Solid Oral Pharmaceutical Compositions for Isoxazoline Compounds

Abstract

A solid oral pharmaceutical composition for delivery of a pharmaceutically acceptable active ingredient to an animal where the composition comprises an isoxazoline compound, a solvent and an excipient, a process for the manufacture of such solid oral pharmaceutical composition and a method of controlling a parasite infection administering such solid oral pharmaceutical composition.

What is claimed is: 
     
         1 . A method of preparing solid oral 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; 
         R 4 =hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, am inocarbonyl, 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, comprising
 a. dissolving the isoxazoline compound of formula (I) in a solvent; 
 b. adding the isoxazoline solution to a solid carrier and mix to form a first mixture; 
 c. adding all other dry excipients to the first mixture and mix to form a second mixture; 
 d. adding liquid ingredients, glycerol and soybean oil, to the second dry mixture; 
 e. mixing to form wet mass; 
 f. melting a polyethylene glycol forming agent and adding to the wet mass; 
 p. mixing to form the final bulk mass; and 
 h. forming soft chewable tablets in a forming machine. 
 
       
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1  wherein the solid carrier is microcrystalline cellulose. 
     
     
         4 . The method of any of  claim 1  wherein the solvent is selected from 2-pyrrolidone, dimethyl acetamide or mixtures thereof. 
     
     
         5 . The method of  claim 1  wherein the solvent is dimethyl acetamide. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1  wherein the isoxazoline compound is fluralaner. 
     
     
         8 . The method of  claim 1  wherein the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide. 
     
     
         9 . The method of  claim 1  wherein the isoxazoline compound is afoxolaner. 
     
     
         10 . The method of  claim 1  wherein 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. 
     
     
         11 . The method of  claim 1  wherein the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide. 
     
     
         12 . The method of  claim 1  wherein the method further comprises the addition of an additional pharmaceutically active compound. 
     
     
         13 . The method of  claim 12  wherein the additional pharmaceutically active compound is a macrocyclic lactone selected from the group of ivermectin, milbemycin, and moxidectin. 
     
     
         14 - 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein n is an integer 1, 2 or 3. 
     
     
         31 . The method of  claim 1 , wherein R 2  is CF 3  or CF 2 Cl. 
     
     
         32 . The method of  claim 1 , wherein two adjacent radicals Y form together a three or four membered chain. 
     
     
         33 . The method of  claim 1 , wherein Z A  is CF 3 .