Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals

Abstract

This invention is directed to a pharmaceutical composition for drinking water administration comprising isoxazoline compounds of formula (I) and a polysorbate surfactant and diethylene glycol monoethyl ether (transcutol); and the use of the composition to treat or prevent parasite infestations of animals.

1 . A method of preventing or treating parasite infestations in animals by administering to such animal in its drinking water Use-f a pharmaceutical composition comprising an isoxazoline compound of formula (I) 
       
         
           
           
               
               
           
         
         Wherein 
         R 1 =halogen, CF 3 , OCF 3 , CN, 
         n=integer from 0 to 3, 
         R 2 =C 1 -C 3 -haloalkyl, 
         T=5- or 6-membered ring, which is optionally substituted by one or more radicals Y, 
         Y=methyl, halomethyl, halogen, CN, NO 2 , NH 2 —C═S, or two adjacent radicals Y form together a chain; 
         Q=X—NR 3 R 4  or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals; 
         X=CH 2 , CH(CH 3 ), CH(CN), CO, CS, 
         R 3 =hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 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, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; 
         or R 3  and R 4  together form a substituent selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         or a salt or solvate thereof, and a pharmaceutically acceptable carrier comprising diethylene glycol monoethyl ether and a polysorbate surfactant. 
       
     
     
         2 . The method according to  claim 1  wherein the isoxazoline compound is afoxolaner, sarolaner or lotilaner. 
     
     
         3 . The method according to  claim 2  comprising between 1.5 mg/ml and 100 mg/ml of the isoxazoline compound. 
     
     
         4 . The method according to  claim 1  wherein the ratio of diethylene glycol monoethyl ether to polysorbate surfactant is <50:50% w/w. 
     
     
         5 . The use method according to  claim 1  wherein the composition further comprises ethyl lactate. 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The method according to  claim 1  wherein the animals are selected from pigs and poultry. 
     
     
         9 . The method according to  claim 8  wherein the animals are laying hens. 
     
     
         10 . The method according to  claim 1  wherein the parasite infestation is a mite infestation. 
     
     
         11 . The method according to  claim 10  wherein the mite infestation is an infestation with  Dermanyssus  sp. or  Ornithonyssus  sp. 
     
     
         12 . A Medicated drinking water comprising a mixture of a pharmaceutical composition comprising an isoxazoline compound of formula (I) 
       
         
           
           
               
               
           
         
         Wherein 
         R 1 =halogen, CF 3 , OCF 3 , CN, 
         n=integer from 0 to 3, 
         R 2 =C 1 -C 3 -haloalkyl, 
         T=5- or 6-membered ring, which is optionally substituted by one or more radicals Y, 
         Y=methyl, halomethyl, halogen, CN, NO 2 , NH 2 —C═S, or two adjacent radicals Y form together a chain; 
         Q=X—NR 3 R 4  or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals; 
         X=CH 2 , CH(CH 3 ), CH(CN), CO, CS, 
         R 3 =hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 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, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; 
         or R 3  and R 4  together form a substituent selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       or a salt or solvate thereof, and a pharmaceutically acceptable carrier comprising diethylene glycol monoethyl ether and a polysorbate surfactant and water. 
     
     
         13 . The Medicated drinking water according to  claim 12  wherein the amount of the isoxazoline compound is between 0.001 and 100 mg/ml. 
     
     
         14 . (canceled) 
     
     
         15 . A Method for preparing medicated drinking water according to  claim 12  wherein the pharmaceutical composition is diluted by injecting through a dosing pump system in a water system or by mixing with water in a medication tank. 
     
     
         16 . The medicated drinking water according to  claim 12  wherein the isoxazoline compound is afoxolaner, sarolaner or lotilaner. 
     
     
         17 . The medicated drinking water according to  claim 12  wherein the composition further comprises ethyl lactate. 
     
     
         18 . The method of  claim 1 , wherein n is 1, 2 or 3. 
     
     
         19 . The method of  claim 1 , wherein R 2  is CF 3  or CF 2 Cl. 
     
     
         20 . The method of  claim 1 , wherein two adjacent radicals Y form together a three or four member chain. 
     
     
         21 . The medicated drinking water according to  claim 12 , wherein n is 1, 2 or 3. 
     
     
         22 . The medicated drinking water according to  claim 12 , wherein R 2  is CF 3  or CF 2 Cl. 
     
     
         23 . The medicated drinking water according to  claim 12 , wherein two adjacent radicals Y form together a three or four member chain. 
     
     
         24 . The method according to  claim 12  wherein the ratio of diethylene glycol monoethyl ether to polysorbate surfactant is <50:50% w/w.