RU2791637C2 - Isoxazoline compositions and their use in the prevention or treatment of parasitic infestations of animals - Google Patents

Abstract

FIELD: veterinary medicine.

SUBSTANCE: invention is aimed at treatment of parasitic invasions of animals. The use of a pharmaceutical composition containing fluralaner, afoxolaner, sarolaner or lotilaner, or their salts, or their solvates, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant is proposed for obtaining a drug for administration through drinking water for the prevention or treatment of parasitic infestations of animals. Also disclosed is the use of the pharmaceutical composition for the prevention or treatment of parasitic infestations in animals after administration to animals through drinking water, therapeutic drinking water and a method for obtaining therapeutic drinking water.

EFFECT: group of inventions provides effective prevention and treatment of parasitic infestations in animals.

36 cl, 5 tbl, 5 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The invention relates to the field of pharmaceutical compositions containing isoxazoline compounds for use in animals.

BACKGROUND OF THE INVENTION

Isoxazoline compounds are known in the art, and compounds from this class are known to have excellent activity against parasitic infestations in animals.

Isoxazoline compounds and their use as antiparasitic agents are described, for example, in US patent application US 2007/0066617, and international patent applications WO 2005/085216, WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/ 003075, WO 2010/070068 and WO 2010/079077.

Although various routes of administration are known, administration of the active ingredients via drinking water systems to intensively reared animals such as pigs and poultry is effective in that it allows simultaneous administration to a large number of animals over a period of time.

Many pig and poultry farms are already equipped with the necessary devices for administering drugs through drinking water systems.

Such on-farm drinking water systems are complex systems of tanks, metering pumps, pipes, coils, machine drinkers and nipples. An average room may contain hundreds of meters of pipes with many turns and hundreds of individual cups and/or nipples.

Water in a drinking water supply system in a pigsty or poultry house follows the principles of laminar flow through pipes and coils and is subjected to so-called "tangential" forces, which will affect the flow rate. In such a complex piping system, there are significant risks for drug segregation or precipitation, of course, when it comes to water-insoluble compounds.

The effectiveness of a drug through the drinking water supply as a whole depends largely on the quality of the composition (and its stability in the drinking water supply) and the palatability of the formulation.

A suitable composition should ensure maximum availability of the active ingredient, minimum or no segregation and precipitation of the active substance in the drinking water supply, in drug pumps, nipples, cups, etc., accurate dosing and uniform distribution of the active ingredient in drinking water, and guaranteed stability of the active ingredient in the composition itself and after dilution to the target concentration in medicinal drinking water.

Such pharmaceutical compositions are not known in the prior art.

The pharmaceutical composition that has been presented in the present invention satisfies these requirements.

SUMMARY OF THE INVENTION

The present invention relates to the use of a pharmaceutical composition containing an isoxazoline compound of formula (I),

Формула (I),

Formula (I),

wherein

R ¹ \u003d halogen, CF ₃ , OCF ₃ , CN,

N = an integer from 0 to 3, preferably 1, 2 or 3,

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

T=5- or 6-membered ring 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, generally a three- or four-membered chain;

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

X \u003d 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-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl , (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

,

,

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

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

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

or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant for the preparation of a medicament for administration through drinking water for the prevention or treatment of parasitic infestations in animals.

Another aspect of the present invention is therapeutic drinking water containing a pharmaceutical composition as described above and water.

Another aspect of the present invention is a method for producing therapeutic drinking water for animals by diluting a pharmaceutical composition as described above with drinking water.

Another aspect of the present invention is therapeutic drinking water, as described above, for use in the treatment or prevention of parasitic infestations in animals.

In particular, the invention includes the use of a pharmaceutical composition containing fluralaner, afoxolaner, sarolaner or lotilaner, or salts or solvates thereof, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant, for the preparation of a medicament for administration by drinking water. water for the prevention or treatment of parasitic infestations of animals.

Preferably, fluralaner, afoxolaner, sarolaner or lotilaner is present at a concentration of 1.5 mg/ml to 100 mg/ml.

The ratio of diethylene glycol monoethyl ether and polysorbate surfactant is <50:50% w/w, preferably 25/75% w/w.

The composition according to the invention may additionally contain ethyl lactate.

In one embodiment, the polysorbate surfactant is polysorbate 80.

Further, the invention includes the use of a pharmaceutical composition containing fluralaner, afoxolaner, sarolaner or lotilaner, or salts or solvates thereof, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant, for the prevention or treatment of parasitic infestations in animals after administration to animals through drinking water.

Preferably, fluralaner, afoxolaner, sarolaner or lotilaner is present at a concentration of 1.5 mg/ml to 100 mg/ml.

Further, the ratio of diethylene glycol monoethyl ether and polysorbate surfactant may be <50:50% wt./mass., preferably 25/75% wt./mass.

In one of the embodiments of the invention, the composition further contains ethyl lactate.

In addition, the polysorbate surfactant may be polysorbate 80.

Preferably, the animals are selected from pigs and poultry.

In one embodiment of the invention, the animals are laying hens.

Further, said parasitic infestation may be a mite infestation.

More specifically, a tick infestation is an infestation by a Dermanyssus spp . or an Ornithonyssus spp..

Further, the invention is a therapeutic drinking water, which contains a mixture

a pharmaceutical composition containing fluralaner, afoxolaner, sarolaner or lotilaner, or a salt or solvate thereof, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant, and

water.

Preferably, the medicinal drinking water of the invention contains 0.001 to 1 mg/ml of fluralaner, afoxolaner, sarolaner or lotilaner.

The ratio of diethylene glycol monoethyl ether and polysorbate surfactant in said composition is <50:50% w/w, preferably 25/75% w/w.

Further, the invention relates to therapeutic drinking water, in accordance with the above, where the composition additionally contains ethyl lactate, and the polysorbate surfactant is polysorbate 80.

Preferably, the animals to which the medicinal drinking water of the invention is administered are selected from pigs and poultry.

In one embodiment of the invention, the animals are laying hens.

Said parasitic infestation may be a mite infestation.

More specifically, a tick infestation is an infestation by a Dermanyssus spp . or an Ornithonyssus spp..

Additionally, the invention includes a process for producing said medicinal drinking water, wherein the pharmaceutical composition is diluted by injection through a dosing pump system into a water supply system or by mixing with water in a drug reservoir.

DETAILED DESCRIPTION OF THE INVENTION

It has been shown by the inventors that the pharmaceutical compositions of the present invention, which contain an isoxazoline compound as described below, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant, are stable and effective in prophylaxis (prevention) and therapy (treatment). ) parasitic invasions of animals.

In addition, it has been shown that such compositions can be used to prepare medicinal water that is sufficiently stable and can be evenly distributed in the system to ensure that an effective amount of the isoxazoline compound is administered to animals through the drinking water supply.

An isoxazoline compound for use in the present invention may be represented by the formula (I):

Формула (I),

Formula (I),

Where

R ¹ \u003d halogen, CF ₃ , OCF ₃ , CN,

n = an integer from 0 to 3, preferably 1, 2 or 3,

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

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

Y \u003d methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C \u003d S, two adjacent Y radicals together form a chain CH-CH \u003d CH-CH, N-CH \u003d CH-CH, CH-N \u003d CH-CH , CH-CH=N-CH or CH-CH=CH-N, HC=HC-CH, CH-CH=CH, CH=CH-N, N-CH=CH;

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

X \u003d 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-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl , (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

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

or

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

,

,

where Z ^A = hydrogen, halogen, cyano, halomethyl (CF ³ ).

In one preferred embodiment, in formula (I), T is selected from

,

,

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

In a preferred embodiment, in formula (I), Q is selected from

,

,

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

Z ^B =

Z ^D =

Preferred isoxazoline compounds of formula (I) for use in the present invention are:

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

Particularly preferred isoxazoline compounds for use in the present invention are

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

A more preferred isoxazoline compound for use in the present invention has the formula (II),

Формула II,

formula II,

wherein

R ^1a , R ^1b , R ^1c are independently 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 is methyl, bromine, Cl, F, CN or C(S)NH ₂ , and

Q is as described above.

In another preferred embodiment, in formula (II), 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 a preferred embodiment, the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N -[(2,2,2- trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3 - USAN fluralaner).

In another embodiment, the isoxazoline compound is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2 -methylbenzamide (CAS RN 928789-76-8).

In another embodiment, the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (CAS RN 1164267-94-0), which was disclosed in WO 2009/0080250.

In another preferred embodiment, the isoxazoline compound is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2- oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (CAS RN 1093861-60-9, USAN - afoxolaner), which was disclosed in WO 2007/079162.

In another embodiment, the isoxazoline compound is 1-[5'-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]spiro [azetidine-3,1'(3'H)-isobenzofuran]-1-yl]-2-(methylsulfonyl)ethanone - (Sarolaner) (CAS RN 1398609-39-6).

In another embodiment, the isoxazoline compound is 5-((5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl)-3-methyl-N- (2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-thiophenecarboxamide - (Lotilaner INN) (CAS RN 1369852-71-0).

In another embodiment, the isoxazoline compound 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 RN 1231754-09-8), which was disclosed in WO 2010/070068.

The method (or use) of the present invention involves the use of racemic mixtures, for example, equal amounts of enantiomers of such isoxazoline compounds as described above. In addition, the method of the present invention includes isoxazoline compounds that are enriched relative to the racemic mixture in an enantiomer of formula 1. Also included are substantially pure enantiomers of such isoxazoline compounds.

In enantiomeric enrichment, one enantiomer is present in greater amounts than the other, and the degree of enrichment can be determined by the expression of enantiomeric excess ("ee"), which is defined as (2x-l)-100%, where x is the mole fraction of the dominant enantiomer in the mixture (for example, ee 20% corresponds to an enantiomeric ratio of 60:40). Preferably the compositions for use according to the present invention have at least 50% enantiomeric excess; more preferably at least 75% enantiomeric excess; even more preferably at least 90% enantiomeric excess; and most preferably at least 94% enantiomeric excess of the more active isomer. Of particular note are enantiomerically pure embodiments of the more active isomer.

The isoxazoline compounds described above may contain additional chiral centers. The method of this invention includes racemic mixtures as well as enriched and substantially pure stereoconfigurations at these additional chiral centers.

Reference to an isoxazoline compound in this specification includes enantiomers, salts and solvates, as well as N-oxides, which can be prepared by conventional methods.

The isoxazoline compound as described above is typically present in the composition of the present invention in an amount of from about 0.001 mg/mL to about 100 mg/mL.

The preferred pharmaceutical composition of the present invention is a concentrated solution. Such a concentrated solution contains from 1.5 mg/ml to 100 mg/ml of an isoxazoline compound, especially fluralaner.

The compositions according to the present invention have particularly advantageous properties such as long-term stability after storage and no precipitation of the isoxazoline compound upon dilution of such a composition in water.

The pharmaceutical composition of the present invention contains a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant.

Such a carrier must be substantially pharmaceutically or veterinarily pure and its components must be non-toxic in the amounts used and must be compatible with the isoxazoline compounds.

Diethylene glycol monoethyl ether is used as a solvent in such a carrier. Diethylene glycol monoethyl ether or Transcutol (CAS No. 31692-85-0) is a compound of formula (III)

R ₁ --[O--(CH ₂ ) ₂ ] _x --OR ₂ Formula (III),

where R ₁ \u003d C ₂ H ₅ , R ₂ \u003d H and x \u003d 2.

Products containing diethylene glycol monoethyl ether are, for example, those known and commercially available, for example under the trade name Transcutol® from Gattefosse, (Saint-Priest, France), in particular Transcutol® V, P and HP products.

Synonymous names for diethylene glycol monoethyl ether or Transcutol are: -dioxa-1-octanol, 3,6-dioxa-1-octanol, 3,6-dioxaoctan-1-ol, ethyl diethylene glycol, APV, carbitol, carbitol cellosolve, carbitol solvent, DEGEE, DEGMEE, diethylene glycol ethyl ether, diethylene glycol monoethyl ether , diglycol monoethyl ether, dioxytol, dovanol, dovanol 17, dovanol DE, ectasolv DE, ethanol, 2,2'-oxybis-, monoethyl ether, ethanol, 2-(2-ethoxyethoxy)-, diethylene glycol monoethyl ether, ethoxy diglycol, ethoxy diglycol , ethyl carbitol, ethyl diethylene glycol, ethyldigol, ethyl diethylene glycol, ethyl carbitol.

Diethylene glycol monoethyl ether is typically present in the composition of the invention in an amount of from about 10% to about 75% by weight of the carrier.

In some embodiments, diethylene glycol monoethyl ether is present in an amount of from about 15% to about 60% by weight, from about 20% to about 55%, or from about 25% to about 50% by weight, or about 12.5%, 25% or 37.5% by weight of the carrier.

In one embodiment, the composition contains at least one additional solvent.

In one embodiment, the composition further comprises ethyl lactate. Ethyl lactate, also known as lactic acid ethyl ester, is a monobasic ester formed from lactic acid and ethanol.

In some embodiments, ethyl lactate is present in an amount of from about 10% to about 50% by weight, or from about 10% to about 40% by weight, or about 12.5%, 25%, or 37.5% by weight of the carrier.

Preferably, the ratio of diethylene glycol monoethyl ether and an additional solvent such as ethyl lactate is about 75%/25% wt./mass.

In one embodiment, such additional solvent is a pyrrolidone solvent such as 2-pyrrole.

In some embodiments, 2-pyrrole is present in an amount of from about 10% to about 30% by weight, or about 12.5% or 25% by weight of the carrier.

Polysorbate surfactants have shown favorable performance in the composition of the present invention. Typically, one or a combination of more than one polysorbate surfactant may be present.

Upon contact with water, the polysorbate surfactant creates micelles around the isoxazoline compound, which is solubilized in diethylene glycol monoethyl ether and retains the solubilized isoxazoline compound in an aqueous medium.

Polysorbate surfactant (sorbitol ester, poly(oxy-1,2-ethanediyl) derivative, tween) is a water-soluble non-ionic surfactant consisting of esters and esters of alkoxy acids derived from hexahydric alcohols, alkylene oxides and fatty acids adding polyoxyethylene chains to the hydroxyl of sorbitol and hexitrol anhydrides (hexitanes and hexides) derived from sorbitol and then partial esterification with common fatty acids such as lauric, palmitic, stearic and oleic acids.

In one embodiment, the polysorbate surfactant is selected from one or more of Tween 20, Tween 40, Tween 60, and Tween 80, also known in the pharmaceutical industry as Polysorbate 20, Polysorbate 40, Polysorbate 60, and Polysorbate 80. Polysorbate 20 (polyoxyethylated sorbitan monolaurate) is an ester of laurate, polysorbate 60 (polyoxyethylated sorbitan monostearate) is a mixture of esters of stearate and palmitate; and polysorbate 80 (polyoxyethylated sorbitan monooleate) is an oleate ester.

Such polysorbate surfactants are commercially available and/or can be prepared by methods known in the art.

In one preferred embodiment, the polysorbate surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate, Tween 80), chemically named polyoxyethylene (20) sorbitan monooleate, for example, available from ICI Specialty Chemicals.

The polysorbate surfactant is present in the composition in an amount of from about 5% to about 89% by weight of the carrier.

In some embodiments, the concentration of the polysorbate surfactant is from about 30% to about 80% by weight, from about 50% to about 75% by weight, or about 75% by weight of the carrier.

The ratio of diethylene glycol monoethyl ether to polysorbate surfactant is <50:50% w/w, preferably 15/85, 20/80, 25/75, 30/70, 35/65, 40/60% w/w wt. In one embodiment, the implementation of the ratio is preferably approximately 25/75% wt./mass. It has been shown to lead to particularly stable pharmaceutical compositions.

In addition, the carrier may contain other inactive ingredients or excipients that are known to the person skilled in the art, for example, as described in the source "Gennaro, Remington: The Science and Practice of Pharmacy" (20th Edition, 2000), incorporated herein by reference. .

Optionally, the pharmaceutical composition may also contain an antifoam agent, such as, for example, 30% USP simethicone emulsion, sodium oleate, sodium caprylate, or mixtures thereof.

The antifoam agent is present at a concentration sufficient to prevent foaming when the composition of the present invention is diluted with water. The simethicone emulsion may be present at a concentration of from about 0.001% by weight to about 0.005% by weight of the carrier.

Optionally, the pharmaceutical composition may also contain a preservative. The preservative is a preservative known to those skilled in the art and may be, for example, benzyl alcohol, butylparaben sodium, methylparaben sodium, propylparaben sodium, and mixtures thereof. It is typically present in an amount of from about 0.01% to about 3% by weight of the carrier.

Optionally, the pharmaceutical composition may also contain an antioxidant. The antioxidant is an antioxidant known to those skilled in the art and may be, for example, butylated hydroanisole, butylated hydrotoluene, tocopherol and its derivative as α-tocopherol polyethylene glycol succinate, and mixtures thereof. It is typically present in an amount of from about 1% to about 10% by weight of the carrier.

One aspect of the present invention is the use of a composition according to the invention for the manufacture of a medicament for the prevention or treatment of a parasitic infestation in an animal.

By "treating" or "treating" or "treatment" is meant the use or administration of a composition of the invention to an animal that has a parasitic infestation to eliminate the parasite or reduce the number of parasites infecting the animal.

The effect of the composition of the present invention may be, for example, ovicidal, larvicidal and/or an effect on adults only, or a combination thereof. The effect can manifest itself directly, i.e. by killing the parasites either immediately or after some time has elapsed, such as when molting occurs, or by destroying their eggs, or indirectly, such as by reducing the number of eggs laid and/or the hatching rate.

"Prophylaxis" or "prevention" means that new infestation of animals with parasites is prevented by killing the adult parasites and any developmental/larval stages that are capable of infecting the host, before infecting the host or immediately after infecting the protected host, or by preventing the generation of offspring of the parasites, e.g. , reducing the number of eggs laid and/or the rate of hatching from eggs.

The term "effective amount" means the dosage or amount of an isoxazoline compound that is required to partially reduce or reduce the number of parasites on an animal and/or in the animal's environment, for example, a house/building, and/or to inhibit the development of a parasitic infection on an animal in whole or in part. .

This value is easily determined by observing or detecting the abundance of parasites either on the animal or in the environment of the animal (for example, using a trap) both before and after the administration of an isoxazoline compound through the drinking water to such animals, for example, the number of parasites is reduced after the first administration by 5 % to about 100%.

Therefore, one aspect of the present invention is a pharmaceutical composition of the present invention containing such a composition for use in the prevention or treatment of parasitic infestations. Such parasitic infestations can be either ectoparasites or endoparasites.

In one embodiment, the parasitic infestation being prevented or treated is an ectoparasitic infestation. Specific examples of ectoparasites include, but are not limited to, fleas ( Ctenocephalides felis , Ctenocephalides spp ., and the like), mites ( Rhipicephalus spp ., Ixodes spp ., Dermacentor spp ., Amblyomma spp., Haemaphysalis spp., Boophilus spp., and the like), and mites ( Demodex spp .). , Sarcoptes spp., Otodectes spp., Cheyletiella spp., Dermanyssus spp., Ornithonyssus spp. and the like), lice ( Trichodectes spp ., Felicola spp., Linognathus spp. and the like), mosquitoes ( Aedes spp., Culex spp., Anopheles spp. and the like), and flies ( Hematobia species, including Haematobia irritans , Musca species, Stomoxys species, including Stomoxys calcitrans , Dermatobia species, Cochliomyia species, and the like).

In particular, the composition according to the present invention can be administered to all animal species in need of treatment or prevention of parasitic infections, such as pigs, cattle, horses, goats, sheep, dogs, cats, birds and fish.

In one embodiment, the animal is livestock such as pigs, cattle, goats, sheep, or poultry.

In another embodiment, the animal is a pet such as dogs, cats or horses. In another embodiment, the animal is a poultry or a pig.

The composition of the present invention is preferably administered via systemic routes. "Systemic administration" is administration to a site remote from the site where at least a portion of the target parasites reside.

When administered systemically, at least a portion of the compound reaches the target parasite via the recipient animal's blood, other body fluids (lymphatic fluid), and/or tissues (eg, skin or adipose tissue).

Typically, the parasite ingests the compound along with the recipient animal's blood, other body fluids, and/or tissues.

Systemic administration may be in several forms, such as oral, parenteral or topical.

The pharmaceutical composition may be administered parenterally, for example by intramuscular injection, intravenous injection or subcutaneous injection.

Alternatively (or additionally), the composition of the present invention may be systemically administered topically using a transdermal formulation (ie, a formulation that passes through the skin).

Such a transdermal formulation may, for example, be in the form of a solution for treatment, spot application, flow application, or spray application. Especially in the case of a spray formulation, the pharmaceutical composition may be diluted with water to form a spray formulation.

Alternatively, the pharmaceutical composition may be administered as a bath or treatment solution, for example for sheep or cattle. In order to prepare such a bath or treatment solution composition, the pharmaceutical composition is diluted with water.

The pharmaceutical composition of the present invention can be diluted directly with water, or a pre-diluted (micellar) solution as described below is diluted with a certain volume of water to an effective (amount) concentration of the isoxazoline compound in water or until the desired route of administration is reached.

A pre-diluted (micellar) solution can be obtained from the pharmaceutical composition as described above (concentrated solution) by mixing with a certain volume of water. This pre-diluted solution can be further diluted 1 to 5 times. Such a pre-diluted solution contains from 1 to 85% vol./about. water, mainly 1, 5, 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80 or 85%. Such a solution can be administered to animals in the form of therapeutic drinking water.

In some embodiments, the composition of the present invention is systemically administered via the oral route in unit dosage form such as, for example, solution, suspension (aqueous or non-aqueous), emulsion (oil-in-water or water-in-oil type), elixir, syrup or liquid dosage form for oral administration.

One preferred form of administration of an oral dosage unit form is an oral liquid dosage form, which is administered, for example, by means of an "infusion syringe" through the mouth of animals, mainly ruminants, such as sheep, goats or cattle, mainly sheep. .

Alternatively, oral administration can be via the recipient animal's food or drinking water, for example, for food, it can be thoroughly dispersed with the recipient animal's normal food, used as a top dressing, or as a liquid that is added to the finished food.

In one preferred embodiment, the composition is orally administered through drinking water. Therefore, the present invention also relates to a pharmaceutical composition as described herein for use in the prevention or treatment of parasitic arthropod infestations in animals.

The examples show (Example 5) that the pharmaceutical composition can be used to effectively control parasitic arthropod infestations in animals.

Example 5 shows that administration of a pharmaceutical composition of the present invention containing an isoxazoline compound as described herein, in this case fluralaner, through drinking water to poultry, resulted in a 99% suppression of red bird mites for at least 15 days. By such parasite suppression, the life cycle of such parasitic arthropods can be interrupted and the establishment of a significant new population in the production unit can be prevented during the entire production cycle.

In one embodiment, these animals are laying hens that produce eggs for human consumption. Such a pharmaceutical composition is also referred to as a "concentrated pharmaceutical composition" or as a "concentrated solution".

Such pharmaceutical compositions can be obtained by methods known in the art. These methods include, for example, a variety of known mixing, dissolving and emulsifying methods.

In a preferred embodiment, the pharmaceutical composition is for use in the preparation of therapeutic drinking water for administering a drug to an animal via the animal's drinking water.

Thus, another embodiment of the present invention provides therapeutic drinking water containing a mixture of a pharmaceutical composition as described above and water.

Medicated drinking water is generally drinking water that contains the pharmaceutically active ingredient and water.

Therapeutic drinking water is prepared by mixing and diluting an amount (volume) of the pharmaceutical composition as described above with water to a concentration of the isoxazoline compound that provides an effective amount of the isoxazoline compound for a number of treated animals with a volume of drinking water that substantially corresponds to the volume to be consumed by such animals during the treatment period.

A pre-diluted (micellar) solution, which can be used in the preparation of medicinal drinking water as described above, can be obtained from a pharmaceutical composition as described above (concentrated solution) by mixing with a certain volume of drinking water.

Such a pre-diluted solution can be further diluted 1 to 5 times to obtain medicinal drinking water. This pre-diluted solution contains from 1 to 85% vol./about. water, mainly 1, 5, 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80 or 85%.

One aspect of the present invention is a method for producing therapeutic drinking water, wherein the pharmaceutical composition is diluted by injection through a metering pump system into a water supply system or by mixing with water in a drug reservoir.

Via therapeutic drinking water, the pharmaceutical composition as described above can be delivered to the target animal via the selected drinking water supply by mixing and diluting the composition with drinking water in a central water tank or in a separate drug and storage tank.

Alternatively, therapeutic drinking water can be obtained by injecting a composition according to the invention continuously into a high or low pressure drinking water distribution ring system using a metering dispenser or a metering pump system or a drug dispenser system.

Dosing pump systems operate a pump that delivers metered amounts of concentrate to the water pipes at a typical dilution of 1-5%.

Within dosing pump systems, it is possible to use electronic dosing pump systems such as Buerkert's KONTI-DOS or mechanical dosing pumps such as dosing pumps with DOSATRON® hydraulic motor, DOSMATIC® hydraulic drive, proportional medicators. The variety of field installations also concerns the water supply systems themselves: dead-end or closed loop systems of various lengths with different pipe materials (e.g. PVC, galvanized iron) and drinkers that are adapted to the target animals, such as bell drinkers, nipples.

In one embodiment, the pharmaceutical composition may be used to treat or prevent parasitic infestations in animals, especially farm animals (eg, cattle, poultry, and pigs), with isoxazoline compounds, eg, fluralaner, through drinking water systems.

The final concentration of the isoxazoline compound in therapeutic drinking water depends on the effective amount, the animal's body weight, the animal's water intake, and the treatment period. In general, the effective amount per kg body weight of treated animals will depend on the type of parasitic infection being treated and is known in the art.

The medicator uses, for example, 10 ml of a pharmaceutical composition as defined above (concentrated composition), and further diluted with water at a ratio of approximately 1:200 to obtain medicinal drinking water having a concentration of an isoxazoline compound, such as fluralaner, from 0.001 to approximately 1 mg/ml, especially from about 0.05 to about 0.5 mg/ml.

In one embodiment, the medicinal water has a concentration of 0.002 to 0.2 mg/ml of the isoxazoline compound.

In one specific embodiment, for a particular isoxazoline compound of fluralaner, the concentration in therapeutic drinking water is calculated to provide a target amount of fluralaner per body weight (BW) of the poultry being treated in the range of about 0.1 mg to about 2 mg of fluralaner per kilogram of body weight in a day.

This amount is present in the volume of drinking water normally consumed by the treated poultry during a treatment period of 2 to 24 hours, preferably 4 to 5 to 8 hours.

The pharmaceutical composition can be made available during the treatment period for one animal; or at the same time for a group of animals or for all animals in the same room (house) or farm through medicinal drinking water.

Administration of the pharmaceutical composition via medicinal drinking water, as previously defined, is particularly beneficial to poultry and pigs. In the case of poultry, it is especially useful for chickens and turkeys.

Administration of the pharmaceutical composition via medicated drinking water, as previously defined, is particularly useful for types of hens that are kept on a commercial scale, such as laying hens, rearing of hens or replacement chicks, breeding hens, and rearing of broiler hens and breeding birds.

However, administration of the pharmaceutical composition through therapeutic drinking water, as previously defined, can also be used on other types of poultry such as, for example, turkeys, geese, ducks, pigeons, quails or pheasants.

Administration to poultry kept for breeding or laying eggs that are kept longer than about 8 weeks is preferred. This includes poultry that do not currently (yet) lay eggs (such as, for example, chicks). Particularly preferred is the administration to laying hens.

The term "laying hen" or "laying hen" is a general term for adult female hens, hen chicks ( Gallus domesticus ), which are primarily kept for oviposition. Such eggs are commonly used for consumption as human food.

The frequency of treatment with the pharmaceutical composition via therapeutic drinking water depends on the parasite being treated or prevented (and its biological life cycle) and the production cycle of the host animal being treated.

The pharmaceutical composition of the present invention is administered via therapeutic drinking water at least once or twice during the production cycle of the host animal to be treated (eg laying period in the case of laying hens).

By thus administering the pharmaceutical composition through medicinal water, a higher efficacy against parasites can be achieved, since different stages of the life cycle of parasites can be influenced. With such an administration scheme, the parasite population can be reduced to a level that causes only minimal injury to the animals and minimal loss of production.

For some parasites, not all stages of the parasite can be affected by a single administration of the pharmaceutical composition through therapeutic drinking water because certain stages of parasites are either not fed to the animal or are not sufficiently controlled by administration of the pharmaceutical composition through therapeutic drinking water.

With the introduction of the second dose of the pharmaceutical composition through medicinal drinking water, parasites that have developed (after the life cycle of parasites) from non-susceptible stages, or stages of parasites that are difficult to influence, for example, those that have matured from juvenile stages of parasites, can be affected. (such as eggs, nymphs or pupae) during this period.

It is particularly preferred to administer the pharmaceutical composition via medicinal drinking water at intervals of approximately 7 days or 14 days (depending on the life cycle of the parasite and the production cycle of the host animal) once or twice during the production cycle. Particularly preferred is administration at intervals of 7 days.

In one embodiment, the pharmaceutical composition is administered via therapeutic drinking water to treat or prevent mite infestation. Some mites migrate from birds, rodents, food material, plant material and house dust and can attack and irritate animals and humans. There are different categories of mites, including northern chicken mites ( Ornithonyssus sylviarum ), red bird mites ( Dermanyssus gallinae ), iron mites ( Demodex folliculorum ), scabies mites or itch mites ( Sarcoptes spp ., Cheyletiella spp., Psorioptes spp.).

In a preferred embodiment, the tick infestation is a tick infestation of a domestic bird, especially a Dermanyssus species (eg D. gallinae ) and/or an Ornithonyssus species, especially Ornithonyssus sylviarum .

In one embodiment, administration of a pharmaceutical composition through treated drinking water according to the invention controls the stages of parasitic arthropods, as described above, that are present in the poultry environment. The stages of parasitic arthropods can be all stages of the life cycle that are known to those skilled in the art, ie both juvenile stages (development/larval stage) and stages of the adult insect.

In one embodiment, administration of a pharmaceutical composition through therapeutic drinking water according to the invention combats arthropods in poultry environments, and especially broiler chickens, which generally do not infect animals directly, but do harm animals such as, for example, darklings.

EXAMPLES

Example 1

Preparation of a concentrated solution

The compositions were obtained in accordance with the following procedure:

The required amount of surfactant and solvent was weighed into the appropriate containers and the excipients were poured into the process vessel and weighed again to enter the required amounts. The mixture was stirred until complete homogenization. The active ingredient (isoxazoline compound) was added to the surfactant/solvent mixture while stirring with a deflocculating paddle, and the mixture was stirred with a deflocculating paddle until the active ingredient was completely dissolved.

Using this method, the following compositions (concentrated solutions) were obtained containing 1% wt./mass. Fluralaner:

Component Composition (%w/w) Transcutol V 25% Twin 80 75%

Component Composition (%w/w) Ethyl lactate 12.5% Transcutol HP 12.5% Twin 80 75%

Component Composition (%w/w) Ethyl lactate 25% Transcutol HP 25% Twin 80 50%

Component Composition (%w/w) Ethyl lactate 37.5% Transcutol HP 37.5% Twin 80 25%

Component Composition (%w/w) Solufor P 12.5% Transcutol HP 12.5% Twin 80 75%

Component Composition (%w/w) Solufor P 25% Transcutol HP 25% Twin 80 50%

The stability of the concentrated solution in 10 ml glass tubes was examined at 25°C/60% RH and 40°C/75% RH for 12 months. The solution was stable for at least 12 months at 25°C/60% RH and 40°C/75% RH.

Example 2

Obtaining a pre-diluted (micellar) solution

Pre-diluted solutions were prepared by preparing a solution of 10% wt./mass. fluralaner either in Transcutol V or in a mixture of Transcutol V/ethyl lactate in a 10 ml glass vial and addition of surfactant and shaking. Thereafter, purified water was added to the solvent/surfactant mixture and shaken.

The stability of a dilute solution of fluralaner was studied at 1 μg/ml (Tween 80/Transcutol V 75/25 10 ml glass tube). Solutions were stable for 2 days at 25°C/60% RH and at least 15 days at 2-8°C.

The following pre-diluted solutions were prepared and tested for solution stability (precipitation). The pre-diluted solutions were monitored at t=0 and one aliquot was stored in the refrigerator at 2-8°C and one at 40°C/75% RH for 28 days. The stability of the solution (precipitate) was assessed visually on days D0, D1, D2, D5, D7, D14, D21 and D28.

The studied formulations are shown in Table 1 below: TRV = Transcutol V, EL = Ethyl lactate

Fluralaner concentration mg/g Solvent
TRV= Transcutol V, EL= Ethyl lactate Surface-active substance Water 99 10% EL/TRV 89% Twin 80 1% 99 10% TRV 89% Twin 80 1% 95 10% EL/TRV 85% Twin 80 5% 95 10% TRV 85% Twin 80 5% 90 10% EL/TRV 80% Twin 80 10% 90 10% TRV 80% Twin 80 10% 80 10% EL/TRV 70% Twin 80 20% 80 10% TRV 70% Twin 80 20% 70 10% EL/TRV 60% Twin 80 thirty% 70 10% TRV 60% Twin 80 thirty% 60 10% EL/TRV 50% Twin 80 40% 60 10% TRV 50% Twin 80 40% 50 10% EL/TRV 40% Twin 80 50% 50 10% TRV 40% Twin 80 50% 45 10% EL/TRV 35% Twin 80 55% 45 10% TRV 35% Twin 80 55% 45 20% EL/TRV 70% Twin 80 10% 40 10% EL/TRV 30% Twin 80 60% 40 10% TRV 30% Twin 80 60% 40 20% EL/TRV 60% Twin 80 20% 40 20% TRV 60% Twin 80 20% 35 10% TRV 25% Twin 80 65% 35 10% EL/TRV 25% Twin 80 65% 35 20% EL/TRV 50% Twin 80 thirty% 35 20% TRV 50% Twin 80 thirty% thirty 10% EL/TRV 20% Twin 80 70% thirty 10% TRV 20% Twin 80 70% thirty 20% EL/TRV 40% Twin 80 40% thirty 20% TRV 40% Twin 80 40% thirty 30% EL/TRV 60% Twin 80 10% thirty 30% TRV 60% Twin 80 10% 25 10% EL/TRV 15% Twin 80 75% 25 10% TRV 15% Twin 80 75% 25 20% EL/TRV 30% Twin 80 50% 25 20% /TRV 30% Twin 80 50% 25 30% EL/TRV 45% Twin 80 25% 25 30% TRV 45% Twin 80 25% 20 10% TRV 10% Twin 80 80% 20 10% EL/TRV 10% Twin 80 80% 20 20% EL/TRV 20% Twin 80 60% 20 20% TRV 20% Twin 80 60% 20 30% EL/TRV 30% Twin 80 40% 20 30% TRV 30% Twin 80 40% 20 40% EL/TRV 40% Twin 80 20% 20 40% TRV 40% Twin 80 20% 15 10% TRV 5% Twin 80 85% 15 10% EL/TRV 5% Twin 80 85% 15 20% EL/TRV 10% Twin 80 70% 15 20% TRV 10% Twin 80 70% 15 30% EL/TRV 15% Twin 80 55% 15 30% TRV 15% Twin 80 55% 15 40% EL/TRV 20% Twin 80 40% 15 40% TRV 20% Twin 80 40% 15 50% EL/TRV 25% Twin 80 25% 15 50% TRV 25% Twin 80 25%

Results:

Stability study of dilute solutions of fluralaner in ethyl lactate/Transcutol V/Tween 80/purified water: No precipitation of fluralaner was observed in dilute solutions within 5 days of dilution, except for diluted solutions of EL/TRV-TW80'-W-40-20-40 , which precipitated on day 5 but not during any other observations during the 28 day period.

Stability study of dilute solutions of Transcutol V/Tween 80/Purified Water: Only one dilute solution of TRV-TW80-W-10-5-85 precipitated on day 5 at 2-8°C and 40°C/75% RH.

Example 3

Stability of medicinal drinking water

The stability of a diluted solution of Fluralaner was evaluated at 1 μg/ml, 2 μg/ml, 10 μg/ml and 20 μg/ml (Tween 80/Transcutol V 75/25 in 25 m tube (PE material)). The solutions were stable for 4 hours (sham treatment).

Example 4

Technological research

The study was carried out in a commercial poultry house for approximately 36,000 replacement chicks with 4 batteries, each with 3 levels. 4 PVC dead-end pipes for water supply (78 m long) supplied water for each battery.

Drinking nipples (large "screw nipple" and "cap" type plugs fitted with a "one shoulder" plastic drip cup) were mounted on water pipes. In this manufacturing facility, delivery of the concentrated formulation to drinking nipples was evaluated using both a metering pump system and a drug reservoir.

a) Dosing pump

The dosing pump and its container for the concentrated solution were mounted in a water hose coming out of the water supply pipe and ending in a water tank into which 105 liters were measured.

The metering pump was set to an injection rate of 5%. The container for the concentrated solution was filled with a total of 8.8 L (175 x 0.05 [5%]).

After the container was filled, a calculated volume of 193 ml of the concentrated composition was poured into the container and then mixed.

The dosing pump was connected to a water distribution pipe and a pipe system filled with medicinal water.

b) Medicine tank

The drug reservoir was filled with 175 liters of tap water.

A calculated volume of 193 ml of the concentrated composition was poured into a container and then stirred.

The drug reservoir was connected to a water distribution pipe and a pipe system filled with medicinal water.

None of the animals were in cages. Therefore, the water lines were opened every 10 minutes to simulate a continuous (periodic) flow of drinking water. In each outlet, 7.3 liters of medicinal water was left to drain into the dead end of the pipe.

Medicated water samples were taken from 6 drinking nipples: the first and last drinking nipple in the drinker line, and from 4 equally spaced drinking nipples at predetermined time points, with a maximum of 4 hours, and analyzed for fluralaner concentration.

Results:

table 2
In a drug reservoir system, concentration of Fluralaner in drinker nipples - percentage of nominal concentration: 11.0 µg/ml = 100% T30 min T60 min T 120 min T 180 min T 240 min Nipple 1 -5 -4 -4 -5 -10 Nipple 2 -7 -5 -4 -5 -4 Nipple 3 -5 -4 -4 -4 -4 Nipple 4 -6 -5 -4 -4 -3 Nipple 5 -8 -4 -4 -4 -6 Nipple 6 -6 -6 -4 -5 -4

Table 3
In the dosing pump system, the concentration of Fluralaner in the nipples of the drinkers is the percentage of the nominal concentration: 9.7 µg/ml = 100% T30 min T60 min T 120 min T 180 min T 240 min Nipple 1 -10 -10 -9 -9 -9 Nipple 2 -9 -14 -12 -9 -9 Nipple 3 -9 -10 -10 -14 -14 Nipple 4 -12 -16 -14 -10 -10 Nipple 5 -12 -10 -eleven -10 -10 Nipple 6 -26 -10 -eleven -eleven -10

The concentration of fluralaner in drinking water remains constant over time and along the drinking water supply line, as a deviation of about 20% is generally acceptable with this form of administration (up to 4 hours).

Example 5

Efficiency Study

The efficacy of fluralaner, administered orally via medicated drinking water, against artificially induced red bird mite ( Dermanyssus gallinae ) infestation in laying hens was investigated. Groups A-D (n=6) were treated with doses of 2, 1 and 0.5 mg fluralaner/kg body weight at a time or 1 mg fluralaner/kg body weight in divided doses (0.5 mg/kg body weight 2 times).

Materials and methods:

The consumption of drinking water in each of the groups was measured three days before administration to calculate the average daily water intake. Medicated water was prepared by diluting a solution of fluralaner (10 mg/ml) as shown in the table below to the calculated concentration of fluralaner.

Components Compound
(%v/v) Compound
(mg/ml) Function Fluralaner 0.95% 10 Active Ingredient Transcutol V
(diethylene glycol monoethyl ether) 24.76% Up to 1ml* Solvent Twin 80 74.29% Surface-active substance

On D0 (group D additional on D7), hens in groups A-D received fluralaner via medicated drinking water. Group E received unlimited drug-free water.

The dose for administration was calculated based on the average body weight of each treatment group obtained one day before treatment (D-1, D 6). A concentrated solution of fluralaner was diluted in drinking water to obtain medicinal water ready for consumption.

The therapeutic drinking water was prepared in such a way that fluralaner was administered according to the following dosing regimen:

The amount of medicinal water offered per group at D0 (group D also at D7) was approximately 50% of the calculated average daily water intake measured previously in the respective group, in order to ensure that the entire dose was consumed.

After all the medicinal water was consumed, the other 50% of the volume of the average daily water intake was supplied as tap water to the same drinker.

On Day 1, Day 5, Day 8, Day 12, D15, D19 and D22, four of the six hens in each group were infested with about 200 viable D. gallinae mites (naked nymphs and adults that had starved prior to infection). within 7 days).

From each infected chicken, approximately 25 bloodshot mites were collected and incubated for approximately 24 hours. Dead, injured and/or live ticks were counted visually with a binocular.

Ticks were classified as dead if no movement was detected or the ticks were in a dorsal position. Ticks were classified as damaged if their movement was uncoordinated.

The percentage of tick mortality and tick suppression was calculated for each treated group compared to the untreated negative control group.

Results:

Fluralaner was well tolerated by chickens.

The % mortality and % suppression of red mites ( Dermanyssus gallinae ) estimated at approximately 24 hours post-challenge in laying hens treated with fluralaner orally via drinking water are shown in Tables 1 and 2. Rapid onset of action was demonstrated by all doses administered.

Table 1
% Mortality of D. gallinae was assessed 24 hours after the invasion Group fluralaner (mg/kg BW) % Tick mortality after 24 hours infestation on D1 D5 D8 D12 D15 D19 D22 A 2 100 100 100 100 77 1 0 B 1 100 100 100 94 77 2 0 C 0.5 100 100 97 55 15 0 0 D 1 (2×0.5) 100 100 100 100 98 59 14

table 2
The suppression of D. gallinae was assessed 24 hours after the invasion. Group fluralaner (mg/kg BW) % suppression of mites after 24 hours infestation on D1 D5 D8 D12 D15 D19 D22 A 2 100 100 100 100 81 14 0 B 1 100 100 100 95 81 3 0 C 0.5 100 100 100 75 19 0 0 D 1 (2×0.5) 100 100 100 100 99 66 27

At each time point assessed, ticks observed in the untreated control group were viable and showed their normal behavior.

Claims (38)

1. The use of a pharmaceutical composition containing fluralaner, afoxolaner, sarolaner or lotilaner, or salts or solvates thereof, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant, for the preparation of a medicament for administration through drinking water for prophylaxis or treatment of parasitic infestations in animals. 2. Use according to claim 1, wherein the fluralaner, afoxolaner, sarolaner or lotilaner is present at a concentration of 1.5 mg/mL to 100 mg/mL. 3. Use according to claim 1 or 2, where the ratio of diethylene glycol monoethyl ether and polysorbate surfactant is <50:50% wt./mass., preferably 25/75% wt./mass. 4. Use according to claim 1 or 2, wherein the composition further comprises ethyl lactate. 5. Use according to claim 3, wherein the composition further comprises ethyl lactate. 6. Use according to claim 1 or 2, wherein the polysorbate surfactant is polysorbate 80. 7. Use according to claim 3, wherein the polysorbate surfactant is polysorbate 80. 8. Use according to claim 4, wherein the polysorbate surfactant is polysorbate 80. 9. Use according to claim 5, wherein the polysorbate surfactant is polysorbate 80. 10. The use of a pharmaceutical composition containing fluralaner, afoxolaner, sarolaner or lotilaner, or their salts, or their solvates, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant, for the prevention or treatment of parasitic infestations in animals after administration to animals through drinking water. 11. Use according to claim 10, wherein the fluralaner, afoxolaner, sarolaner or lotilaner is present at a concentration of 1.5 mg/mL to 100 mg/mL. 12. Use according to claim 10 or 11, where the ratio of diethylene glycol monoethyl ether and polysorbate surfactant is <50:50% wt./mass., preferably 25/75% wt./mass. 13. Use according to claim 10 or 11, wherein the composition further comprises ethyl lactate. 14. Use according to claim 12, wherein the composition further comprises ethyl lactate. 15. Use according to claim 10 or 11, wherein the polysorbate surfactant is polysorbate 80. 16. Use according to claim 12, wherein the polysorbate surfactant is polysorbate 80. 17. Use according to claim 13, wherein the polysorbate surfactant is polysorbate 80. 18. Use according to claim 14, wherein the polysorbate surfactant is polysorbate 80. 19. Use according to any one of claims 10 to 18, wherein the animals are selected from pigs and poultry. 20. Use according to claim 19, wherein the animals are laying hens. 21. Use according to any one of claims 10-20, wherein the parasitic infestation is a mite infestation. 22. Use according to claim 21, wherein the infestation by the mite is an infestation by a Dermanyssus spp . or an Ornithonyssus spp. 23. Medicinal drinking water for the prevention or treatment of parasitic infestations in animals, containing a mixture a pharmaceutical composition containing fluralaner, afoxolaner, sarolaner or lotilaner, or a salt or solvate thereof, and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant, and water. 24. Medicinal drinking water according to claim 23, containing from 0.001 to 1 mg/ml of fluralaner, afoxolaner, sarolaner or lotilaner. 25. Medicinal drinking water according to claim 23 or 24, where the ratio of diethylene glycol monoethyl ether and polysorbate surfactant in the composition is <50:50% wt./mass., preferably 25/75% wt./mass. 26. Medicinal drinking water according to claim 23 or 24, where the composition additionally contains ethyl lactate. 27. Medicinal drinking water according to claim 25, where the composition additionally contains ethyl lactate. 28. The medicinal drinking water of claim 23 or 24, wherein the polysorbate surfactant is polysorbate 80. 29. The medicinal drinking water of claim 25, wherein the polysorbate surfactant is polysorbate 80. 30. The medicinal drinking water of claim 26, wherein the polysorbate surfactant is polysorbate 80. 31. The medicinal drinking water of claim 27, wherein the polysorbate surfactant is polysorbate 80. 32. Medicinal drinking water according to any one of claims 23-31, wherein the animals are selected from pigs and poultry. 33. Medicinal drinking water according to claim 32, where the animals are laying hens. 34. The therapeutic drinking water according to any one of claims 23-33, wherein the parasitic infestation is a mite infestation. 35. The medicinal drinking water of claim 34, wherein the mite infestation is a Dermanyssus spp. or Ornithonyssus spp. 36. A method for producing therapeutic drinking water according to any one of claims 23 to 31, wherein the pharmaceutical composition is diluted by injection through a metering pump system into a water supply system or by mixing with water in a drug reservoir.