Solid Oral Pharmaceutical Compositions for Isoxazoline Compounds
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.
1 . A solid oral pharmaceutical composition comprising an isoxazoline compound;
Formula (II),
wherein
R 1a , R 1b , R 1c are independently from each other hydrogen, Cl or CF 3 ,
T is
wherein Y is methyl, bromine, Cl, F, CN or C(S)NH 2 ,
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, 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, a solid carrier and a solvent; wherein the isoxazoline compound is dissolved in the solvent and then the resulting solution is adsorbed on to the solid carrier.
2 . The solid oral pharmaceutical composition of claim 1 wherein the composition is prepared by a method comprising
a. dissolving the isoxazoline compound of formula (I) in a solvent to form an isooxazoline solution;
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, qlycerol 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;
g. mixing to form the final bulk mass; and
h. forming soft chewable tablets in a forming machine.
3 . The solid oral pharmaceutical composition of claim 1 wherein the solid carrier is microcrystalline cellulose.
4 . The solid oral pharmaceutical composition of claim 1 claim 1 wherein the solvent is selected from 2-pyrrolidone, dimethyl acetamide or mixtures thereof.
5 . The solid oral pharmaceutical composition of claim 1 wherein the solvent is dimethyl acetamide.
6 . (canceled)
7 . The solid oral pharmaceutical composition of claim 1 wherein the isoxazoline compound is fluralaner.
8 . The solid oral pharmaceutical composition 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 solid oral pharmaceutical composition of claim 1 wherein the isoxazoline compound is afoxolaner.
10 . The solid oral pharmaceutical composition 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 solid oral pharmaceutical composition 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 solid oral pharmaceutical composition of claim 1 wherein the method further comprises an additional pharmaceutically active compound.
13 . The solid oral pharmaceutical composition 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 solid oral pharmaceutical composition of claim 1 , wherein Z A is CF 3 .
31 . The solid oral pharmaceutical composition of claim 1 , wherein the solid carrier is corn starch.
32 . The solid oral pharmaceutical composition of claim 1 , wherein the solvent is Miglyol 812.
33 . The solid oral pharmaceutical composition of claim 1 , wherein the solid oral pharmaceutical composition comprises PEG and PVP.