanone, 2-heptanone, isophorone and 4- Hydroxy-4-methyl-2-pentanone, acetates such as ethyl acetate, benzyl acetate, isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate and isobornyl acetate, other esters, For example alkylated lactate esters, dibasic esters and γ-butyrolactone, and alcohols which may be linear, branched, saturated or unsaturated, such as phenyl ethyl alcohol, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol , Isobutyl alcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexane Ol, tetrahydrofurfuryl alcohol, diacetone alcohol and benzyl alcohol.

In addition, these solvents are glycerol esters of saturated and unsaturated fatty acids (typically C ₆ -C ₂₂ ), such as plant seeds and fruit oils (such as olive, castor, flaxseed, sesame, corn (maize), peanut, sunflower, grape seed, safflower , Cottonseed, soybean, rapeseed, coconut and palm kernel oils, and mixtures thereof, such as polyethoxylated castor oil). In addition, such solvents include alkylated fatty acids (such as methylated, ethylated, butylated), wherein the fatty acids can be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation.

In one embodiment the solvent is N,N-diethyl-3-methylbenzamide; The co-solvent is acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethyl sulfoxide, dimethylformamide, dipropylene glycol n-butyl ether, ethyl alcohol, isopropanol, methanol, phenylethyl alcohol, isopropanol, ethylene glycol mono Ethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycol, propylene glycol, N-methylpyrrolidone, 2-pyrrolidone, limonene, eucalyptol, diethylene Glycol monoethyl ether, ethylene glycol, diethyl phthalate, polyethoxylated castor oil, methyl ethyl ketone, glycofurol, ethyl-L-lactate, and mixtures of at least two of these co-solvents.

In another embodiment the co-solvent is dimethyl sulfoxide, acetone, dimethylacetamide, ethyl alcohol, dipropylene glycol monomethyl ether, methylethyl ketone, glycofurol, ethyl-L-lactate, and mixtures of at least two of these co-solvents. It is selected from the group consisting of.

In one embodiment the liquid carrier vehicle comprises N,N-diethyl-3-methylbenzamide as the solvent and the organic co-solvent is selected from acetone, ethyl-L-lactate, dimethyl sulfoxide, dimethylacetamide and glycofurol. do.

In another embodiment the organic solvent in the topical application formulation is N,N-diethyl-3-methylbenzamide and the organic co-solvent is at least of acetone, ethyl-L-lactate, dimethyl sulfoxide, dimethylacetamide and glycofurol. It is a mixture of two.

The co-solvent may be advantageously present in the composition depending on the volume/volume (V/V) to N,N-diethyl-3-methylbenzamide ratio of about 4/1 to about 1/5.

Pour-on or spot-on formulations are generally in a proportion of about 0 to about 50%, preferably about 5 to about 35%, about 5%, 10%, 15%, 20%, 25%, 30%, Acetone can be advantageously included in a proportion of 35% (percentage as volume per volume=V/V).

Pour-on or spot-on formulations are generally in a proportion of about 0 to about 60%, preferably about 5 to about 50%, about 5%, 10%, 15%, 20%, 25%, 30%, Dimethylacetamide can be advantageously included in proportions of 35%, 40%, 45%, 50% (percentage as volume per volume = V/V).

*Pour-on or spot-on formulations are generally in a proportion of about 0 to about 50%, preferably about 5 to about 35%, about 5%, 10%, 15%, 20%, 25%, 30% , Dimethylsulfoxide may be advantageously included in a proportion of 35% (percentage by volume per volume).

Pour-on or spot-on formulations are generally in a proportion of about 0 to about 50%, preferably about 5 to about 35%, about 5%, 10%, 15%, 20%, 25%, 30%, N-methylpyrrolidone can be advantageously included in a proportion of 35% (percentage by volume per volume).

Pour-on or spot-on formulations are generally in a proportion of about 0 to about 50%, preferably about 5 to about 40%, about 5%, 10%, 15%, 20%, 25%, 30%, Methyl ethyl ketone can be advantageously included in a ratio of 35% and 40% (percentage by volume per volume).

In addition, topical formulations may contain one or more additional ingredients. Examples of suitable additional ingredients are permeation accelerators, thickening agents, stabilizers such as antioxidants/preservatives, adhesion enhancers and viscosity improvers, crystallization inhibitors, UV blockers or absorbers, moisture removers and colorants. Surfactants including anionic, cationic, non-ionic and amphoteric surfactants may also be included in these formulations.

In some embodiments, topical formulations (especially pour-on or spot-on formulations) promote absorption or penetration of isoxazoline through the skin into the bloodstream, other body fluids (lymphatic fluid), and/or body tissues (fat tissue). It includes a carrier. Contemplated examples of skin penetration enhancers include, for example, dimethyl sulfoxide, isopropyl myristate, dipropylene glycol pelagonate, silicone oils, aliphatic esters, triglycerides, and fatty alcohols.

Topical application formulations may also (or alternatively) include, for example, one or more agents. These substances act as carriers that aid in the distribution of the active ingredient to the hair or skin of animal receptors. They may include, for example, isopropyl myristate, dipropylene glycol pelagnate, silicone oils, fatty acid esters, triglycerides, and/or fatty alcohols.

In addition, various expansion oil/solvent combinations, such as oil-containing solutions, alcohol-based and isopropanol-based solutions (e.g., solutions of 2-octyl dodecanol or oleyl alcohol), esters of monocarboxylic acids (e.g., isopropyl myristate) , Isopropyl palmitate, lauric acid oxalic ester, oleic acid oleyl ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate, and capro of saturated fatty alcohols having 12 to 18 carbon chains Acid esters), esters of dicarboxylic acids (e.g. dibutyl phthalate, diisopropyl isophthalate, adipic diisopropyl ester, and di-n-butyl adipate), or esters of aliphatic acids Solutions of (e.g., glycol) may be suitable. When the formulation contains a securing agent, a dispersant such as pyrrolidin-2-one, N-alkylpyrrolidin-2-one, acetone, polyethylene glycol, or ether or ester thereof, propylene glycol, or synthetic triglycerides It may be advantageous to include.

Optionally crystallization inhibitors are anionic surfactants, cationic surfactants, non-ionic surfactants, amine salts, amphoteric surfactants or polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, Benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan ester; It may be selected from the group consisting of lecithin, sodium carboxymethylcellulose, and acrylic derivatives, or mixtures of such crystallization inhibitors.

In addition, the formulation may contain antioxidants intended to inhibit oxidation in the air. Particularly preferred antioxidants are those conventional in the art and include, for example, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate or mixtures thereof.

Exemplary polymers suitable for gelling and/or adhesion (“polymeric material”) that can be used in the composition of the present invention are colloidal silicone dioxide, ethyl cellulose, methyl cellulose, methacrylic ester copolymer, carboxylated vinyl acetate , And polyvinylpropylene (PVP)/vinyl acetate copolymer, poloxamer 124, poloxamer 188, polybutene, povidone K17 and povidone K90, but are not limited thereto.

The additional components discussed above are well known to those of skill in the art and are commercially available or available through known techniques.

Topical application formulations are in a small volume of about 0.01 to 1 ml per kg, preferably about 0.05 to 0.1 ml per kg, in a total volume of 0.3 to 100 ml per animal, preferably a maximum of about 50 ml, depending on the target species. Is limited to

The volume applied for small companion animals such as dogs and cats is about 0.3 to about 6 ml, preferably about 0.4 to 2.0 ml per dose for cats and about 0.4 to 2.0 ml per dose, depending on the weight of the animal. It may be about 0.4 to about 5 ml.

Exemplary compositions for topical administration to warm-blooded animals typically include about 1% to 50% w/v of the isoxazoline compound of formula I, on a weight-to-volume basis; About 5-25% w/v of N,N-diethyl-3-methylbenzamide; About 5% to 95% v/v of a co-solvent or solvent mixture, such as DMSO alone or in combination with about 10 to 20% v/v of acetone, and/or about 10 to 20% v/v of a second co-solvent Includes.

Exemplary compositions for topical administration to warm-blooded animals typically include about 1% to 50% w/v of the isoxazoline compound of formula I, on a weight-to-volume basis; About 5-25% w/v of N,N-diethyl-3-methylbenzamide; About 5% to 95% v/v of a co-solvent or solvent mixture, such as N-methylpyrrolidone alone or in combination with about 10 to 50% v/v of acetone, and/or about 10 to 20% w/v Contains co-solvent of.

Exemplary compositions for topical administration to warm-blooded animals typically include about 1% to 50% w/v of the isoxazoline compound of formula I, on a weight-to-volume basis; About 5-25% w/v of N,N-diethyl-3-methylbenzamide; About 5% to 95% v/v of a cosolvent or solvent mixture, such as DMA alone or in combination with about 10 to 50% v/v of acetone, and/or about 10 to 20% v/v of a cosolvent. do.

Exemplary compositions for topical administration to warm-blooded animals typically include about 1% to 50% w/v of the isoxazoline compound of formula I, on a weight-to-volume basis; About 5-25% v/v of N,N-diethyl-3-methylbenzamide; About 5% to 95% v/v of a co-solvent or solvent mixture, such as DMA alone or in combination with about 10 to 50% v/v of DMSO, and/or about 10 to 20% v/v of a co-solvent. .

Exemplary compositions for topical administration to warm-blooded animals typically include about 1% to 50% w/v of the isoxazoline compound of formula I, on a weight-to-volume basis; About 5-25% w/v of N,N-diethyl-3-methylbenzamide; About 5% to 95% v/v cosolvent or solvent mixture, such as DMSO alone or in combination with about 10 to 50% v/v propylene glycol methyl ether, and/or about 10 to 20% v/v cosolvent Includes a hawk.

Exemplary compositions for topical administration to warm-blooded animals typically include about 1% to 50% w/v of the isoxazoline compound of formula I, on a weight-to-volume basis; About 5-25% w/v of N,N-diethyl-3-methylbenzamide; About 5% to 95% v/v of a co-solvent or solvent mixture, such as DMA or DMSO alone or in combination with about 10 to 50% v/v of methyl ethyl ketone, and/or of about 10 to 20% w/v Contains co-solvent.

In one embodiment of the invention the topical formulation comprises at least one isoxazoline compound of formula (I) and a macrocyclic lactone compound of avermectin or milbemycin class compound. Macrocyclic lactone compounds are natural products or semi-synthetic derivatives thereof. At least the structure of a particular macrocyclic lactone compound is closely related, for example by sharing a complex 16-membered macrocyclic lactone ring.

One compound for use within the scope of the present invention is ivermectin. Another macrocyclic lactone is moxidectin. Moxidectin, also known as LL-F28249 alpha, is known from US Pat. No. 4,916,154. Another macrocyclic lactone is selamectin. Selamectin is 25-cyclohexyl-25-de(l-methylpropyl)-5-deoxy-22,23-dihydro-5-(hydroxyimino)-abrmectin B1 monosaccharide. Another preferred compound is milbemycin, in particular milbemycin oxime. Milbemycin, or B41, is a substance isolated from fermentation broth of a milbemycin-producing strain of Streptomyces. Microorganisms, fermentation conditions and isolation procedures are described in U.S. Patent Nos. 3,950,360 and 3,984,564.

Emamectin (4"-deoxy-4"-epi-methylaminoabrmectin B1), which can be prepared as described in U.S. Patent Nos. 5,288,710 and 5,399,717, is a two homologous 4"-deoxy-4 It is a mixture of "-epi-methylaminoabrmectin Bla and 4"-deoxy-4"-epi-methylaminoabrmectin B1. Preferably, a salt of emamectin is used. Chemically, eprinomectin is known as 4"-epi-acetylamino-4"-deoxy-abrmectin B1.

For latectin, "International Nonproprietary Names for Pharmaceutical Substances (INN)" [World Health Organization (WHO) Drug Information, vol. 17, no. 4, page 278-279, (2003)].

Lepimectin is (6R,13R,25R)-5-O-demethyl-28-deoxy-6,28-epoxy-25-ethyl-13-[(Z)-[(methoxyimino)phenylacetyl]oxy ](6R,13R,25R)-5-O-demethyl-28-deoxy-6,28-epoxy-13-[(Z)-[(methoxyimino)phenylacetyl]oxy]- with milbemycin B 25-methylmilbemycin B mixture.

Most particularly preferred, the composition is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N -[( 2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (Compound A) and moxidectin; Or compound A; And selamectin, or Compound A and Milbemycin, or Compound A and eprinomectin.

Macrocyclic lactone compounds are well known to those skilled in the art and are readily available commercially or through techniques known in the art.

The effective amount of the macrocyclic lactone compound is preferably about 0.001 mg per kg body weight, preferably about 0.005 to 10 mg per kg body weight. The weight ratio of the isoxazoline compound of formula (I) and the macrocyclic lactone compound is preferably from about 5/1 to about 1/0.0001.

Other biologically active compounds useful in the formulations of the present invention include Insect Growth Regulators (IGRs), such as phenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, Since it can be selected from methoprene, pyriproxyfen, and the like, it provides both early and persistent control of parasites (at all stages of insect development, including eggs) on the animal subject as well as within the environment of the animal subject.

Most particularly preferred is that the composition comprises Compound A; And diflubenzuron or compound A and methoprene, or compound A; And pyriproxyfen, or compound A and phenoxycarb, or compound A; And fluazuron.

The effective amount of the IGR compound is preferably about 0.1 mg, preferably about 1 mg to about 10 mg per kg body weight. The weight ratio of the isoxazoline compound of formula I and the IGR compound is preferably from about 5/1 to about 0.000/1.

One aspect of the present invention is a method of permanently eradicating parasites in an environment in which an animal is under intense pressure by the parasite by administering topical formulations at a much lower frequency than daily administration. For example, it would be desirable to carry out the treatment according to the invention monthly, every 2 months, every 3 months, every 4 months, every 5 months, or every 6 months, especially on dogs, cats or ruminants (such as cattle or sheep). I can.

The period between treatments depends on factors such as the parasite being treated, the degree of infection, the type of mammal or bird and the living environment. Determining a specific duration of administration for a specific situation is within the skill level of the expert.

In some embodiments of the invention, topical formulations of isoxazoline of formula I are administered to treat a parasitic infection in an animal (or to prepare a medicament for the treatment of a parasitic infection in an animal). The term “parasitic infection” includes pathological conditions and diseases directly related to or caused by one or more ectoparasites, such as anemia and flea allergic dermatitis. In addition, the term refers to pathological conditions or diseases associated with or caused by pathogens transmitted by one or more vectors, such as Lyme disease, Elychosis (especially Kane Elychosis), and Rockysan erythema from infectious vector ticks. Includes. The phrase “treatment of parasitic infections” means that the occurrence of parasitic infections in parasitic-prone animals is partially or completely inhibited, and/or the symptoms of parasitic infections in parasitic-infected animals are reduced or completely eliminated, and/or parasites in parasitic-infected animals. It means curing the infection partially or completely. In general, the treatment of parasitic infections is achieved by controlling ectoparasitic infections by administering a formulation according to the invention comprising isoxazoline of formula I.

The present invention also relates to a method of treatment wherein the at least ancillary goal of ectoparasite control in and/or on an animal is to control ectoparasitic infection in an environment occupied by the animal (periodically or continuously). In some such embodiments, for example, the animal is a companion animal (such as a cat or dog). The environment may be, for example, a home or other shelter; room; Us; Confinement, or other means of detention; Bedding; Etc.

The topical formulations of the present invention are particularly suitable for eradicating parasites that infect mammals (including humans). Mammalian subjects include primates (e.g., monkeys), bovines (e.g. beef cattle or cows), hogs (e.g. pigs or pigs), sheep (e.g. goats or sheep), horses (e.g. horses), canines (e.g., Dogs), felines (eg, house cats), camels, deer, donkeys, water buffalo, antelopes, rabbits, and rodents (eg guinea pigs, squirrels, rats, mice, gerbils, and hamsters). Of particular note is the embodiment wherein the animals to be protected are pet dogs (ie Canis lupus familiaris) and pet house cats (ie Felis catus).

Examples of invertebrate parasites controlled by administering a topical formulation of the present invention to an animal to be protected include ectoparasites (arthropods, ticks, etc.) and endoparasites (worms such as nematodes, flukes, tapeworms, shoeworms, etc.) .

In particular, the formulations of the present invention are effective against ectoparasites including: flies, such as Haematobia (Lyperosia) irritans (horn fly), S. Stomoxys calcitrans (stable fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), Morellia simplex (Sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypoderma lineatum, Lucilia sericata , Lucilia cuprina (green blowfly), Calliphora spp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly), Culicoy Culicoides spp. (midges), Hippobosca equine, Gastrophilus instestinalis, Gastrophilus haemorrhoidalis and Gastrophilus Gastrophilus naslis; Lice, such as Bovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicola subrostratus, Heterodoxus spiniger, Lignonathus setosus and Trichodectes canis; sheep ticks such as Melophagus ovinus; mites such as Psoroptes Psoroptes spp., Sarcoptes scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp., Notoedres cati ), Trombicula spp. and Otodectes cyanotis (ear mites); mites such as Ixodes spp., Bophilus spp., Rhipicephalus spp., Ambleomma spp., Dermacentor spp., Hyaloma spp. and Haemaphysalis spp.; And fleas , Such as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dog flea).

In addition, the invention relates to kits suitable for use, for example, for carrying out the aforementioned treatment methods. In general, such kits will contain a topical formulation according to the invention comprising a therapeutically effective amount of isoxazoline of formula I and additional component(s). The additional component(s) can be, for example, one or more of the following: a diagnostic tool, instructions for administering the composition, a device for administering the composition, an excipient or other active ingredient to be administered in admixture with or in combination with the composition. Container, or memory aid (eg, a stamp affixed to a calendar reminding the animal owner of the timing of the subsequent dose administration of the composition).

As used herein and in the claims, the terms “about” and “approximately” indicate that the values are within a statistically meaningful range. Such ranges may be typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The permissible changes encompassed by the terms “about” and “approximately” depend on the particular system being studied and can be readily understood by one of ordinary skill in the art.

As used herein, the term “w/w” refers to weight/weight, the term “w/v” refers to weight/volume, and the term “mg/kg” refers to milligrams per kilogram of body weight.

Example 1

Preparation of the formulation according to the invention:

Composition C

Calculated amount, such as 7 grams of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N -[ (2,2,2-Trifluoro-ethylcarbamoyl)-methyl]-benzamide (Compound A) was weighed and injected into the flask. The required amount of excipient, such as 8 mL of DMA and 6.25 mL of DMSO was added. Compound A was dissolved under mild agitation or shaking. This solution was introduced in a final volume of 25 mL containing ethyl lactate.

Using essentially the same procedure as described above for composition C, compositions A through V of Table 2 and formulations of Table 3 were prepared. An alternative approach to manufacturing was to weigh the excipient. The required weight was calculated based on the density of each product. Alternatively, the order of addition was reversed, e.g., the excipients were blended and Compound A was introduced in a later step.

The physicochemical parameters indicating the suitability of the formulation for topical application (eg spot-on) administration were evaluated. Compositions A-V of Table 2 were tested using the following procedure.

Viscosity: Newtonian viscosity (η) was measured at 20° C. using a rotating viscometer in a double spaced cup and rotor system.

Degree of evaporation: The degree of evaporation was measured on a weight-recording balance. The sample pan was heated to 50° C. over 4 hours and the weight loss was recorded.

Expansion diameter: The diameter of three 20 μL spots of the test product on the plastic sheet was measured to measure the expansion diameter.

Absorption: After 1 day, the water absorption was measured by measuring the moisture concentration of the test product in contact with the surrounding atmosphere at a temperature of 25°C. In addition, the physical state of the test product was also recorded, such as whether it was a clear solution.

Solubility: A saturated solution, i.e., a solution of the test compound in contact with the undissolved particles of the test compound, was prepared and constantly shaken to record the temperature. After about 24 hours the content of the compound in the solvent was determined by HPLC. The content result was taken as solubility. In some cases, the content was measured again after 48 hours and the lower of the two results was taken as the solubility.

Compatibility: Binary mixtures of test compounds and excipients were prepared and stored under limited storage conditions, such as 40° C., 75% RH. Samples were analyzed for appearance, content and degradation products at the start of the study and after a limited storage period.

The physicochemical parameters of the formulations in Table 2 are summarized in Table 2a.

The results of Table 2a and in vivo experiments in which the formulations were administered to dogs show that the test formulations are suitable for topical administration of isoxazoline compounds to animals.

Comparative Example 2

Indicative of their suitability as formulations for topical application administration of conventional topical formulations and, for example, isoxazoline compound solvents proposed in WO 2009/024541 and preparing spot-on formulations for topical administration of isoxazoline compounds to animals Solubility was tested in vitro.

An overview of the details of the test formulation is shown in Table 4a (Comparative Examples 1 to 7).

At room temperature and 5° C. Compound A was insoluble in Comparative Formulations 1, 2 and 3.

Crystals/precipitation were found in comparative formulations 4 and 5a after exposing the formulation to the ambient atmosphere for a period of time.

Example 3

In vivo experiment-spot-on administration of the formulation to dogs

4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N- in a dose of 25 mg/kg body weight The formulation of Table 2 as [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (Compound A) was administered as a spot-on to dogs. Dogs were observed for local and systemic tolerance of the treatment and the aesthetics of the administration site was evaluated.

Plasma samples of all dogs were taken weekly before and 2, 4, 8 hours after administration, on the day of administration, on the 1st, 3rd, 7th and, 14th and 56th days thereafter. Plasma for Compound A was analyzed by HPLC-MS/MS.

Results: The average concentration of Compound A in dog plasma is shown in Figs. 1 to 6.

No local or systemic rejection was observed. The aesthetics to the formulation was acceptable, and only minor effects on appearance were found for a short period of time.

Example 4

In Vivo Experiment-Spot-On Administration of Formulations Containing Compound A and Moxidectin to Dogs

Dogs were spot-on dosed with Formulation N of Table 2 with a dose of 25 mg per kg body weight of Compound A and a dose of 2.5 mg per kg body weight moxidectin. Dogs were observed for local and systemic tolerance of the treatment and the aesthetics of the administration site was evaluated. Plasma samples of all dogs were taken weekly before and 2, 4, 8 hours after administration, on the day of administration, on the 1st, 3rd, 7th and, 14th and 56th days thereafter. Plasma was analyzed for compound A and moxidectin concentration.

Results: Fig. 7 shows the average plasma concentrations of Compound A and Moxidectin in dogs.

No local or systemic rejection was observed. The aesthetic was acceptable.

Example 5

Evaluation of the efficacy of the test formulation against ticks in dogs

In this evaluation, hybrid beagle dogs were used and assigned as treatment and control. Two days before dosing, each dog was infected with 50 unfed adult ticks, R. sanguineus.

On the day of administration, dogs were treated with Compound A at a dose of 25 mg/kg body weight (formulation shown in Table 1). The formulation was administered using a pipette. The dosage was applied linearly in the dorsal neck at the base of the skull.

One group was left untreated. Dogs were observed for any immediate response to treatment, rejection after treatment, skin irritation, and at the time of treatment, about 2, 4, and 8 hours after treatment administration, and at 1, 2 and 7 days. The behavior of the test formulation was observed. The dog was then observed once daily for the remainder of the study.

All ticks were removed 48 hours after treatment. The ticks removed were evaluated according to the following categories: no efficacy: survival free, survival adhesion-survival congestion/noncongestion, and death-congestion, efficacy: death, free, adhesion death noncongestion.

The tick count was changed and the geometric mean was used to calculate the% efficacy for treatment. Table 1 shows the results.

[Table 1]

Example 6

Evaluation of cosmetic effects after topical administration in various dog breeds and hair lengths and characteristics

Test formulations C and H in Table 2 were evaluated.

The study was conducted using 40 mixed adult dogs (20 per formulation) of a range of weights and ages. The formulation was administered locally on the skin between the shoulder blade and the lumbosacral region. The length of the line was determined by the dosage.

The application site and hairs were closely observed to determine whether any spot-on solutions flowed from the animals during and immediately after administration and for the integrity of the formulation. In addition, the application site was observed for traces of residue and moisture after 8, 24, 48 and 96 hours of administration. In addition to observation of the appearance of the application site, the overall appearance of the dog's fur was assessed, especially near the site of administration, the fur, such as dryness, brittle appearance, fragility, insensitivity, for signs of hair loss and appearance of residues, and of the fur and skin. The smell was evaluated.

The skin was evaluated for signs of local irritation. Also, dogs were observed for systemic tolerance.

Each evaluation variable was scored as 0 = no change, 1 = slight change, 2 = moderate change, or 3 = severe change (compared to the pre-dose score on the day of dosing).

Results: The scores are summarized in Tables A-D.

The formulation was easy to apply and did not emit any pronounced malodor. For both formulations, drying time was quick after application. Formulation C showed a tendency to produce some powdery residue in the hairs of 10 dogs at the 8 hour evaluation. As for the overall appearance at 24 hours, the site of application of 17 dogs for formulation C and 15 dogs for formulation H was not conspicuous.

Example 7

Evaluation of cosmetic effects after topical administration in various dog breeds and hair lengths and characteristics

Formulation N in Table 2 was evaluated.

The study was conducted using 38 mixed adult dogs of a range of weights and ages. The formulation was administered locally on the skin between the shoulder blade and the lumbosacral region. The length of the line was determined by the dosage.

The application site and hairs were closely observed to determine whether any spot-on solutions flowed from the animals during and immediately after administration and for the integrity of the formulation. In addition, the application site was observed for traces of residue and moisture after 8, 24, 48 and 96 hours of administration. In addition to observation of the appearance of the application site, the overall appearance of the dog's fur was assessed, especially near the site of administration, the fur, such as dryness, brittle appearance, fragility, insensitivity, for signs of hair loss and appearance of residues, and of the fur and skin. The smell was evaluated.

The skin was evaluated for signs of local irritation. Also, dogs were observed for systemic tolerance.

Each evaluation variable was scored as 0 = no change, 1 = slight change, 2 = moderate change, or 3 = severe change (compared to the pre-dose score on the day of dosing).

Results: Summarized ratings are shown in Tables E and F.

Formulation N was easy to apply and did not emit any pronounced malodor. Drying time was quick after application. As for the overall appearance at 24 hours, the application site was visible in 13 dogs, but not conspicuous in the remaining 25 dogs.

Comparative Example 8

Spot-on formulations were prepared comprising conventional topical formulations and, for example, the isoxazoline compound solvent proposed in WO2009/024541. These formulations were administered spot-on to dogs to evaluate their aesthetics after topical application administration to animals.

An overview of the details of the test formulation is shown in Table 4b.

Crystals/precipitation were found several hours later in the majority of dogs under evaluation after administration of Comparative Formulations 5b, 6 and 7. Other observations regarding aesthetics were the specific stickiness of the hair at the administration site and noticeable moisture in a few dogs.

*[Table 2]

[Table 2a]

[Table 3]

[Table 4a]

[Table 4b]

Claims (7)

4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N- in an amount of 20-50 w/v% Topical application for the treatment or prevention of parasitic infections in animals, including [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide and a veterinarily acceptable liquid carrier vehicle localized) formulation, wherein the liquid carrier vehicle comprises N,N-diethyl-3-methylbenzamide as a solvent. The topical formulation of claim 1 comprising 1 to 50 w/v% N,N-diethyl-3-methylbenzamide. The method of claim 1 or 2, further comprising an effective amount of a macrocyclic lactone compound selected from ivermectin, moxidectin, milbemycin, selamectin, emamectin, latidectin, lepimectin and salts thereof. Formulations for topical application. The insect growth regulator according to claim 1 or 2, wherein an effective amount of an insect growth regulator is selected from phenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, methoprene and pyriproxyfen Formulations for topical application further comprising a compound. It includes spot-on or pour-on administration of the topical formulation of claim 1 or 2, wherein the applied volume is 0.3 to 6 ml per dose for cats and dogs. About 0.4 to 5 ml, a method for the treatment or prevention of parasitic infections in non-human animals. The method of claim 5, wherein the topical formulation further comprises an effective amount of a macrocyclic lactone compound selected from ivermectin, moxidectin, milbemycin, selamectin, emamectin, latidectin, lepimectin and salts thereof. . The insect growth regulator according to claim 5, wherein the topical formulation is selected from phenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, methoprene and pyriproxyfen. The method further comprising a compound.

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