Isoxazoline solution containing vitamin e for use with sanitized drinking water

Abstract

For the prevention of parasite infestation of animals, an isoxazoline can be administered by drinking water route. However the inventors have found that when the drinking water is sanitized, for instance by using hypochlorite, the isoxazoline becomes degraded. Surprisingly, the isoxazoline can be protected from degradation by the use of a vitamin E. A pharmaceutical composition can now be prepared containing a concentrated solution of the isoxazoline in a solvent and co-solvent, with vitamin E. The composition can be diluted in drinking water, even when sanitized, to prepare medicated drinking water for animals. This way an anti-parasitic treatment can be mass-administered, leading to a highly effective reduction of the parasite infestation of an animal, and its surroundings.

1 . A Pharmaceutical composition comprising an isoxazoline in a pharmaceutically acceptable solvent and a co-solvent, and vitamin E, wherein the isoxazoline is the compound 
       
         
           
           
               
               
           
         
         wherein 
         R 1 =halogen, CF 3 , OCF 3 , or CN; 
         n=integer from 0 up to and including 3; 
         m=1 or 2; 
         R 2 =C 1 -C 3  haloalkyl; 
         T=ring structure: 5-, or 6-membered, or bicyclic, 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 together form a chain; 
         Q=X—NR 3 R 4 , NR 5 —NR 6 —X—R 3 , X—R 3 , 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, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         Z A =hydrogen, halogen, cyano, or halomethyl; 
         R 4 =hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methyl carbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; 
         R 5 =H, alkyl, or haloalkyl; 
         R 6 =H, alkyl, or haloalkyl; 
         or wherein R 3  and R 4  together form a substituent selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       and
 wherein the pharmaceutical composition comprises between about 1% and about 20% of vitamin E. 
 
     
     
         2 . The Pharmaceutical composition according to  claim 1 , wherein Z A  is CF 3 . 
     
     
         3 . The Pharmaceutical composition according to  claim 1 , wherein the isoxazoline is one or more selected from the group consisting of: Fluralaner, Afoxolaner, Lotilaner, and Sarolaner. 
     
     
         4 . A Method for the preparation of the pharmaceutical composition according to  claim 1 , the method comprising the step of dissolving the isoxazoline and the vitamin E in the pharmaceutically acceptable solvent and the co-solvent. 
     
     
         5 . A Medicated drinking water comprising the pharmaceutical composition according to  claim 1  and drinking water. 
     
     
         6 . The Medicated drinking water according to  claim 5 , wherein the medicated drinking water further comprises a water sanitizer. 
     
     
         7 . A Method for the preparation of the medicated drinking water according to  claim 6 , the method comprising the step of diluting into drinking water the pharmaceutical composition. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A Method for the treatment or prevention of parasite infestation of animals, comprising the administration to the animals of the pharmaceutical composition of  claim 1  via medicated drinking water. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . A Method for the treatment or prevention of parasite infestation of animals, comprising the administration to the animals of the medicated drinking water according to  claim 6 . 
     
     
         15 . A Method for controlling and/or reducing parasitic arthropods in animal surroundings, the method comprising the administration to the animals of the medicated drinking water according to  claim 6 . 
     
     
         16 . (canceled) 
     
     
         17 . A Container comprising the pharmaceutical composition according to  claim 1 . 
     
     
         18 . A Kit of parts, the kit comprising a container comprising the pharmaceutical composition according to  claim 1 , and instructions for use of the pharmaceutical composition according to  claim 1  for preparing a medicated drinking water for animals. 
     
     
         19 . The medicated drinking water according to  claim 6 , wherein the isoxazoline is one or more selected from the group consisting of: Fluralaner, Afoxolaner, Lotilaner, and Sarolaner. 
     
     
         20 . The medicated drinking water according to  claim 6 , wherein drinking water contains at least about 0.1 ppm of a water sanitizer. 
     
     
         21 . The medicated drinking water according to  claim 6 , wherein the water sanitizer is an oxidizing sanitizer. 
     
     
         22 . The medicated drinking water according to  claim 6 , wherein water sanitizer is a hypochlorite or chlorine dioxide. 
     
     
         23 . The method according to  claim 7 , wherein the isoxazoline is one or more selected from the group consisting of: Fluralaner, Afoxolaner, Lotilaner, and Sarolaner. 
     
     
         24 . The method according to  claim 7 , wherein the drinking water contains at least about 0.1 ppm of a water sanitizer. 
     
     
         25 . The method according to  claim 7 , wherein the drinking water is sanitized with an oxidizing sanitizer. 
     
     
         26 . The method according to  claim 7 , wherein the drinking water is sanitized with a hypochlorite or chlorine dioxide. 
     
     
         27 . The method according to  claim 14 , wherein the isoxazoline is one or more selected from the group consisting of: Fluralaner, Afoxolaner, Lotilaner, and Sarolaner. 
     
     
         28 . The method according to  claim 15 , wherein the isoxazoline is one or more selected from the group consisting of: Fluralaner, Afoxolaner, Lotilaner, and Sarolaner.